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| Publications of Staci D. Bilbo :recent first alphabetical combined listing:%% Journal Articles @article{fds250804, Author = {Bilbo, SD and Klein, SL and DeVries, AC and Nelson, RJ}, Title = {Lipopolysaccharide facilitates partner preference behaviors in female prairie voles.}, Journal = {Physiology & behavior}, Volume = {68}, Number = {1-2}, Pages = {151-156}, Year = {1999}, Month = {December}, ISSN = {0031-9384}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10627074}, Abstract = {Exposure to proinflammatory cytokines (e.g., IL-1beta) or lipopolysaccharide (LPS) produces an acute activation of the immune response and results in a repertoire of behavioral patterns collectively termed sickness behaviors. Although nonspecific responses to pathogenic infection have traditionally been viewed as maladaptive effects of infection, sickness behaviors may have significant, adaptive value for the host. One set of adaptive behaviors affected by infection among mammals and birds is mate choice. In Experiment 1, female prairie voles exhibited the expected increase in blood corticosterone concentrations in response to a 0.1 cc i.p. LPS injection (50 microg), indicating activation of the endocrine system. A separate cohort of females was injected with LPS or saline and paired for 6 h with a novel, previously unpaired male. Following the cohabitation period, LPS-injected females spent significantly more time (p < 0.05) with the familiar partner when given a choice between familiar and unfamiliar males in a three-chamber apparatus designed to test partner preferences. Saline-injected females spent significantly more time with the unfamiliar male. In Experiment 2, males injected with LPS or saline spent equal amounts of time with familiar and unfamiliar females following a 6 h cohabitation with a naive female, and therefore, did not exhibit preferences. From a proximate perspective, this study provides evidence that sickness behaviors influence female, but not male, partner preference in prairie voles.}, Doi = {10.1016/s0031-9384(99)00154-7}, Key = {fds250804} } @article{fds250805, Author = {Bilbo, SD and Day, LB and Wilczynski, W}, Title = {Anticholinergic effects in frogs in a Morris water maze analog.}, Journal = {Physiology & behavior}, Volume = {69}, Number = {3}, Pages = {351-357}, Year = {2000}, Month = {May}, ISSN = {0031-9384}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10869602}, Abstract = {We determined the effect of two doses of the centrally acting anticholinergic drug, atropine sulfate (AS), on the performance of female Northern Leopard frogs (Rana pipiens) in a visual cue analog of the Morris water task. Untreated frogs learned the visually cued task, while frogs treated with 150 mg/kg AS were significantly slower than controls in learning to escape warm water by finding a visible platform, and there was a dose-dependent response, with frogs treated with 50 mg/kg AS performing midway between the higher dose and control frogs. These results suggest that the general role of the cholinergic system in learning is important in amphibians, and that this role is evolutionarily conserved across vertebrate species.}, Doi = {10.1016/s0031-9384(99)00251-6}, Key = {fds250805} } @article{fds250802, Author = {Bilbo, SD and Nelson, RJ}, Title = {Sex steroid hormones enhance immune function in male and female Siberian hamsters.}, Journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, Volume = {280}, Number = {1}, Pages = {R207-R213}, Year = {2001}, Month = {January}, ISSN = {0363-6119}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11124153}, Abstract = {Immune function is better in females than in males of many vertebrate species, and this dimorphism has been attributed to the presence of immunosuppressive androgens in males. We investigated the influence of sex steroid hormones on immune function in male and female Siberian hamsters. Previous studies indicated that immune function was impaired in male and female hamsters housed under short-day photoperiods when androgen and estrogen concentrations were virtually undetectable. In experiment 1, animals were gonadally intact, gonadectomized (gx), or gx with hormone replacement. Females exhibited the expected increase in antibody production over males, independent of hormone treatment condition, whereas male and female gx animals exhibited decreased lymphocyte proliferation to the T cell mitogen, phytohemagglutinin (PHA) compared with intact animals, and this effect was reversed in gx hamsters following testosterone and estradiol treatment, respectively. In experiment 2, testosterone, dihydrotestosterone, and estradiol all enhanced cell-mediated immunity in vitro, suggesting that sex steroid hormones may be enhancing immune function through direct actions on immune cells. In experiment 3, an acute mitogen challenge of lipopolysaccharide significantly suppressed lymphocyte proliferation to PHA in intact males but not females, suggesting that males may be less reactive to a subsequent mitogenic challenge than females. Contrary to evidence in many species such as rats, mice, and humans, these data suggest that sex steroid hormones enhance immunity in both male and female Siberian hamsters.}, Doi = {10.1152/ajpregu.2001.280.1.r207}, Key = {fds250802} } @article{fds250807, Author = {Bilbo, SD and Nelson, RJ}, Title = {Behavioral phenotyping of transgenic and knockout animals: a cautionary tale.}, Journal = {Lab animal}, Volume = {30}, Number = {1}, Pages = {24-29}, Year = {2001}, Month = {January}, ISSN = {0093-7355}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11385723}, Abstract = {Knockout and transgenic mice are extremely useful for behavioral research, especially for linking specific genes with behaviors. The authors present caveats to be aware of when using such mice in research situations.}, Key = {fds250807} } @article{fds250803, Author = {Drazen, DL and Bilu, D and Bilbo, SD and Nelson, RJ}, Title = {Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist.}, Journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, Volume = {280}, Number = {5}, Pages = {R1476-R1482}, Year = {2001}, Month = {May}, ISSN = {0363-6119}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11294771}, Abstract = {In addition to marked seasonal changes in reproductive, metabolic, and other physiological functions, many vertebrate species undergo seasonal changes in immune function. Despite growing evidence that photoperiod mediates seasonal changes in immune function, little is known regarding the neuroendocrine mechanisms underlying these changes. Increased immunity in short days is hypothesized to be due to the increase in the duration of nightly melatonin secretion, and recent studies indicate that melatonin acts directly on immune cells to enhance immune parameters. The present study examined the contribution of melatonin receptors in mediating the enhancement of splenocyte proliferation in response to the T cell mitogen Concanavalin A in mice. The administration of luzindole, a high-affinity melatonin receptor antagonist, either in vitro or in vivo significantly attenuated the ability of in vitro melatonin to enhance splenic lymphocyte proliferation during the day or night. In the absence of melatonin or luzindole, splenocyte proliferation was intrinsically higher during the night than during the day. In the absence of melatonin administration, luzindole reduced the ability of spleen cells to proliferate during the night, when endogenous melatonin concentrations are naturally high. This effect was not observed during the day, when melatonin concentrations are low. Taken together, these results suggest that melatonin enhancement of splenocyte proliferation is mediated directly by melatonin receptors on splenocytes and that there is diurnal variation in splenocyte proliferation in mice that is also mediated by splenic melatonin receptors.}, Doi = {10.1152/ajpregu.2001.280.5.r1476}, Key = {fds250803} } @article{fds250809, Author = {Bilbo, SD and Drazen, DL and Quan, N and He, L and Nelson, RJ}, Title = {Short day lengths attenuate the symptoms of infection in Siberian hamsters.}, Journal = {Proceedings. Biological sciences}, Volume = {269}, Number = {1490}, Pages = {447-454}, Year = {2002}, Month = {March}, ISSN = {0962-8452}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11886635}, Abstract = {Symptoms of infection, such as fever, anorexia and lethargy, are ubiquitous among vertebrates. Rather than nonspecific manifestations of illness, these responses are organized, adaptive strategies that are often critical to host survival. During times of energetic shortage such as winter, however, it may be detrimental for individuals to prolong energetically demanding symptoms such as fever. Individuals may adjust their immune responses prior to winter by using day length to anticipate energetically-demanding conditions. If the expression of sickness behaviours is constrained by energy availability, then cytokine production, fever, and anorexia should be attenuated in infected Siberian hamsters housed under simulated winter photoperiods. We housed hamsters in either long (14 L : 10 D) or short (10 L : 14 D) day lengths and assessed cytokines, anorexia and fever following injections of lipopolysaccharide (LPS). Short days attenuated the response to lipopolysaccharide, by decreasing the production of interleukin (IL)-6 and IL-1beta, and diminishing the duration of fever and anorexia. Short-day exposure in hamsters also decreased the ingestion of dietary iron, a nutrient vital to bacterial replication. Taken together, short day lengths attenuated the symptoms of infection, presumably to optimize energy expenditure and survival outcome.}, Doi = {10.1098/rspb.2001.1915}, Key = {fds250809} } @article{fds250811, Author = {Bilbo, SD and Dhabhar, FS and Viswanathan, K and Saul, A and Yellon, SM and Nelson, RJ}, Title = {Short day lengths augment stress-induced leukocyte trafficking and stress-induced enhancement of skin immune function.}, Journal = {Proceedings of the National Academy of Sciences of the United States of America}, Volume = {99}, Number = {6}, Pages = {4067-4072}, Year = {2002}, Month = {March}, ISSN = {0027-8424}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11904451}, Abstract = {Environmental conditions influence the onset and severity of infection and disease. Stressful conditions during winter may weaken immune function and further compromise survival by means of hypothermia, starvation, or shock. To test the hypothesis that animals may use photoperiod to anticipate the onset of seasonal stressors and adjust immune function, we evaluated glucocorticoids and the distribution of blood leukocytes in Siberian hamsters (Phodopus sungorus) exposed to long day lengths (i.e., summer) or short day (SD) lengths (i.e., winter) at baseline and during acute stress. We also investigated the influence of photoperiod and acute stress on a delayed-type hypersensitivity response in the skin. SDs increased glucocorticoid concentrations and the absolute number of circulating blood leukocytes, lymphocytes, T cells, and natural killer cells at baseline in hamsters. During stressful challenges, it appears beneficial for immune cells to exit the blood and move to primary immune defense areas such as the skin, in preparation for potential injury or infection. Acute (2 h) restraint stress induced trafficking of lymphocytes and monocytes out of the blood. This trafficking occurred more rapidly in SDs compared to long days. Baseline delayed-type hypersensitivity responses were enhanced during SDs; this effect was augmented by acute stress and likely reflected more rapid redistribution of leukocytes out of the blood and into the skin. These results suggest that photoperiod may provide a useful cue by which stressors in the environment may be anticipated to adjust the repertoire of available immune cells and increase survival likelihood.}, Doi = {10.1073/pnas.062001899}, Key = {fds250811} } @article{fds250810, Author = {Bilbo, SD and Nelson, RJ}, Title = {Melatonin regulates energy balance and attenuates fever in Siberian hamsters.}, Journal = {Endocrinology}, Volume = {143}, Number = {7}, Pages = {2527-2533}, Year = {2002}, Month = {July}, ISSN = {0013-7227}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12072384}, Abstract = {Fever is considered an important host defense response but requires significant metabolic energy. During winter many animals must balance immune function with competing physiological demands (i.e. thermoregulation) to survive. Winterlike patterns of melatonin secretion induce a number of energy-saving adaptations. For instance, Siberian hamsters attenuate the duration of fever during simulated short winter day lengths, presumably to conserve energy. To determine the proximate role of melatonin in mediating this photoperiodic response, hamsters housed in long days were injected with saline or melatonin 4 h before lights off for either 1 or 6 wk and assessed for fever following injections of bacterial lipopolysaccharide. Fever duration was attenuated (32%) only in hamsters that decreased body mass, increased cortisol, and exhibited gonadal regression in response to 6 wk of melatonin. Because melatonin-treated hamsters lost significant body mass, fever was assessed in a second long-day group following ad libitum food intake, food restriction, or 24-h food deprivation. Food restriction sufficient to reduce body mass by approximately 25%, but not to reduce leptin, did not influence fever, and 24-h food deprivation virtually abolished fever. Our data suggest that long-term exposure to long-duration melatonin signals is required to induce the physiological changes necessary for short-day immune responses, perhaps involving interactions with hormones such as cortisol and leptin.}, Doi = {10.1210/endo.143.7.8922}, Key = {fds250810} } @article{fds69264, Author = {Bilbo, SD and Hotchkiss, AH and Chiavegatto, S and Nelson, RJ}, Title = {Blunted stress responses in delayed type hypersensitivity in mice lacking the neuronal isoform of nitric oxide synthase}, Journal = {Journal of Neuroimmunology}, Volume = {140}, Pages = {41-48}, Year = {2003}, Key = {fds69264} } @article{fds69266, Author = {Bilbo, SD and Dhabhar, FS and Viswanathan, K and Light, A and Nelson, RJ}, Title = {Photoperiod affects the expression of sex and species differences in leukocyte number and leukocyte trafficking of congeneric hamsters}, Journal = {Psychoneuroendocrinology}, Volume = {28}, Number = {8}, Pages = {1027-1043}, Year = {2003}, Key = {fds69266} } @article{fds250812, Author = {Prendergast, BJ and Hotchkiss, AK and Bilbo, SD and Kinsey, SG and Nelson, RJ}, Title = {Photoperiodic adjustments in immune function protect Siberian hamsters from lethal endotoxemia.}, Journal = {Journal of biological rhythms}, Volume = {18}, Number = {1}, Pages = {51-62}, Year = {2003}, Month = {February}, ISSN = {0748-7304}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12568244}, Keywords = {Animals • Body Weight • Cell Division • Cricetinae • Cytokines • Endotoxins • Female • Immunity, Cellular • Lethal Dose 50 • Lymphocytes • Macrophages • Male • Organ Size • Phodopus • Photoperiod* • Sex Characteristics • Shock, Septic • Spleen • Survival Analysis • Testis • Tumor Necrosis Factor-alpha • biosynthesis • chemistry • drug effects • immunology • metabolism • physiology • physiology* • physiopathology • toxicity*}, Abstract = {Seasonal changes in day length enhance or suppress components of immune function in individuals of several mammalian species. Siberian hamsters (Phodopus sungorus) exhibit multiple changes in neuroendocrine, reproductive, and immune function after exposure to short days. The manner in which these changes are integrated into the host response to pathogens is not well understood. The present experiments tested the hypothesis that short-day changes in immune function alter the pathogenesis of septic shock and survival after challenge with endotoxin. Male and female Siberian hamsters raised in long-day photoperiods were transferred as adults to short days or remained in their natal photoperiod. Six to 8 weeks later, hamsters were injected i.p. with 0, 1, 2.5, 10, 25, or 50 mg/kg bacterial lipopolysaccharide (LPS) (the biologically active constituent of endotoxin), and survival was monitored for 96 h. Short days significantly improved survival of male hamsters treated with 10 or 25 mg/kg LPS and improved survival in females treated with 50 mg/kg LPS. Transfer from long to short days shifted the LD50 in males by approximately 90%, from 5.3 to 9.9 mg/kg, and in females from 11.1 to 15.0 mg/kg (+35%). Long-day females were more resistant than were males to lethal endotoxemia. In vitro production of the proinflammatory cytokine TNFalpha in response to LPS stimulation was significantly lower in macrophages extracted from short-day relative to long-day hamsters, as were circulating concentrations of TNFalpha in vivo after i.p. administration of LPS, suggesting that diminished cytokine responses to LPS in short days may mitigate the lethality of endotoxemia. Adaptation to short days induces changes in immune parameters that affect survival in the face of immune challenges.}, Language = {eng}, Doi = {10.1177/0748730402239676}, Key = {fds250812} } @article{fds250813, Author = {Bilbo, SD and Hotchkiss, AK and Chiavegatto, S and Nelson, RJ}, Title = {Blunted stress responses in delayed type hypersensitivity in mice lacking the neuronal isoform of nitric oxide synthase.}, Journal = {Journal of neuroimmunology}, Volume = {140}, Number = {1-2}, Pages = {41-48}, Year = {2003}, Month = {July}, ISSN = {0165-5728}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12864970}, Keywords = {Animals • Behavior, Animal • Body Mass Index • Corticosterone • Hypersensitivity, Delayed • Immunosuppression • Isoenzymes • Male • Mice • Mice, Inbred C57BL • Mice, Knockout • Motor Activity • Nerve Tissue Proteins • Neurons • Nitric Oxide Synthase • Nitric Oxide Synthase Type I • Restraint, Physical • Stress, Physiological • blood • deficiency • deficiency* • enzymology* • genetics • genetics* • immunology • physiology • prevention & control}, Abstract = {Nitric oxide (NO) is implicated in inflammation and hypothalamic-pituitary responses to immune stimuli; however, the specific role of NO from neurons during stress-induced immune responses remains unspecified. We measured antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin of wild-type (WT) and neuronal nitric oxide synthase knockout (nNOS(-/-)) mice at baseline and after 2 h of restraint. Baseline corticosterone concentrations were higher in nNOS(-/-) than WT mice. However, stress-induced increases in corticosterone were dampened in nNOS(-/-) mice, and restraint suppressed DTH only in WT animals. Furthermore, WT mice lost more body mass after stress, and exhibited more anxiety-like behavior in the open field, than nNOS(-/-) mice. Neuronal NO appears to be involved in the neuroendocrine-immune response to stress, perhaps via glucocorticoid regulation.}, Language = {eng}, Doi = {10.1016/s0165-5728(03)00175-9}, Key = {fds250813} } @article{fds250814, Author = {Bilbo, SD and Quan, N and Prendergast, BJ and Bowers, SL and Nelson, RJ}, Title = {Photoperiod alters the time course of brain cyclooxygenase-2 expression in Siberian hamsters.}, Journal = {Journal of neuroendocrinology}, Volume = {15}, Number = {10}, Pages = {958-964}, Year = {2003}, Month = {October}, ISSN = {0953-8194}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12969240}, Keywords = {Adjuvants, Immunologic • Animals • Body Temperature • Body Weight • Brain • Cricetinae • Cyclooxygenase 2 • Dinoprostone • Endothelium, Vascular • Fever • Immunohistochemistry • Isoenzymes • Lipopolysaccharides • Male • Nerve Tissue Proteins • Organ Size • Phodopus • Photoperiod* • Preoptic Area • Prostaglandin-Endoperoxide Synthases • RNA, Messenger • Radioimmunoassay • Testis • Time Factors • biosynthesis • biosynthesis* • chemically induced • cytology • drug effects • enzymology* • metabolism • physiology}, Abstract = {Fever is initiated by activation of the arachidonic acid cascade and the biosynthesis of prostaglandins within the brain. Inducible cyclooxygenase (COX-2) is a rate-limiting enzyme in prostaglandin synthesis, and the number of blood vessels expressing COX-2 correlates with elevated body temperature following peripheral lipopolysaccharide (LPS). Despite its importance in host defense, fever is energetically expensive and we hypothesized that fever may be limited by available metabolic resources. During winter, when competing metabolic demands are constrained by low temperatures and food availability, it was predicted that fever duration would be reduced in seasonally breeding Siberian hamsters (Phodopus sungorus). We measured LPS-induced COX-2 expression in blood vessels of hamsters to test whether photoperiodic alterations in fever duration are centrally mediated, or whether they reflect changes in peripheral modulation of body temperature. Hamsters housed in long, 'summer-like' or short, 'winter-like' day lengths for 10 weeks were injected with LPS, and brains were collected 2, 4, or 8 h later. COX-2 expression was comparably increased in long- and short-day hamsters by 2 h and 4 h post-LPS; however, short-day hamsters exhibited significantly fewer COX-2-positive cells and blood vessels by 8 h post-LPS compared to long-day hamsters, corresponding with reduced fever duration in short-day hamsters. Cortisol concentrations increased more than two-fold in short-day compared to long-day hamsters by 4 h; this increase may have contributed to the decrease in COX-2 expression observed by 8 h in short days. We conclude that short photoperiods significantly altered the time course of central COX-2 protein expression in hamsters in a manner consistent with reduced fever duration.}, Language = {eng}, Doi = {10.1046/j.1365-2826.2003.01084.x}, Key = {fds250814} } @article{fds250815, Author = {Bilbo, SD and Dhabhar, FS and Viswanathan, K and Saul, A and Nelson, RJ}, Title = {Photoperiod affects the expression of sex and species differences in leukocyte number and leukocyte trafficking in congeneric hamsters.}, Journal = {Psychoneuroendocrinology}, Volume = {28}, Number = {8}, Pages = {1027-1043}, Year = {2003}, Month = {November}, ISSN = {0306-4530}, url = {http://www.ncbi.nlm.nih.gov/pubmed/14529706}, Keywords = {Animals • Cricetinae • Female • Hydrocortisone • Immune System • Leukocyte Count • Leukocytes • Male • Maternal Behavior • Paternal Behavior • Phodopus • Photoperiod* • Reproduction • Seasons • Sex Characteristics • Species Specificity • Stress, Physiological • blood* • immunology • immunology* • physiology • physiology*}, Abstract = {Sex differences in immune function are well documented. These sex differences may be modulated by social and environmental factors. Individuals of polygynous species generally exhibit more pronounced sex differences in immune parameters than individuals of monogamous species, often displaying an energetic trade-off between enhanced immunity and high mating success. During winter, animals contend with environmental conditions (e.g. low temperatures and decreased food availability) that evoke energetic-stress responses; many mammals restrict reproduction in response to photoperiod as part of an annual winter coping strategy. To test the hypothesis that extant sex and species differences in immune surveillance may be modulated by photoperiod, we examined leukocyte numbers in males and females of two closely related hamster species (Phodopus). As predicted, uniparental P. sungorus exhibited a robust sex difference, with total white blood cells, total lymphocytes, T cells, and B cells higher in females than males, during long days when reproduction occurs, but not during short days when reproduction usually stops. In contrast, biparental male and female P. campbelli exhibited comparable leukocyte numbers during both long and short days. To study sex differences in stress responses, we also examined immune cell trafficking in response to an acute (2 h) restraint stressor. During stressful challenges, it appears beneficial for immune cells to exit the blood and move to primary immune defense areas such as the skin, in preparation for potential injury or infection. Acute stress moved lymphocytes and monocytes out of the blood in all animals. Blood cortisol concentrations were increased in P. sungorus females compared to males at baseline (52%) and in response to restraint stress (38%), but only in long days. P. campbelli males and females exhibited comparable blood cortisol and stress responses during both long and short days. Our results suggest that interactions among social factors and the environment play a significant role in modulating sex and seasonal alterations in leukocyte numbers and stress responses.}, Language = {eng}, Doi = {10.1016/s0306-4530(02)00122-1}, Key = {fds250815} } @article{fds250816, Author = {Bilbo, SD and Nelson, RJ}, Title = {Sex differences in photoperiodic and stress-induced enhancement of immune function in Siberian hamsters.}, Journal = {Brain, behavior, and immunity}, Volume = {17}, Number = {6}, Pages = {462-472}, Year = {2003}, Month = {December}, ISSN = {0889-1591}, url = {http://www.ncbi.nlm.nih.gov/pubmed/14583238}, Keywords = {Adaptation, Physiological • Animals • Cricetinae • Female • Gonadal Steroid Hormones • Hydrocortisone • Hypersensitivity, Delayed • Male • Phodopus • Photoperiod* • Reproduction • Seasons • Sex Factors • Stress, Physiological • blood • immunology • immunology*}, Abstract = {Siberian hamsters breed during the long days of spring and summer when environmental conditions (e.g., ambient temperatures, food availability) are favorable for reproduction. Environmental conditions may also influence the onset and severity of infection and disease, and photoperiodic alterations in immune function may comprise part of a repertoire of seasonal adaptations to help survive winter. In order to test the hypothesis that animals use day length to anticipate seasonal stressors and adjust immune function, we measured antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin of male and female hamsters during long, "summer-like," or short, "winter-like" days, at baseline and following acute restraint stress. Sex steroid hormones were lower, and cortisol was higher, in males and females during short days. Baseline DTH was enhanced in short- compared to long-day males, and acute stress augmented this effect. In contrast, photoperiod alone did not influence the DTH response in females. As predicted, female hamsters exhibited significantly higher DTH responses than males during long days, but not during short days. However, this enhancement was observed in acutely stressed females only. Cortisol concentrations were significantly higher at baseline in females, and increased more in response to stress, compared to males in both photoperiods. These results suggest that photoperiod provides a useful cue by which stressors in the environment may be anticipated in order to adjust immune function. Furthermore, interactions among reproductive status and stress responses appear to mediate the expression of sex differences in immune responses in hamsters.}, Language = {eng}, Doi = {10.1016/s0889-1591(03)00063-1}, Key = {fds250816} } @article{fds197419, Author = {BJ Prendergast and SD Bilbo and RJ Nelson}, Title = {Photoperiod controls the induction, retention, and retrieval of antigen-specific immunological memory.}, Journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, Volume = {286}, Number = {1}, Pages = {R54-60}, Year = {2004}, Month = {January}, ISSN = {0363-6119}, url = {http://dx.doi.org/10.1152/ajpregu.00381.2003}, Keywords = {Animals • Antibody Formation • Cricetinae • Dinitrofluorobenzene • Hemocyanin • Hypersensitivity, Delayed • Immunization • Immunologic Memory • Male • Phodopus • Photoperiod* • Reproduction • immunology* • physiology* • physiopathology • radiation effects • radiation effects*}, Abstract = {Changes in day length affect several measures of immunity in seasonally breeding mammals. In Siberian hamsters (Phodopus sungorus), short day lengths suppress specific secondary antibody responses to the keyhole limpet hemocyanin (KLH) antigen and enhance cutaneous delayed-type hypersensitivity (DTH) responses to dinitrofluorobenzene (DNFB). These experiments tested whether day length affects secondary antibody and DTH responses by altering immune function solely during the interval after the initial exposure to each antigen, solely during the interval after the second exposure, or during both stages of the respective immune responses. Adult male Siberian hamsters were exposed to either a long (16 h light/day; LD) or a short (8 h light/day; SD) photoperiod for 7.5 wk before receiving an initial exposure to each antigen (KLH injection, cutaneous DNFB treatment; separate groups of animals for each antigen). A subset of LD hamsters was transferred to the SD photo-period, and a subset of SD hamsters was transferred to the LD photoperiod. Other hamsters remained in LD or SD. Eight weeks later, all hamsters were challenged with a second subcutaneous injection of KLH or a second application of DNFB to the ear, and immune responses were measured. Exposure to SD during the primary antibody response did not affect secondary IgG responses, but SD exposure during the secondary response significantly suppressed IgG production independent of day length during the initial KLH treatment. In contrast, exposure to SD during the DNFB challenge enhanced the ensuing DTH response, but this enhancement depended on the photoperiod prevailing during the initial exposure. Exposure to SD during the sensitization stage did not enhance DTH in hamsters subsequently exposed to LD. The data suggest that short photoperiods have enduring effects on immune responsiveness and on the establishment and retention of immunological memory.}, Language = {eng}, Doi = {10.1152/ajpregu.00381.2003}, Key = {fds197419} } @article{fds250851, Author = {Prendergast, BJ and Bilbo, SD and Nelson, RJ}, Title = {Photoperiod controls the induction, retention, and retrieval of antigen-specific immunological memory.}, Journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, Volume = {286}, Number = {1}, Pages = {R54-R60}, Year = {2004}, Month = {January}, ISSN = {0363-6119}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12958060}, Abstract = {Changes in day length affect several measures of immunity in seasonally breeding mammals. In Siberian hamsters (Phodopus sungorus), short day lengths suppress specific secondary antibody responses to the keyhole limpet hemocyanin (KLH) antigen and enhance cutaneous delayed-type hypersensitivity (DTH) responses to dinitrofluorobenzene (DNFB). These experiments tested whether day length affects secondary antibody and DTH responses by altering immune function solely during the interval after the initial exposure to each antigen, solely during the interval after the second exposure, or during both stages of the respective immune responses. Adult male Siberian hamsters were exposed to either a long (16 h light/day; LD) or a short (8 h light/day; SD) photoperiod for 7.5 wk before receiving an initial exposure to each antigen (KLH injection, cutaneous DNFB treatment; separate groups of animals for each antigen). A subset of LD hamsters was transferred to the SD photo-period, and a subset of SD hamsters was transferred to the LD photoperiod. Other hamsters remained in LD or SD. Eight weeks later, all hamsters were challenged with a second subcutaneous injection of KLH or a second application of DNFB to the ear, and immune responses were measured. Exposure to SD during the primary antibody response did not affect secondary IgG responses, but SD exposure during the secondary response significantly suppressed IgG production independent of day length during the initial KLH treatment. In contrast, exposure to SD during the DNFB challenge enhanced the ensuing DTH response, but this enhancement depended on the photoperiod prevailing during the initial exposure. Exposure to SD during the sensitization stage did not enhance DTH in hamsters subsequently exposed to LD. The data suggest that short photoperiods have enduring effects on immune responsiveness and on the establishment and retention of immunological memory.}, Doi = {10.1152/ajpregu.00381.2003}, Key = {fds250851} } @article{fds197415, Author = {SD Bilbo and RJ Nelson}, Title = {Photoperiod influences the effects of exercise and food restriction on an antigen-specific immune response in Siberian hamsters.}, Journal = {Endocrinology}, Volume = {145}, Number = {2}, Pages = {556-64}, Year = {2004}, Month = {February}, ISSN = {0013-7227}, url = {http://dx.doi.org/10.1210/en.2003-1035}, Keywords = {Animals • Antigens • Cricetinae • Eating • Energy Metabolism • Food Deprivation* • Hydrocortisone • Hypersensitivity, Delayed • Immunity* • Male • Phodopus • Photoperiod* • Physical Exertion • Reproduction • Seasons • blood • immunology* • physiology*}, Abstract = {Environmental conditions influence the onset and severity of illness and infection and may compromise survival. Energetically challenging conditions during winter may directly induce death through hypothermia, starvation, or shock. The ability to forecast and prepare for the arrival of challenging conditions associated with winter (e.g. low temperatures, decreased food) likely confers survival advantages. Siberian hamsters (Phodopus sungorus) stop reproduction and reduce body mass (approximately 25%) during short, winter-like day lengths, resulting in energetic savings. Hamsters also increase circulating glucocorticoids and lymphocytes (e.g. T cells, NK cells), and exhibit enhanced antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin during short days (SDs). We tested the hypothesis that Siberian hamsters use SD lengths to signal the onset of winter to mediate the energetic trade-offs among body mass, reproductive function, and immune function. Long-day (LD; 16 h light, 8 h dark) and SD (8 h light, 16 h dark) hamsters were either food restricted (25%) or provided ad libitum (ad lib) food for 4 wk; half of all hamsters in each food condition had voluntary access to a running wheel, and half remained sedentary. SD hamsters enhanced DTH responses compared with LD hamsters under sedentary ad lib conditions. Exercise enhanced DTH in LD hamsters regardless of food intake. Furthermore, food-restriction did not significantly influence DTH in LD hamsters. In contrast, food-restriction suppressed DTH in SD hamsters regardless of activity condition, and exercise modestly enhanced DTH only in SD hamsters with ad lib access to food. In sum, moderate energetic deficiency suppressed DTH in SD (but not LD) hamsters, and this suggests that hamsters may have evolved to enhance immune responses during winter in preparation for increased metabolic stressors.}, Language = {eng}, Doi = {10.1210/en.2003-1035}, Key = {fds197415} } @article{fds250850, Author = {Bilbo, SD and Nelson, RJ}, Title = {Photoperiod influences the effects of exercise and food restriction on an antigen-specific immune response in Siberian hamsters.}, Journal = {Endocrinology}, Volume = {145}, Number = {2}, Pages = {556-564}, Year = {2004}, Month = {February}, ISSN = {0013-7227}, url = {http://www.ncbi.nlm.nih.gov/pubmed/14605007}, Abstract = {Environmental conditions influence the onset and severity of illness and infection and may compromise survival. Energetically challenging conditions during winter may directly induce death through hypothermia, starvation, or shock. The ability to forecast and prepare for the arrival of challenging conditions associated with winter (e.g. low temperatures, decreased food) likely confers survival advantages. Siberian hamsters (Phodopus sungorus) stop reproduction and reduce body mass (approximately 25%) during short, winter-like day lengths, resulting in energetic savings. Hamsters also increase circulating glucocorticoids and lymphocytes (e.g. T cells, NK cells), and exhibit enhanced antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin during short days (SDs). We tested the hypothesis that Siberian hamsters use SD lengths to signal the onset of winter to mediate the energetic trade-offs among body mass, reproductive function, and immune function. Long-day (LD; 16 h light, 8 h dark) and SD (8 h light, 16 h dark) hamsters were either food restricted (25%) or provided ad libitum (ad lib) food for 4 wk; half of all hamsters in each food condition had voluntary access to a running wheel, and half remained sedentary. SD hamsters enhanced DTH responses compared with LD hamsters under sedentary ad lib conditions. Exercise enhanced DTH in LD hamsters regardless of food intake. Furthermore, food-restriction did not significantly influence DTH in LD hamsters. In contrast, food-restriction suppressed DTH in SD hamsters regardless of activity condition, and exercise modestly enhanced DTH only in SD hamsters with ad lib access to food. In sum, moderate energetic deficiency suppressed DTH in SD (but not LD) hamsters, and this suggests that hamsters may have evolved to enhance immune responses during winter in preparation for increased metabolic stressors.}, Doi = {10.1210/en.2003-1035}, Key = {fds250850} } @article{fds197414, Author = {BJ Prendergast and AK Hotchkiss and SD Bilbo and RJ Nelson}, Title = {Peripubertal immune challenges attenuate reproductive development in male Siberian hamsters (Phodopus sungorus).}, Journal = {Biology of reproduction}, Volume = {70}, Number = {3}, Pages = {813-20}, Year = {2004}, Month = {March}, ISSN = {0006-3363}, url = {http://dx.doi.org/10.1095/biolreprod.103.023408}, Keywords = {Animals • Body Temperature • Body Weight • Cricetinae • Eating • Female • Hemocyanin • Immunoglobulin G • Immunoglobulin M • Male • Phodopus • Photoperiod* • Reproduction • Sexual Maturation • Testosterone • blood • immunology • immunology*}, Abstract = {Differential allocation of energy to reproduction versus host defense is assumed to drive the seasonal antiphase relation between peak reproductive function and immunocompetence; however, evidence supporting this assumption is only correlational. These experiments tested whether photoperiod affects immune responses to antigens in peripubertal Siberian hamsters, whether such activation of the immune system exacts energetic and reproductive costs, and whether such costs vary seasonally. Male Siberian hamsters were raised from birth in long (LD) or short days (SD), which respectively initiate or inhibit the onset of puberty. To elicit a specific immune response, hamsters were injected with a novel antigen (keyhole limpet hemocyanin [KLH]) as juveniles. Reproductive development was attenuated and body temperature was elevated in LD hamsters relative to saline-injected control animals. In contrast, KLH treatments affected neither thermoregulation nor reproductive development in photoinhibited SD hamsters. In experiment 2, juvenile male hamsters were challenged with bacterial lipopolysaccharide (LPS) in order to elicit an innate immune response. Febrile and anorexic responses to LPS were greater in reproductively stimulated LD hamsters relative to reproductively inhibited SD hamsters. LPS treatments attenuated somatic and testicular development in LD hamsters, but did not significantly affect circulating testosterone concentrations. In contrast, LPS treatments were without effect on somatic and reproductive development in SD hamsters. These experiments indicate that photoperiod affects antigen-specific antibody production, febrile responses to LPS, and sickness behaviors in juvenile Siberian hamsters, and that peripubertal activation of the immune system exacts energetic and metabolic costs that can diminish the magnitude of somatic and reproductive maturation in LD. The data also underscore the importance of seasonally dependent life history factors in assessing physiological tradeoffs.}, Language = {eng}, Doi = {10.1095/biolreprod.103.023408}, Key = {fds197414} } @article{fds250849, Author = {Prendergast, BJ and Hotchkiss, AK and Bilbo, SD and Nelson, RJ}, Title = {Peripubertal immune challenges attenuate reproductive development in male Siberian hamsters (Phodopus sungorus).}, Journal = {Biology of reproduction}, Volume = {70}, Number = {3}, Pages = {813-820}, Year = {2004}, Month = {March}, ISSN = {0006-3363}, url = {http://www.ncbi.nlm.nih.gov/pubmed/14627552}, Abstract = {Differential allocation of energy to reproduction versus host defense is assumed to drive the seasonal antiphase relation between peak reproductive function and immunocompetence; however, evidence supporting this assumption is only correlational. These experiments tested whether photoperiod affects immune responses to antigens in peripubertal Siberian hamsters, whether such activation of the immune system exacts energetic and reproductive costs, and whether such costs vary seasonally. Male Siberian hamsters were raised from birth in long (LD) or short days (SD), which respectively initiate or inhibit the onset of puberty. To elicit a specific immune response, hamsters were injected with a novel antigen (keyhole limpet hemocyanin [KLH]) as juveniles. Reproductive development was attenuated and body temperature was elevated in LD hamsters relative to saline-injected control animals. In contrast, KLH treatments affected neither thermoregulation nor reproductive development in photoinhibited SD hamsters. In experiment 2, juvenile male hamsters were challenged with bacterial lipopolysaccharide (LPS) in order to elicit an innate immune response. Febrile and anorexic responses to LPS were greater in reproductively stimulated LD hamsters relative to reproductively inhibited SD hamsters. LPS treatments attenuated somatic and testicular development in LD hamsters, but did not significantly affect circulating testosterone concentrations. In contrast, LPS treatments were without effect on somatic and reproductive development in SD hamsters. These experiments indicate that photoperiod affects antigen-specific antibody production, febrile responses to LPS, and sickness behaviors in juvenile Siberian hamsters, and that peripubertal activation of the immune system exacts energetic and metabolic costs that can diminish the magnitude of somatic and reproductive maturation in LD. The data also underscore the importance of seasonally dependent life history factors in assessing physiological tradeoffs.}, Doi = {10.1095/biolreprod.103.023408}, Key = {fds250849} } @article{fds197413, Author = {BJ Prendergast and SD Bilbo and FS Dhabhar and RJ Nelson}, Title = {Effects of photoperiod history on immune responses to intermediate day lengths in Siberian hamsters (Phodopus sungorus).}, Journal = {Journal of neuroimmunology}, Volume = {149}, Number = {1-2}, Pages = {31-9}, Year = {2004}, Month = {April}, ISSN = {0165-5728}, url = {http://dx.doi.org/10.1016/j.jneuroim.2003.12.006}, Keywords = {Age Factors • Analysis of Variance • Animals • Animals, Newborn • Behavior, Animal • Body Weight • Cricetinae • Dinitrobenzenes • Environment • Enzyme-Linked Immunosorbent Assay • Female • Hair • Hemocyanin • Immune System • Immunization • Immunoglobulins • Leukocyte Count • Leukocytes • Lymphocyte Activation • Male • Organ Size • Phodopus • Photoperiod* • Pregnancy • Seasons* • Testis • Time Factors • blood • immunology • immunology* • metabolism • methods • pharmacology • physiology • radiation effects • radiation effects*}, Abstract = {Seasonal changes in day length enhance or suppress immune function in individuals of several mammalian species. Siberian hamsters (Phodopus sungorus) are long-day breeders that adjust reproductive physiology and behavior, body mass, and immune function following exposure to short photoperiods. Photoperiods of intermediate-duration, encountered in nature by juvenile hamsters born in early-spring and by those born in mid-summer, trigger gonadal development in the former cohort and inhibit the onset of puberty in the latter. Divergent reproductive responses to the same intermediate photoperiod depend on a photoperiod history, communicated during gestation. These experiments assessed whether photoperiod history during gestation likewise impacts immunological responses to intermediate photoperiods. Male hamsters were gestated in long photoperiods and remained in long photoperiods postnatally, or were transferred to an intermediate-duration or a short-duration photoperiod; other males were gestated in short days and transferred to an intermediate-duration photoperiod at birth. Long days stimulated, and short days inhibited, somatic and reproductive development; intermediate day lengths either accelerated or inhibited somatic and reproductive development, depending on whether hamsters were gestated in short days or long days, respectively. By contrast, photoperiod during gestation did not affect most immune endpoints. The data suggest that photoperiodic mechanisms that enhance and suppress several aspects of immunity in young-adult hamsters are not responsive to prenatally communicated photoperiod history information.}, Language = {eng}, Doi = {10.1016/j.jneuroim.2003.12.006}, Key = {fds197413} } @article{fds250848, Author = {Prendergast, BJ and Bilbo, SD and Dhabhar, FS and Nelson, RJ}, Title = {Effects of photoperiod history on immune responses to intermediate day lengths in Siberian hamsters (Phodopus sungorus).}, Journal = {Journal of neuroimmunology}, Volume = {149}, Number = {1-2}, Pages = {31-39}, Year = {2004}, Month = {April}, ISSN = {0165-5728}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15020062}, Abstract = {Seasonal changes in day length enhance or suppress immune function in individuals of several mammalian species. Siberian hamsters (Phodopus sungorus) are long-day breeders that adjust reproductive physiology and behavior, body mass, and immune function following exposure to short photoperiods. Photoperiods of intermediate-duration, encountered in nature by juvenile hamsters born in early-spring and by those born in mid-summer, trigger gonadal development in the former cohort and inhibit the onset of puberty in the latter. Divergent reproductive responses to the same intermediate photoperiod depend on a photoperiod history, communicated during gestation. These experiments assessed whether photoperiod history during gestation likewise impacts immunological responses to intermediate photoperiods. Male hamsters were gestated in long photoperiods and remained in long photoperiods postnatally, or were transferred to an intermediate-duration or a short-duration photoperiod; other males were gestated in short days and transferred to an intermediate-duration photoperiod at birth. Long days stimulated, and short days inhibited, somatic and reproductive development; intermediate day lengths either accelerated or inhibited somatic and reproductive development, depending on whether hamsters were gestated in short days or long days, respectively. By contrast, photoperiod during gestation did not affect most immune endpoints. The data suggest that photoperiodic mechanisms that enhance and suppress several aspects of immunity in young-adult hamsters are not responsive to prenatally communicated photoperiod history information.}, Doi = {10.1016/j.jneuroim.2003.12.006}, Key = {fds250848} } @article{fds197412, Author = {GN Neigh and SD Bilbo and AK Hotchkiss and RJ Nelson}, Title = {Exogenous pyruvate prevents stress-evoked suppression of mitogen-stimulated proliferation.}, Journal = {Brain, behavior, and immunity}, Volume = {18}, Number = {5}, Pages = {425-33}, Year = {2004}, Month = {September}, ISSN = {0889-1591}, url = {http://dx.doi.org/10.1016/j.bbi.2003.10.001}, Keywords = {Analysis of Variance • Animals • Cell Division • Corticosterone • Dose-Response Relationship, Drug • Down-Regulation • Energy Metabolism • Injections, Intraperitoneal • Lactic Acid • Male • Mice • Mice, Inbred C57BL • Mitogens • Pyruvic Acid • Restraint, Physical • Spleen • Stress, Psychological • administration & dosage* • blood • cytology* • drug effects • immunology • metabolism* • pharmacology • physiology • physiology* • physiopathology • psychology}, Abstract = {Although the phenomenon that psychological stress influences disease onset and progression is well established, the mechanisms underlying stress-evoked compromise of immune function remain unspecified. To test the hypothesis that energetic shortages compromise immunity, we evaluated the effectiveness of pyruvate, a metabolic supplement, to prevent stress-evoked suppression of mitogen-stimulated splenocyte proliferation. Male C57BL/6 mice were subjected to 2h of restraint once daily for 14 days. Consistent with previous studies, mitogen-stimulated splenocyte proliferation was reduced after restraint; in contrast, mice that received pyruvate injections immediately following each episode of restraint did not reduce splenocyte proliferation. In addition, restraint-evoked corticosterone elevation did not habituate in animals treated with pyruvate, suggesting that glucocorticoids are not exclusively immunosuppressive. The ratio of pyruvate to lactate, an index of aerobic metabolism, was elevated in mice exposed to restraint suggesting that mice exposed to restraint were preferentially using aerobic metabolism and producing more ATP per unit of pyruvate than non-restrained mice. Furthermore, two of the effective doses of pyruvate (0.5 and 500.0mg/kg) altered glucose levels suggesting a metabolic function of the supplement. Although several different mechanisms could possibly mediate the changes in splenocyte proliferation, these results support the hypothesis that stress-evoked immunosuppression may be a function of metabolic energy shortages and can be prevented via pyruvate supplementation.}, Language = {eng}, Doi = {10.1016/j.bbi.2003.10.001}, Key = {fds197412} } @article{fds250847, Author = {Neigh, GN and Bilbo, SD and Hotchkiss, AK and Nelson, RJ}, Title = {Exogenous pyruvate prevents stress-evoked suppression of mitogen-stimulated proliferation.}, Journal = {Brain, behavior, and immunity}, Volume = {18}, Number = {5}, Pages = {425-433}, Year = {2004}, Month = {September}, ISSN = {0889-1591}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15265535}, Abstract = {Although the phenomenon that psychological stress influences disease onset and progression is well established, the mechanisms underlying stress-evoked compromise of immune function remain unspecified. To test the hypothesis that energetic shortages compromise immunity, we evaluated the effectiveness of pyruvate, a metabolic supplement, to prevent stress-evoked suppression of mitogen-stimulated splenocyte proliferation. Male C57BL/6 mice were subjected to 2h of restraint once daily for 14 days. Consistent with previous studies, mitogen-stimulated splenocyte proliferation was reduced after restraint; in contrast, mice that received pyruvate injections immediately following each episode of restraint did not reduce splenocyte proliferation. In addition, restraint-evoked corticosterone elevation did not habituate in animals treated with pyruvate, suggesting that glucocorticoids are not exclusively immunosuppressive. The ratio of pyruvate to lactate, an index of aerobic metabolism, was elevated in mice exposed to restraint suggesting that mice exposed to restraint were preferentially using aerobic metabolism and producing more ATP per unit of pyruvate than non-restrained mice. Furthermore, two of the effective doses of pyruvate (0.5 and 500.0mg/kg) altered glucose levels suggesting a metabolic function of the supplement. Although several different mechanisms could possibly mediate the changes in splenocyte proliferation, these results support the hypothesis that stress-evoked immunosuppression may be a function of metabolic energy shortages and can be prevented via pyruvate supplementation.}, Doi = {10.1016/j.bbi.2003.10.001}, Key = {fds250847} } @article{fds197411, Author = {BJ Prendergast and SD Bilbo and RJ Nelson}, Title = {Short day lengths enhance skin immune responses in gonadectomised Siberian hamsters.}, Journal = {Journal of neuroendocrinology}, Volume = {17}, Number = {1}, Pages = {18-21}, Year = {2005}, Month = {January}, ISSN = {0953-8194}, url = {http://dx.doi.org/10.1111/j.1365-2826.2005.01273.x}, Keywords = {Androgens • Animals • Cricetinae • Hypersensitivity, Delayed • Immune System • Male • Orchiectomy • Periodicity • Phodopus • Photoperiod* • Skin • Testosterone • drug effects • immunology* • pharmacology* • physiology • physiopathology*}, Abstract = {In Siberian hamsters and other photoperiodic rodents, exposure to short photoperiods simultaneously inhibits gonadal hormone secretion and enhances some measures of immune function. The present study tested whether gonadal hormones mediate the effects of short days on skin immune function (delayed-type hypersensitivity reactions) in male Siberian hamsters. The magnitude of delayed-type hypersensitivity reactions was greater in hamsters exposed to short days relative to those in long days. Comparable effects of photoperiod were obtained in castrated hamsters bearing empty or testosterone-filled implants. The data suggest that contemporary gonadal hormone secretion is neither necessary, nor sufficient to mediate the effects of short photoperiods on skin immune function.}, Language = {eng}, Doi = {10.1111/j.1365-2826.2005.01273.x}, Key = {fds197411} } @article{fds250853, Author = {Prendergast, BJ and Bilbo, SD and Nelson, RJ}, Title = {Short day lengths enhance skin immune responses in gonadectomised Siberian hamsters.}, Journal = {Journal of neuroendocrinology}, Volume = {17}, Number = {1}, Pages = {18-21}, Year = {2005}, Month = {January}, ISSN = {0953-8194}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15720471}, Abstract = {In Siberian hamsters and other photoperiodic rodents, exposure to short photoperiods simultaneously inhibits gonadal hormone secretion and enhances some measures of immune function. The present study tested whether gonadal hormones mediate the effects of short days on skin immune function (delayed-type hypersensitivity reactions) in male Siberian hamsters. The magnitude of delayed-type hypersensitivity reactions was greater in hamsters exposed to short days relative to those in long days. Comparable effects of photoperiod were obtained in castrated hamsters bearing empty or testosterone-filled implants. The data suggest that contemporary gonadal hormone secretion is neither necessary, nor sufficient to mediate the effects of short photoperiods on skin immune function.}, Doi = {10.1111/j.1365-2826.2005.01273.x}, Key = {fds250853} } @article{fds197410, Author = {SD Bilbo and LH Levkoff and JH Mahoney and LR Watkins and JW Rudy and SF Maier}, Title = {Neonatal infection induces memory impairments following an immune challenge in adulthood.}, Journal = {Behavioral neuroscience}, Volume = {119}, Number = {1}, Pages = {293-301}, Year = {2005}, Month = {February}, ISSN = {0735-7044}, url = {http://dx.doi.org/10.1037/0735-7044.119.1.293}, Keywords = {Animals • Astrocytes • Escherichia coli • Escherichia coli Infections • Female • Hippocampus • Interleukin-1 • Lipopolysaccharides • Male • Memory Disorders • Pregnancy • Pregnancy Complications, Infectious • Prenatal Exposure Delayed Effects* • Rats • analysis • complications* • immunology • immunology* • pathogenicity* • pathology* • pharmacology • physiology • physiopathology* • poisoning • psychology* • veterinary}, Abstract = {Exposure to infectious agents during early postnatal life often alters glucocorticoid responses to stress and immune outcomes in adulthood. The authors examined whether neonatal infection results in memory impairments in adult animals. Rats infected with Escherichia coli (E. coli) as neonates displayed impaired memory for a recently explored context in adulthood. This impairment, however, was only observed in rats that received a peripheral immune challenge (lipopolysaccharide; LPS) immediately following context exposure. Adult rats treated neonatally with E. coli also had decreased hippocampal astrocytes compared with phosphate-buffered saline-treated rats, but displayed increased astrocyte reactivity in the hippocampus and decreased brain interleukin-1beta following lipopolysaccharide. Infection during development appears to alter glia within the hippocampus, which may contribute to altered cytokine responses and memory impairment.}, Language = {eng}, Doi = {10.1037/0735-7044.119.1.293}, Key = {fds197410} } @article{fds250854, Author = {Bilbo, SD and Levkoff, LH and Mahoney, JH and Watkins, LR and Rudy, JW and Maier, SF}, Title = {Neonatal infection induces memory impairments following an immune challenge in adulthood.}, Journal = {Behavioral neuroscience}, Volume = {119}, Number = {1}, Pages = {293-301}, Year = {2005}, Month = {February}, ISSN = {0735-7044}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15727533}, Abstract = {Exposure to infectious agents during early postnatal life often alters glucocorticoid responses to stress and immune outcomes in adulthood. The authors examined whether neonatal infection results in memory impairments in adult animals. Rats infected with Escherichia coli (E. coli) as neonates displayed impaired memory for a recently explored context in adulthood. This impairment, however, was only observed in rats that received a peripheral immune challenge (lipopolysaccharide; LPS) immediately following context exposure. Adult rats treated neonatally with E. coli also had decreased hippocampal astrocytes compared with phosphate-buffered saline-treated rats, but displayed increased astrocyte reactivity in the hippocampus and decreased brain interleukin-1beta following lipopolysaccharide. Infection during development appears to alter glia within the hippocampus, which may contribute to altered cytokine responses and memory impairment.}, Doi = {10.1037/0735-7044.119.1.293}, Key = {fds250854} } @article{fds250855, Author = {Bilbo, SD and Biedenkapp, JC and Der-Avakian, A and Watkins, LR and Rudy, JW and Maier, SF}, Title = {Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition.}, Journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, Volume = {25}, Number = {35}, Pages = {8000-8009}, Year = {2005}, Month = {August}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16135757}, Abstract = {We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.}, Doi = {10.1523/jneurosci.1748-05.2005}, Key = {fds250855} } @article{fds197408, Author = {SD Bilbo and JC Biedenkapp and A Der-Avakian and LR Watkins and JW Rudy and SF Maier}, Title = {Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition.}, Journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, Volume = {25}, Number = {35}, Pages = {8000-9}, Year = {2005}, Month = {August}, ISSN = {1529-2401}, url = {http://dx.doi.org/10.1523/JNEUROSCI.1748-05.2005}, Keywords = {Age Factors • Animals • Animals, Newborn • Caspase 1 • Enzyme Inhibitors • Escherichia coli Infections • Female • Hippocampus • Interleukin-1 • Lipopolysaccharides • Male • Memory Disorders • Pregnancy • Rats • Rats, Sprague-Dawley • antagonists & inhibitors • antagonists & inhibitors* • chemically induced • drug effects • drug therapy • enzymology • enzymology* • metabolism • microbiology • pharmacology • physiology • prevention & control* • therapeutic use* • toxicity*}, Abstract = {We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.}, Language = {eng}, Doi = {10.1523/JNEUROSCI.1748-05.2005}, Key = {fds197408} } @article{fds197409, Author = {GN Neigh and ER Glasper and SD Bilbo and RJ Traystman and A Courtney DeVries}, Title = {Cardiac arrest/cardiopulmonary resuscitation augments cell-mediated immune function and transiently suppresses humoral immune function.}, Journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, Volume = {25}, Number = {11}, Pages = {1424-32}, Year = {2005}, Month = {November}, ISSN = {0271-678X}, url = {http://dx.doi.org/10.1038/sj.jcbfm.9600137}, Keywords = {Animals • Antibody Formation • Antigens • Cardiopulmonary Resuscitation* • Corticosterone • Heart Arrest • Hippocampus • Humans • Hypersensitivity, Delayed • Hypothalamo-Hypophyseal System • Hypothermia • Immunity, Cellular • Ischemia • Male • Mice • Neurons • Pituitary-Adrenal System • blood • immunology • immunology* • injuries • metabolism • methods • prevention & control • therapy}, Abstract = {Immune system activation has implications for cerebrovascular health, but little is known about the function of the immune system after a major cerebrovascular event, such as cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Cardiac arrest and cardiopulmonary resuscitation damages the hippocampus, an important component of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in HPA axis activity can affect immune function. We tested the hypothesis that CA/CPR (approximately 8 mins) would cause HPA axis dysregulation and alter the delayed type hypersensitivity (DTH) response to antigenic challenge. We also assessed the primary and secondary antibody response of mice exposed to CA/CPR. Of the mice exposed to CA/CPR, half had brains protected by hypothermia to isolate the effects of the CA/CPR procedure from the effects of CA/CPR-induced neuronal damage. Cardiac arrest and cardiopulmonary resuscitation-induced neuronal damage resulted in a persistent elevation of blood corticosterone concentration and a concomitant augmentation of the DTH response to antigenic challenge. Furthermore, immune activation before CA/CPR decreased survival after global ischemia. These data highlight the potential impact of neuronal damage on cell-mediated immune function and the role of humoral immune activation in outcome after global ischemia.}, Language = {eng}, Doi = {10.1038/sj.jcbfm.9600137}, Key = {fds197409} } @article{fds250852, Author = {Neigh, GN and Glasper, ER and Bilbo, SD and Traystman, RJ and Courtney DeVries, A}, Title = {Cardiac arrest/cardiopulmonary resuscitation augments cell-mediated immune function and transiently suppresses humoral immune function.}, Journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, Volume = {25}, Number = {11}, Pages = {1424-1432}, Year = {2005}, Month = {November}, ISSN = {0271-678X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15874972}, Abstract = {Immune system activation has implications for cerebrovascular health, but little is known about the function of the immune system after a major cerebrovascular event, such as cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Cardiac arrest and cardiopulmonary resuscitation damages the hippocampus, an important component of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in HPA axis activity can affect immune function. We tested the hypothesis that CA/CPR (approximately 8 mins) would cause HPA axis dysregulation and alter the delayed type hypersensitivity (DTH) response to antigenic challenge. We also assessed the primary and secondary antibody response of mice exposed to CA/CPR. Of the mice exposed to CA/CPR, half had brains protected by hypothermia to isolate the effects of the CA/CPR procedure from the effects of CA/CPR-induced neuronal damage. Cardiac arrest and cardiopulmonary resuscitation-induced neuronal damage resulted in a persistent elevation of blood corticosterone concentration and a concomitant augmentation of the DTH response to antigenic challenge. Furthermore, immune activation before CA/CPR decreased survival after global ischemia. These data highlight the potential impact of neuronal damage on cell-mediated immune function and the role of humoral immune activation in outcome after global ischemia.}, Doi = {10.1038/sj.jcbfm.9600137}, Key = {fds250852} } @article{fds250799, Author = {Maier, SF and Bilbo, SD}, Title = {The impact of infection early in life on the formation of long-term memories in adulthood}, Journal = {NEUROPSYCHOPHARMACOLOGY}, Volume = {30}, Pages = {S8-S9}, Publisher = {NATURE PUBLISHING GROUP}, Year = {2005}, Month = {December}, ISSN = {0893-133X}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000233442100024&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Key = {fds250799} } @article{fds250845, Author = {Bilbo, SD and Rudy, JW and Watkins, LR and Maier, SF}, Title = {A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats.}, Journal = {Behavioural brain research}, Volume = {169}, Number = {1}, Pages = {39-47}, Year = {2006}, Month = {April}, ISSN = {0166-4328}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16413067}, Abstract = {We have reported that exposure to bacteria (Escherichia coli) during the neonatal period in rats is associated with impaired memory for a novel context in adulthood. However, impairment is only observed if a peripheral immune challenge (bacterial lipopolysaccharide (LPS)) is administered immediately following context exposure. The goal of the current study was to more fully characterize this phenomenon. In Experiment 1, memory impairment as a result of neonatal infection and subsequent LPS challenge was observed in juvenile rats, indicating that the changes induced by infection occur early on and are then manifest throughout the lifespan. In Experiment 2, infection in juvenile rats did not lead to LPS-induced memory impairment in adulthood, suggesting there is a critical period for early infection-induced alterations. In Experiments 3 and 4, memory for a novel context was impaired in neonatally infected rats, a task that is dependent on the hippocampus, whereas cued memory for a tone, which does not depend on the hippocampus, was not impaired. Furthermore, long-term, but not short-term contextual memory was impaired in adult rats infected as neonates following an LPS challenge either 24 h before or immediately after conditioning. Finally, in Experiment 5, no neonatal group differences were observed in corticosterone or open field behaviour, suggesting that decreased freezing to a conditioned context reflects impaired memory, and not simply hyperactivity or altered stress reactivity. Taken together, we have demonstrated that neonatal infection results in robust hippocampal-dependent memory impairment following an immune challenge in adulthood using a number of conditioning paradigms.}, Doi = {10.1016/j.bbr.2005.12.002}, Key = {fds250845} } @article{fds197407, Author = {SD Bilbo and JW Rudy and LR Watkins and SF Maier}, Title = {A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats.}, Journal = {Behavioural brain research}, Volume = {169}, Number = {1}, Pages = {39-47}, Year = {2006}, Month = {April}, ISSN = {0166-4328}, url = {http://dx.doi.org/10.1016/j.bbr.2005.12.002}, Keywords = {Age Factors • Amnesia, Retrograde • Animals • Animals, Newborn • Association Learning • Bacterial Infections • Behavior, Animal • Conditioning, Classical • Critical Period (Psychology) • Disease Models, Animal • Fear • Female • Hippocampus • Lipopolysaccharides • Male • Rats • Rats, Sprague-Dawley • complications • etiology • immunology • immunology* • physiology • physiology* • physiopathology}, Abstract = {We have reported that exposure to bacteria (Escherichia coli) during the neonatal period in rats is associated with impaired memory for a novel context in adulthood. However, impairment is only observed if a peripheral immune challenge (bacterial lipopolysaccharide (LPS)) is administered immediately following context exposure. The goal of the current study was to more fully characterize this phenomenon. In Experiment 1, memory impairment as a result of neonatal infection and subsequent LPS challenge was observed in juvenile rats, indicating that the changes induced by infection occur early on and are then manifest throughout the lifespan. In Experiment 2, infection in juvenile rats did not lead to LPS-induced memory impairment in adulthood, suggesting there is a critical period for early infection-induced alterations. In Experiments 3 and 4, memory for a novel context was impaired in neonatally infected rats, a task that is dependent on the hippocampus, whereas cued memory for a tone, which does not depend on the hippocampus, was not impaired. Furthermore, long-term, but not short-term contextual memory was impaired in adult rats infected as neonates following an LPS challenge either 24 h before or immediately after conditioning. Finally, in Experiment 5, no neonatal group differences were observed in corticosterone or open field behaviour, suggesting that decreased freezing to a conditioned context reflects impaired memory, and not simply hyperactivity or altered stress reactivity. Taken together, we have demonstrated that neonatal infection results in robust hippocampal-dependent memory impairment following an immune challenge in adulthood using a number of conditioning paradigms.}, Language = {eng}, Doi = {10.1016/j.bbr.2005.12.002}, Key = {fds197407} } @article{fds250801, Author = {Bilbo, SD and Newsum, NJ and Mahoney, JH and Sprunger, DP and Watkins, LR and Rudy, JW and Maier, SF}, Title = {Maternal care modulation of neonatal infection-facilitated cognitive impairment in adulthood}, Journal = {Frontiers in Neuroendocrinology}, Volume = {27}, Number = {1}, Pages = {107-107}, Publisher = {Elsevier BV}, Year = {2006}, Month = {May}, ISSN = {0091-3022}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000238456300205&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Doi = {10.1016/j.yfrne.2006.03.265}, Key = {fds250801} } @article{fds197406, Author = {SD Bilbo and NJ Newsum and DB Sprunger and LR Watkins and JW Rudy and SF Maier}, Title = {Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood.}, Journal = {Brain, behavior, and immunity}, Volume = {21}, Number = {3}, Pages = {332-42}, Year = {2007}, Month = {March}, ISSN = {0889-1591}, url = {http://dx.doi.org/10.1016/j.bbi.2006.10.005}, Keywords = {Age Factors • Analysis of Variance • Animals • Animals, Newborn • Bacterial Infections • Behavior, Animal • Cognition • Critical Period (Psychology) • Fear • Female • Handling (Psychology) • Hippocampus • Interleukin-10 • Learning • Lipopolysaccharides • Male • Neuroglia • Neuroimmunomodulation • Rats • Rats, Sprague-Dawley • Stress, Psychological • immunology • immunology* • metabolism • physiology • physiology*}, Abstract = {We have previously demonstrated that bacterial infection (Escherichia coli) in neonatal rats is associated with impaired memory in a fear-conditioning task in adulthood. This impairment, however, is only observed if a peripheral immune challenge (lipopolysaccharide; LPS) is administered around the time of learning. We used a brief separation/handling paradigm to determine if the adult memory impairment associated with neonatal-infection could be prevented. Naturally occurring variations in maternal care promote striking variations in offspring cognitive development, and handling paradigms are used to manipulate the quality and quantity of maternal care. Rats were injected on post natal (P) day 4 with E. coli or PBS, and half from each group were handled for 15 min/day from P4 to 20. All rats were then tested in adulthood. Neonatal handling of rats infected as neonates prevented the increase in microglial cell marker reactivity within the hippocampus, and the exaggerated brain IL-1beta production to LPS normally produced by the infection. Thus, these neural processes were now comparable to levels of non-infected PBS controls. Furthermore, handling completely prevented LPS-induced memory impairment in a context-fear task in adult rats infected as neonates. Finally, neonatal handling dramatically improved spatial learning and memory and decreased anxiety in rats treated early with PBS, but had no beneficial effect on these measures in rats infected as neonates. Taken together, these data suggest that maternal care may profoundly influence neuroinflammatory processes in adulthood, and that infection may also prevent maternal care influences on cognition later in life.}, Language = {eng}, Doi = {10.1016/j.bbi.2006.10.005}, Key = {fds197406} } @article{fds250846, Author = {Bilbo, SD and Newsum, NJ and Sprunger, DB and Watkins, LR and Rudy, JW and Maier, SF}, Title = {Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood.}, Journal = {Brain, behavior, and immunity}, Volume = {21}, Number = {3}, Pages = {332-342}, Year = {2007}, Month = {March}, ISSN = {0889-1591}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17126527}, Abstract = {We have previously demonstrated that bacterial infection (Escherichia coli) in neonatal rats is associated with impaired memory in a fear-conditioning task in adulthood. This impairment, however, is only observed if a peripheral immune challenge (lipopolysaccharide; LPS) is administered around the time of learning. We used a brief separation/handling paradigm to determine if the adult memory impairment associated with neonatal-infection could be prevented. Naturally occurring variations in maternal care promote striking variations in offspring cognitive development, and handling paradigms are used to manipulate the quality and quantity of maternal care. Rats were injected on post natal (P) day 4 with E. coli or PBS, and half from each group were handled for 15 min/day from P4 to 20. All rats were then tested in adulthood. Neonatal handling of rats infected as neonates prevented the increase in microglial cell marker reactivity within the hippocampus, and the exaggerated brain IL-1beta production to LPS normally produced by the infection. Thus, these neural processes were now comparable to levels of non-infected PBS controls. Furthermore, handling completely prevented LPS-induced memory impairment in a context-fear task in adult rats infected as neonates. Finally, neonatal handling dramatically improved spatial learning and memory and decreased anxiety in rats treated early with PBS, but had no beneficial effect on these measures in rats infected as neonates. Taken together, these data suggest that maternal care may profoundly influence neuroinflammatory processes in adulthood, and that infection may also prevent maternal care influences on cognition later in life.}, Doi = {10.1016/j.bbi.2006.10.005}, Key = {fds250846} } @article{fds250833, Author = {Bowers, SL and Bilbo, SD and Dhabhar, FS and Nelson, RJ}, Title = {Stressor-specific alterations in corticosterone and immune responses in mice.}, Journal = {Brain, behavior, and immunity}, Volume = {22}, Number = {1}, Pages = {105-113}, Year = {2008}, Month = {January}, ISSN = {1090-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17890050}, Keywords = {Animals • Chronic Disease • Cold Temperature • Corticosterone • Handling (Psychology) • Hypersensitivity, Delayed • Leukocyte Count • Male • Mice • Mice, Inbred C57BL • Monocytes • Osmolar Concentration • Restraint, Physical • Skin • Social Isolation • Stress, Physiological • Swimming • Volition • blood • blood* • etiology* • immunology* • pathology}, Abstract = {Different stressors likely elicit different physiological and behavioral responses. Previously reported differences in the effects of stressors on immune function may reflect qualitatively different physiological responses to stressors; alternatively, both large and subtle differences in testing protocols and methods among laboratories may make direct comparisons among studies difficult. Here we examine the effects of chronic stressors on plasma corticosterone concentrations, leukocyte redistribution, and skin delayed-type hypersensitivity (DTH), and the effects of acute stressors on plasma corticosterone and leukocyte redistribution. The effects of several commonly used laboratory stressors including restraint, forced swim, isolation, and low ambient temperatures (4 degrees C) were examined. Exposure to each stressor elevated corticosterone concentrations, with restraint (a putative psychological stressor) evoking a significantly higher glucocorticoid response than other stressors. Chronic restraint and forced swim enhanced the DTH response compared to the handled, low temperature, or isolation conditions. Restraint, low temperature, and isolation significantly increased trafficking of lymphocytes and monocytes compared to forced swim or handling. Generally, acute restraint, low temperature, isolation, and handling increased trafficking of lymphocytes and monocytes. Considered together, our results suggest that the different stressors commonly used in psychoneuroimmunology research may not activate the physiological stress response to the same extent. The variation observed in the measured immune responses may reflect differential glucocorticoid activation, differential metabolic adjustments, or both processes in response to specific stressors.}, Language = {eng}, Doi = {10.1016/j.bbi.2007.07.012}, Key = {fds250833} } @article{fds250834, Author = {Zala, SM and Chan, BK and Bilbo, SD and Potts, WK and Nelson, RJ and Penn, DJ}, Title = {Genetic resistance to infection influences a male's sexual attractiveness and modulation of testosterone.}, Journal = {Brain, behavior, and immunity}, Volume = {22}, Number = {3}, Pages = {381-387}, Year = {2008}, Month = {March}, ISSN = {1090-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17945466}, Keywords = {Animals • Choice Behavior • Female • Immunity, Innate • Male • Mice • Mice, Inbred BALB C • Odors • Salmonella Infections • Scent Glands • Sexual Behavior, Animal* • Testosterone • Urine • blood • blood* • genetics* • immunology* • secretion}, Abstract = {Females may be attracted to males genetically resistant to infectious diseases, and one potential mechanism for this mating bias is that such males may be better able to maintain high testosterone. To test these two hypotheses, we collected scent-marks from male house mice (Mus domesticus) genetically resistant and susceptible to Salmonella due to a single locus (Nramp 1, also known as Slc11a1). We tested whether females are more attracted to the scent-marks of resistant males, and whether such males are better able to maintain testosterone concentrations during an experimental Salmonella infection. We found that females preferred the scent-marks of genetically resistant males compared to susceptible ones; but they showed no preferences 5d after males were infected. As predicted, genetically resistant males maintained their testosterone concentrations during the experimental infection, whereas susceptible males showed a significant decline 14 d after inoculation. These differences in the males' ability to modulate testosterone, however, do not explain females' attraction to resistant males. Thus, our results indicate that females sometimes prefer males genetically resistant to infection, and they provide the first evidence that males modulate their testosterone depending upon their genetic resistance to infection; however, we found no evidence to link these two findings.}, Language = {eng}, Doi = {10.1016/j.bbi.2007.09.003}, Key = {fds250834} } @article{fds250844, Author = {Bilbo, SD and Yirmiya, R and Amat, J and Paul, ED and Watkins, LR and Maier, SF}, Title = {Bacterial infection early in life protects against stressor-induced depressive-like symptoms in adult rats.}, Journal = {Psychoneuroendocrinology}, Volume = {33}, Number = {3}, Pages = {261-269}, Year = {2008}, Month = {April}, ISSN = {0306-4530}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18164556}, Abstract = {Both early-life stress and immune system activation in adulthood have been linked independently to depression in a number of studies. However, the relationship between early-life infection, which may be considered a "stressor", and later-life depression has not been explored. We have reported that neonatal bacterial infection in rats leads to exaggerated brain cytokine production, as well as memory impairments, to a subsequent peripheral immune challenge in adulthood, and therefore predicted that stressor-induced depressive-like symptoms would be more severe in these rats as well. Rats treated on postnatal day 4 with PBS or Escherichia coli were as adults exposed to inescapable tailshock stress (IS), and then tested for sucrose preference, social exploration with a juvenile, and overall activity, 1, 3, 5, and 7 days following the stressor. Serum corticosterone and extracellular 5-HT within the basolateral amygdala were measured in a second group of rats in response to the IS. IS resulted in profound depressive-like behaviors in adult rats, but, surprisingly, rats that suffered a bacterial infection early in life had blunted corticosterone responses to the stressor and were remarkably protected from the depressive symptoms compared to controls. These data suggest that early-life infection should be considered within a cost/benefit perspective, in which outcomes in adulthood may be differentially protected or impaired. These data also suggest that the immune system likely plays a previously unsuspected role in "homeostatic" HPA programming and brain development, which may ultimately lend insight into the often-contradictory literature on cytokines, inflammation, and depression.}, Doi = {10.1016/j.psyneuen.2007.11.008}, Key = {fds250844} } @article{fds250835, Author = {Bilbo, SD and Barrientos, RM and Eads, AS and Northcutt, A and Watkins, LR and Rudy, JW and Maier, SF}, Title = {Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood.}, Journal = {Brain, behavior, and immunity}, Volume = {22}, Number = {4}, Pages = {451-455}, Year = {2008}, Month = {May}, ISSN = {1090-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17997277}, Keywords = {Age Factors • Animals • Animals, Newborn • Brain-Derived Neurotrophic Factor • Conditioning (Psychology) • Endotoxemia • Escherichia coli Infections • Fear • Female • Gene Expression Regulation • Hippocampus • Interleukin-1beta • Lipopolysaccharides • Male • Memory Disorders • RNA, Messenger • Rats • Rats, Sprague-Dawley • genetics* • immunology • immunology* • pharmacology • physiology • physiology* • physiopathology • physiopathology*}, Abstract = {Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments following a peripheral immune challenge in adulthood. Here, we determined whether neonatal infection plus an immune challenge in adult rats is associated with impaired induction of brain-derived neurotrophic factor (BDNF) within the hippocampus (CA1, CA3, and dentate gyrus) following fear conditioning. BDNF is well characterized for its critical role in learning and memory. Rats injected on postnatal day 4 with PBS (vehicle) or Escherichia coli received as adults either no conditioning or a single 2min trial of fear conditioning. Half of the rats in the conditioned group then received a peripheral injection of 25mug/kg lipopolysaccharide (LPS) and all were sacrificed 1 or 4h later. Basal (unconditioned) BDNF mRNA did not differ between groups. However, following conditioning, neonatal infection with E. coli led to decreased BDNF mRNA induction in all regions compared to PBS-treated rats. This decrease in E. coli-treated rats was accompanied by a large increase in IL-1beta mRNA in CA1. Taken together, these data indicate that early infection strongly influences the induction of IL-1beta and BDNF within distinct regions of the hippocampus, which likely contribute to observed memory impairments in adulthood.}, Language = {eng}, Doi = {10.1016/j.bbi.2007.10.003}, Key = {fds250835} } @article{fds250837, Author = {Bilbo, SD and Schwarz, JM}, Title = {Early-life programming of later-life brain and behavior: a critical role for the immune system.}, Journal = {Frontiers in behavioral neuroscience}, Volume = {3}, Number = {3}, Pages = {14}, Year = {2009}, Month = {January}, ISSN = {1662-5153}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19738918}, Keywords = {Animals • Animals, Newborn • Antimetabolites • Brain • Bromodeoxyuridine • Cell Count • Cell Proliferation • Cell Survival • Central Nervous System Infections • Cognition • Escherichia coli Infections • Female • Immunohistochemistry • Lipopolysaccharides • Male • Neuroglia • Neurons • Phenotype • Rats • Rats, Sprague-Dawley • diagnostic use • pathology* • pharmacology • physiology • physiology* • psychology*}, Abstract = {The immune system is well characterized for its critical role in host defense. Far beyond this limited role however, there is mounting evidence for the vital role the immune system plays within the brain, in both normal, "homeostatic" processes (e.g., sleep, metabolism, memory), as well as in pathology, when the dysregulation of immune molecules may occur. This recognition is especially critical in the area of brain development. Microglia and astrocytes, the primary immunocompetent cells of the CNS, are involved in every major aspect of brain development and function, including synaptogenesis, apoptosis, and angiogenesis. Cytokines such as tumor necrosis factor (TNF)alpha, interleukin [IL]-1beta, and IL-6 are produced by glia within the CNS, and are implicated in synaptic formation and scaling, long-term potentiation, and neurogenesis. Importantly, cytokines are involved in both injury and repair, and the conditions underlying these distinct outcomes are under intense investigation and debate. Evidence from both animal and human studies implicates the immune system in a number of disorders with known or suspected developmental origins, including schizophrenia, anxiety/depression, and cognitive dysfunction. We review the evidence that infection during the perinatal period of life acts as a vulnerability factor for later-life alterations in cytokine production, and marked changes in cognitive and affective behaviors throughout the remainder of the lifespan. We also discuss the hypothesis that long-term changes in brain glial cell function underlie this vulnerability.}, Language = {eng}, Doi = {10.3389/neuro.08.014.2009}, Key = {fds250837} } @article{fds250798, Author = {Bilbo, SD}, Title = {Early life environment influences on neuroimmune interactions and behavior in adulthood}, Journal = {INTEGRATIVE AND COMPARATIVE BIOLOGY}, Volume = {49}, Pages = {E15-E15}, Publisher = {OXFORD UNIV PRESS INC}, Year = {2009}, Month = {February}, ISSN = {1540-7063}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000268808800061&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Key = {fds250798} } @article{fds250838, Author = {Bland, ST and Beckley, JT and Young, S and Tsang, V and Watkins, LR and Maier, SF and Bilbo, SD}, Title = {Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain.}, Journal = {Brain, behavior, and immunity}, Volume = {24}, Number = {3}, Pages = {329-338}, Year = {2010}, Month = {March}, ISSN = {1090-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19782746}, Keywords = {Animals • Animals, Newborn • Antimetabolites • Brain • Bromodeoxyuridine • Cell Count • Cell Proliferation • Cell Survival • Central Nervous System Infections • Cognition • Escherichia coli Infections • Female • Immunohistochemistry • Lipopolysaccharides • Male • Neuroglia • Neurons • Phenotype • Rats • Rats, Sprague-Dawley • diagnostic use • pathology* • pharmacology • physiology • physiology* • psychology*}, Abstract = {Systemic infection with Escherichia coli on postnatal day (P) 4 in rats results in significantly altered brain cytokine responses and behavioral changes in adulthood, but only in response to a subsequent immune challenge with lipopolysaccharide [LPS]. The basis for these changes may be long-term changes in glial cell function. We assessed glial and neural cell genesis in the hippocampus, parietal cortex (PAR), and prefrontal cortex (PFC), in neonates just after the infection, as well as in adulthood in response to LPS. E. coli increased the number of newborn microglia within the hippocampus and PAR compared to controls. The total number of microglia was also significantly increased in E. coli-treated pups, with a concomitant decrease in total proliferation. On P33, there were large decreases in numbers of cells coexpressing BrdU and NeuN in all brain regions of E. coli rats compared to controls. In adulthood, basal neurogenesis within the dentate gyrus (DG) did not differ between groups; however, in response to LPS, there was a decrease in neurogenesis in early-infected rats, but an increase in controls to the same challenge. There were also significantly more microglia in the adult DG of early-infected rats, although microglial proliferation in response to LPS was increased in controls. Taken together, we have provided evidence that systemic infection with E. coli early in life has significant, enduring consequences for brain development and subsequent adult function. These changes include marked alterations in glia, as well as influences on neurogenesis in brain regions important for cognition.}, Language = {eng}, Doi = {10.1016/j.bbi.2009.09.012}, Key = {fds250838} } @article{fds250836, Author = {Bilbo, SD and Wieseler, JL and Barrientos, RM and Tsang, V and Watkins, LR and Maier, SF}, Title = {Neonatal bacterial infection alters fever to live and simulated infections in adulthood.}, Journal = {Psychoneuroendocrinology}, Volume = {35}, Number = {3}, Pages = {369-381}, Year = {2010}, Month = {April}, ISSN = {1873-3360}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19682802}, Keywords = {Age Factors • Animals • Animals, Newborn • Bacterial Infections • Cyclooxygenase 2 • Escherichia coli • Escherichia coli Infections • Female • Fever* • Immune Tolerance • Immunologic Memory • Inflammation • Lipopolysaccharides • Male • Neuroimmunomodulation • Rats • Rats, Sprague-Dawley • Weight Loss • chemically induced • complications • drug effects • etiology • genetics • immunology • immunology* • metabolism • pharmacology* • physiology • physiology* • physiopathology}, Abstract = {Fever is a critical component of the host immune response to infection. An emerging literature demonstrates that experience with infectious organisms early in life, during the perinatal period, may permanently program immune responses later in life, including fever. We explored the influence of neonatal infection with Escherichia coli on fever responses to lipopolysaccharide (LPS) and E. coli in adulthood. Fever to a low dose of LPS in adulthood did not significantly differ as a consequence of early-life infection. Eight days after the LPS injection, the same group of rats received a high dose of live E. coli. This time, neonatally infected rats exhibited a markedly longer fever than controls. In a subsequent experiment, fever to a single high dose of E. coli without prior LPS in adulthood did not differ by group, suggesting that the previous difference was a lack of tolerance to the dual challenges in early-infected rats. Finally, both groups exhibited decreased tumor necrosis factor (TNF)-alpha and toll-like-receptor (TLR) 4 production to dual LPS challenges in isolated splenocytes, whereas only rats infected as neonates exhibited increased cyclooxygenase-2 within the hypothalamus in response to adult infection, suggesting that early infection-induced changes in fever regulation may involve a change in central mechanisms. Taken together, these data indicate that early-life infection is associated with marked changes in host temperature regulation in adulthood.}, Language = {eng}, Doi = {10.1016/j.psyneuen.2009.07.014}, Key = {fds250836} } @article{fds250839, Author = {Bland, ST and Beckley, JT and Watkins, LR and Maier, SF and Bilbo, SD}, Title = {Neonatal Escherichia coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats.}, Journal = {Neuroscience letters}, Volume = {474}, Number = {1}, Pages = {52-57}, Year = {2010}, Month = {April}, ISSN = {1872-7972}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20223277}, Keywords = {Age Factors • Amphetamine • Animals • Animals, Newborn • Antigens, CD • Antigens, CD11b • Central Nervous System Stimulants • Cytokines • Cytoskeletal Proteins • Escherichia coli Infections • Gene Expression • Glial Fibrillary Acidic Protein • Male • Membrane Proteins • Nerve Tissue Proteins • Neuroglia • Neurons • RNA, Messenger • Rats • biosynthesis • biosynthesis* • complications • drug effects* • genetics • immunology* • metabolism • metabolism* • pharmacology*}, Abstract = {Neonatal bacterial infection in rats alters the responses to a variety of subsequent challenges later in life. Here we explored the effects of neonatal bacterial infection on a subsequent drug challenge during adolescence, using administration of the psychostimulant amphetamine. Male rat pups were injected on postnatal day 4 (P4) with live Escherichia coli (E. coli) or PBS vehicle, and then received amphetamine (15mg/kg) or saline on P40. Quantitative RT-PCR was performed on micropunches taken from medial prefrontal cortex, nucleus accumbens, and the CA1 subfield of the hippocampus. mRNA for glial and neuronal activation markers as well as pro-inflammatory and anti-inflammatory cytokines were assessed. Amphetamine produced brain region specific increases in many of these genes in PBS controls, while these effects were blunted or absent in neonatal E. coli treated rats. In contrast to the potentiating effect of neonatal E. coli on glial and cytokine responses to an immune challenge previously observed, neonatal E. coli infection attenuates glial and cytokine responses to an amphetamine challenge.}, Language = {eng}, Doi = {10.1016/j.neulet.2010.03.006}, Key = {fds250839} } @article{fds250822, Author = {Bilbo, SD and Tsang, V}, Title = {Enduring consequences of maternal obesity for brain inflammation and behavior of offspring.}, Journal = {FASEB J}, Volume = {24}, Number = {6}, Pages = {2104-2115}, Year = {2010}, Month = {June}, ISSN = {1530-6860}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20124437}, Keywords = {Animals • Animals, Newborn • Behavior, Animal* • Brain • Cytokines • Diet, Fat-Restricted • Dietary Fats • Energy Metabolism • Female • Leptin • Male • Maternal Nutritional Physiological Phenomena* • Obesity • Phenotype • Pregnancy • Prenatal Exposure Delayed Effects • Rats • Rats, Sprague-Dawley • Weaning • administration & dosage* • immunology* • metabolism • pathology* • physiopathology*}, Abstract = {Obesity is well characterized as a systemic inflammatory condition, and is also associated with cognitive disruption, suggesting a link between the two. We assessed whether peripheral inflammation in maternal obesity may be transferred to the offspring brain, in particular, the hippocampus, and thereby result in cognitive dysfunction. Rat dams were fed a high-saturated-fat diet (SFD), a high-trans-fat diet (TFD), or a low-fat diet (LFD) for 4 wk prior to mating, and remained on the diet throughout pregnancy and lactation. SFD/TFD exposure significantly increased body weight in both dams and pups compared to controls. Microglial activation markers were increased in the hippocampus of SFD/TFD pups at birth. At weaning and in adulthood, proinflammatory cytokine expression was strikingly increased in the periphery and hippocampus following a bacterial challenge [lipopolysaccharide (LPS)] in the SFD/TFD groups compared to controls. Microglial activation within the hippocampus was also increased basally in SFD rats, suggesting a chronic priming of the cells. Finally, there were marked changes in anxiety and spatial learning in SFD/TFD groups. These effects were all observed in adulthood, even after the pups were placed on standard chow at weaning, suggesting these outcomes were programmed early in life.}, Language = {eng}, Doi = {10.1096/fj.09-144014}, Key = {fds250822} } @article{fds250840, Author = {Bilbo, SD}, Title = {Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline.}, Journal = {Neurobiology of learning and memory}, Volume = {94}, Number = {1}, Pages = {57-64}, Year = {2010}, Month = {July}, ISSN = {1095-9564}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20388544}, Keywords = {Aging* • Animals • Animals, Newborn • Anxiety • Brain • Cognition Disorders • Conditioning, Classical • Escherichia coli Infections • Fear • Infection* • Male • Maze Learning • Memory • Memory Disorders • Neuroglia • Neuropsychological Tests • Rats • Receptors, N-Methyl-D-Aspartate • Time Factors • metabolism • metabolism* • physiology • physiopathology • physiopathology*}, Abstract = {There is significant individual variability in cognitive decline during aging, suggesting the existence of "vulnerability factors" for eventual deficits. Neuroinflammation may be one such factor; increased glial reactivity is a common outcome of aging, which in turn is associated with numerous neurodegenerative conditions. Early-life infection leads to cognitive impairment in conjunction with an inflammatory challenge in young adulthood, which led us to explore whether it might also accelerate the cognitive decline associated with aging. Rats were treated on postnatal day 4 with PBS or Escherichia coli, and then tested for learning and memory at 2 or 16months of age, using two fear-conditioning tasks (context pre-exposure and ambiguous cue), and a spatial water maze task. Neonatally-infected rats exhibited memory impairments in both the ambiguous cue fear-conditioning task and in the water maze, but only at 16months. There were no differences in anxiety between groups. Neonatally-infected rats also exhibited greater aging-induced increases in glial markers (CD11b and MHCII on microglia, and GFAP on astrocytes), as well as selective changes in NMDA receptor subunit expression within the hippocampus, but not in amygdala or parietal cortex compared to controls. Taken together, these data suggest that early-life infection leads to less successful cognitive aging, which may be linked to changes in glial reactivity.}, Language = {eng}, Doi = {10.1016/j.nlm.2010.04.001}, Key = {fds250840} } @article{fds250817, Author = {Bilbo, SD}, Title = {How cytokines leave their mark: the role of the placenta in developmental programming of brain and behavior.}, Journal = {Brain, behavior, and immunity}, Volume = {25}, Number = {4}, Pages = {602-603}, Year = {2011}, Month = {May}, ISSN = {1090-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21296146}, Keywords = {Animals • Communicable Diseases • Cytokines • Decidua • Female • Fetal Development • Humans • Infection • Maternal Exposure • Placenta • Pregnancy • Prenatal Exposure Delayed Effects • immunology • immunology*}, Abstract = {An immune challenge during the neonatal period can significantly affect the development of the nervous and immune systems, such that long-term abnormalities in immune function and behavior persist into adulthood. Given that immune activation and individual cytokines have been linked to the etiology of many developmental neuropsychiatric disorders, a complete characterization of the neonatal immune response within the brain is warranted. In this study, rats were treated peripherally on postnatal day (P) 4 with either a live Escherichia coli (E. coli) infection or lipopolysaccharide (LPS), two common models of neonatal immune activation. Inflammatory gene expression was measured within the hippocampus 2 and 24h later. We determined that E. coli and LPS produce very distinct inflammatory profiles within the brain. Infection with E. coli produced a robust, yet relatively IL-1 pathway focused activation of the neonatal immune system within the brain, while LPS produced a very broad and robust immune response within the brain. This analysis also identified common inflammatory genes up-regulated by both E. coli and LPS treatment.}, Language = {eng}, Doi = {10.1016/j.bbi.2011.01.018}, Key = {fds250817} } @article{fds250841, Author = {Schwarz, JM and Bilbo, SD}, Title = {LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats.}, Journal = {Neuroscience letters}, Volume = {497}, Number = {2}, Pages = {110-115}, Year = {2011}, Month = {June}, ISSN = {1872-7972}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21536105}, Abstract = {An immune challenge during the neonatal period can significantly affect the development of the nervous and immune systems, such that long-term abnormalities in immune function and behavior persist into adulthood. Given that immune activation and individual cytokines have been linked to the etiology of many developmental neuropsychiatric disorders, a complete characterization of the neonatal immune response within the brain is warranted. In this study, rats were treated peripherally on postnatal day (P) 4 with either a live Escherichia coli (E. coli) infection or lipopolysaccharide (LPS), two common models of neonatal immune activation. Inflammatory gene expression was measured within the hippocampus 2 and 24h later. We determined that E. coli and LPS produce very distinct inflammatory profiles within the brain. Infection with E. coli produced a robust, yet relatively IL-1 pathway focused activation of the neonatal immune system within the brain, while LPS produced a very broad and robust immune response within the brain. This analysis also identified common inflammatory genes up-regulated by both E. coli and LPS treatment.}, Language = {eng}, Doi = {10.1016/j.neulet.2011.04.042}, Key = {fds250841} } @article{fds250843, Author = {Bilbo, SD and Smith, SH and Schwarz, JM}, Title = {A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia.}, Journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, Volume = {31}, Number = {43}, Pages = {15511-15521}, Year = {2011}, Month = {August}, ISSN = {1557-1904}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21822589}, Abstract = {Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual's risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or "re-programming" of this crucial process by external events (e.g., stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life.}, Language = {ENG}, Doi = {10.1007/s11481-011-9299-y}, Key = {fds250843} } @article{fds250842, Author = {Bilbo, SD and Wray, GA and Perkins, SE and Parker, W}, Title = {Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases.}, Journal = {Med Hypotheses}, Volume = {77}, Number = {4}, Pages = {494-504}, Year = {2011}, Month = {October}, ISSN = {1532-2777}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21741180}, Abstract = {A wide range of hyperimmune-associated diseases plague post-industrial society, with a prevalence and impact that is staggering. Strong evidence points towards a loss of helminths from the ecosystem of the human body (the human biome) as the most important factor in this epidemic. Helminths, intestinal worms which are largely eradicated by elements of post-industrial culture including toilets and water treatment facilities, have an otherwise ubiquitous presence in vertebrates, and have co-evolved with the immune system. Not only do helminths discourage allergic and autoimmune reactions by diverting the immune system away from these pathologic processes and stimulating host regulatory networks, helminths release a variety of factors which down-modulate the immune system. A comprehensive view of hyperimmune-related disease based on studies in immunology, parasitology, evolutionary biology, epidemiology, and neurobiology indicates that the effects of biome depletion may not yet be fully realized, and may have an unexpectedly broad impact on many areas of human biology, including cognition. Fortunately, colonization with helminths results in a cure of numerous autoimmune and allergic diseases in laboratory rodents, and clinical studies in humans have indicated their utility for treatment of both multiple sclerosis and inflammatory bowel disease. Based on these considerations, commitment of considerable resources toward understanding the effects of "biome depletion" and systematically evaluating the most effective approach toward biome reconstitution is strongly encouraged.}, Language = {eng}, Doi = {10.1016/j.mehy.2011.06.019}, Key = {fds250842} } @article{fds250823, Author = {Williamson, LL and Sholar, PW and Mistry, RS and Smith, SH and Bilbo, SD}, Title = {Microglia and memory: modulation by early-life infection.}, Journal = {J Neurosci}, Volume = {31}, Number = {43}, Pages = {15511-15521}, Year = {2011}, Month = {October}, ISSN = {1529-2401}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22031897}, Abstract = {The proinflammatory cytokine interleukin-1β (IL-1β) is critical for normal hippocampus (HP)-dependent cognition, whereas high levels can disrupt memory and are implicated in neurodegeneration. However, the cellular source of IL-1β during learning has not been shown, and little is known about the risk factors leading to cytokine dysregulation within the HP. We have reported that neonatal bacterial infection in rats leads to marked HP-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge [lipopolysaccharide (LPS)] around the time of learning. These data implicate a long-term change within the immune system that, upon activation with the "second hit," LPS, acutely impacts the neural processes underlying memory. Indeed, inhibiting brain IL-1β before the LPS challenge prevents memory impairment in neonatally infected (NI) rats. We aimed to determine the cellular source of IL-1β during normal learning and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. We show for the first time that CD11b(+) enriched cells are the source of IL-1β during normal HP-dependent learning. CD11b(+) cells from NI rats are functionally sensitized within the adult HP and produce exaggerated IL-1β ex vivo compared with controls. However, an exaggerated IL-1β response in vivo requires LPS before learning. Moreover, preventing microglial activation during learning prevents memory impairment in NI rats, even following an LPS challenge. Thus, early-life events can significantly modulate normal learning-dependent cytokine activity within the HP, via a specific, enduring impact on brain microglial function.}, Language = {eng}, Doi = {10.1523/JNEUROSCI.3688-11.2011}, Key = {fds250823} } @article{fds250832, Author = {Schwarz, JM and Hutchinson, MR and Bilbo, SD}, Title = {Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.}, Journal = {J Neurosci}, Volume = {31}, Number = {49}, Pages = {17835-17847}, Year = {2011}, Month = {December}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22159099}, Abstract = {A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.}, Doi = {10.1523/JNEUROSCI.3297-11.2011}, Key = {fds250832} } @article{fds250825, Author = {Bilbo, SD and Jones, JP and Parker, W}, Title = {Is autism a member of a family of diseases resulting from genetic/cultural mismatches? Implications for treatment and prevention.}, Journal = {Autism Res Treat}, Volume = {2012}, Pages = {910946}, Year = {2012}, ISSN = {2090-1933}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22928103}, Abstract = {Several lines of evidence support the view that autism is a typical member of a large family of immune-related, noninfectious, chronic diseases associated with postindustrial society. This family of diseases includes a wide range of inflammatory, allergic, and autoimmune diseases and results from consequences of genetic/culture mismatches which profoundly destabilize the immune system. Principle among these consequences is depletion of important components, particularly helminths, from the ecosystem of the human body, the human biome. Autism shares a wide range of features in common with this family of diseases, including the contribution of genetics/epigenetics, the identification of disease-inducing triggers, the apparent role of immunity in pathogenesis, high prevalence, complex etiologies and manifestations, and potentially some aspects of epidemiology. Fortunately, using available resources and technology, modern medicine has the potential to effectively reconstitute the human biome, thus treating or even avoiding altogether the consequences of genetic/cultural mismatches which underpin this entire family of disease. Thus, if indeed autism is an epidemic of postindustrial society associated with immune hypersensitivity, we can expect that the disease is readily preventable.}, Language = {eng}, Doi = {10.1155/2012/910946}, Key = {fds250825} } @article{fds250826, Author = {Bolton, JL and Huff, NC and Smith, SH and Potts Kant and EN and Mason, SN and Auten, RL and Bilbo, SD}, Title = {Synergism in Fetal Programming: The Combined Effects of Prenatal Air Pollution & Stress Exposures on Offspring Neuroimmune Function & Behavior}, Journal = {Molecular Psychiatry}, Year = {2012}, Key = {fds250826} } @article{fds250827, Author = {Williamson, LL and Bilbo, SD}, Title = {The plasticity of the hippocampus is the reason for its vulnerability: Neuroimmune interactions and their role in the hippocampus}, Journal = {Brain, Behavior, and Immunity}, Year = {2012}, Key = {fds250827} } @article{fds250828, Author = {Schwarz, JM and Smith, SH and Bilbo, SD}, Title = {Neuronal-glial interactions in the nucleus accumbens following morphine.}, Journal = {Glia}, Year = {2012}, Key = {fds250828} } @article{fds250820, Author = {Schwarz, JM and Sholar, PW and Bilbo, SD}, Title = {Sex differences in microglial colonization of the developing rat brain.}, Journal = {Journal of neurochemistry}, Volume = {120}, Number = {6}, Pages = {948-963}, Year = {2012}, Month = {March}, ISSN = {1471-4159}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22182318}, Keywords = {Age Factors • Animals • Animals, Newborn • Brain • Calcium-Binding Proteins • Cell Count • Chemokine CXCL9 • Embryo, Mammalian • Enzyme-Linked Immunosorbent Assay • Female • Flow Cytometry • Gene Expression Regulation, Developmental • Interleukin-10 • Interleukin-1beta • Male • Microfilament Proteins • Microglia • RNA, Messenger • Rats • Rats, Sprague-Dawley • Sex Characteristics* • cytology* • genetics • growth & development* • metabolism • physiology*}, Abstract = {Microglia are the resident immune cells within the brain and their production of immune molecules such as cytokines and chemokines is critical for the processes of normal brain development including neurogenesis, axonal migration, synapse formation, and programmed cell death. Notably, sex differences exist in many of these processes throughout brain development; however, it is unknown whether a sex difference concurrently exists in the colonization, number, or morphology of microglia within the developing brain. We demonstrate for the first time that the number and morphology of microglia throughout development is dependent upon the sex and age of the individual, as well as the brain region of interest. Males have overall more microglia early in postnatal development [postnatal day (P) 4], whereas females have more microglia with an activated/amoeboid morphology later in development, as juveniles and adults (P30-60). Finally, gene expression of a large number of cytokines, chemokines and their receptors shifts dramatically over development, and is highly dependent upon sex. Taken together, these data warrant further research into the role that sex-dependent mechanisms may play in microglial colonization, number, and function, and their potential contribution to neural development, function, or potential dysfunction.}, Language = {eng}, Doi = {10.1111/j.1471-4159.2011.07630.x}, Key = {fds250820} } @article{fds250821, Author = {Williamson, LL and Chao, A and Bilbo, SD}, Title = {Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus.}, Journal = {Brain, behavior, and immunity}, Volume = {26}, Number = {3}, Pages = {500-510}, Year = {2012}, Month = {March}, ISSN = {1090-2139}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22281279}, Keywords = {Animals • Astrocytes • Brain-Derived Neurotrophic Factor • Calcium-Binding Proteins • Chemokines • Corticosterone • Cytokines • Dentate Gyrus • Environment* • Gene Expression • Glial Fibrillary Acidic Protein • Hippocampus • Inflammation Mediators • Lipopolysaccharides • Male • Microfilament Proteins • Microglia • Neurogenesis* • Rats • Rats, Sprague-Dawley • immunology • immunology* • metabolism}, Abstract = {Neurogenesis is a well-characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Environmental enrichment (EE) in rodents increases neurogenesis, enhances cognition, and promotes recovery from injury. However, little is known about the effects of EE on glia (astrocytes and microglia). Given their importance in neural repair, we predicted that EE would modulate glial phenotype and/or function within the hippocampus. Adult male rats were housed either 12 h/day in an enriched environment or in a standard home cage. Rats were injected with BrdU at 1 week, and after 7 weeks, half of the rats from each housing group were injected with lipopolysaccharide (LPS), and cytokine and chemokine expression was assessed within the periphery, hippocampus and cortex. Enriched rats had a markedly blunted pro-inflammatory response to LPS within the hippocampus. Specifically, expression of the chemokines Ccl2, Ccl3 and Cxcl2, several members of the tumor necrosis factor (TNF) family, and the pro-inflammatory cytokine IL-1β were all significantly decreased following LPS administration in EE rats compared to controls. EE did not impact the inflammatory response to LPS in the cortex. Moreover, EE significantly increased both astrocyte (GFAP+) and microglia (Iba1+) antigen expression within the DG, but not in the CA1, CA3, or cortex. Measures of neurogenesis were not impacted by EE (BrdU and DCX staining), although hippocampal BDNF mRNA was significantly increased by EE. This study demonstrates the importance of environmental factors on the function of the immune system specifically within the brain, which can have profound effects on neural function.}, Language = {eng}, Doi = {10.1016/j.bbi.2012.01.003}, Key = {fds250821} } @article{fds250800, Author = {Bilbo, SD}, Title = {Sex Differences in Early-Life Programming of Neuroinflammation and Behavioral Abnormalities by High Fat Diet}, Journal = {BIOLOGICAL PSYCHIATRY}, Volume = {71}, Number = {8}, Pages = {12S-12S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2012}, Month = {April}, ISSN = {0006-3223}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000302466000040&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Key = {fds250800} } @article{fds250830, Author = {Bolton, JL and Smith, SH and Huff, NC and Gilmour, MI and Foster, WM and Auten, RL and Bilbo, SD}, Title = {Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner.}, Journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, Volume = {26}, Number = {11}, Pages = {4743-4754}, Year = {2012}, Month = {July}, ISSN = {1530-6860}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22815382}, Abstract = {Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46-390% over FA). As adults, offspring were fed either a low-fat diet (LFD) or high-fat diet (HFD) for 6 wk. Adult DE male offspring weighed 12% more and were 35% less active than FA male offspring at baseline, whereas there were no differences in females. Following HFD, DE males gained weight at the same rate as FA males, whereas DE females gained 340% more weight than FA females. DE-HFD males had 450% higher endpoint insulin levels than FA-HFD males, and all males on HFD showed decreased activity and increased anxiety, whereas females showed no differences. Finally, both DE males and females fed HFD showed increased microglial activation (30-66%) within several brain regions. Thus, prenatal air pollution exposure can "program" offspring for increased susceptibility to diet-induced weight gain and neuroinflammation in adulthood in a sex-specific manner.-Bolton, J. L., Smith, S. H., Huff, N. C., Gilmour, M. I., Foster, W. M., Auten, R. L., Bilbo, S. D. Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner.}, Language = {eng}, Doi = {10.1096/fj.12-210989}, Key = {fds250830} } @article{fds250818, Author = {Bilbo, SD and Klein, SL}, Title = {Special Issue: the neuroendocrine-immune axis in health and disease.}, Journal = {Hormones and behavior}, Volume = {62}, Number = {3}, Pages = {187-190}, Year = {2012}, Month = {August}, ISSN = {1095-6867}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22789778}, Language = {eng}, Doi = {10.1016/j.yhbeh.2012.06.005}, Key = {fds250818} } @article{fds250819, Author = {Bilbo, SD and Schwarz, JM}, Title = {The immune system and developmental programming of brain and behavior.}, Journal = {Front Neuroendocrinol}, Volume = {33}, Number = {3}, Pages = {267-286}, Year = {2012}, Month = {August}, ISSN = {1095-6808}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22982535}, Abstract = {The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone-behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition.}, Language = {eng}, Doi = {10.1016/j.yfrne.2012.08.006}, Key = {fds250819} } @article{fds250831, Author = {Schwarz, JM and Bilbo, SD}, Title = {Sex, glia, and development: interactions in health and disease.}, Journal = {Horm Behav}, Volume = {62}, Number = {3}, Pages = {243-253}, Year = {2012}, Month = {August}, ISSN = {1095-6867}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22387107}, Abstract = {Microglia and astrocytes are the primary immune cells within the central nervous system. Microglia influence processes including neural development, synaptic plasticity and cognition; while their activation and production of immune molecules can induce stereotyped sickness behaviors or pathologies including cognitive dysfunction. Given their role in health and disease, we propose that glia may also be a critical link in understanding the etiology of many neuropsychiatric disorders that present with a strong sex-bias in their symptoms or prevalence. Specifically, males are more likely to be diagnosed with disorders that have distinct developmental origins such as autism or schizophrenia. In contrast, females are more likely to be diagnosed with disorders that present later in life, after the onset of adolescence, such as depression and anxiety disorders. In this review we will summarize the evidence suggesting that sex differences in the colonization and function of glia within the normal developing brain may contribute to distinct windows of vulnerability between males and females. We will also highlight the current gaps in our knowledge as well as the future directions and considerations of research aimed at understanding the link between neuroimmune function and sex differences in mental health disorders.}, Language = {eng}, Doi = {10.1016/j.yhbeh.2012.02.018}, Key = {fds250831} } @article{fds250829, Author = {Block, ML and Elder, A and Auten, RL and Bilbo, SD and Chen, H and Chen, JC and Cory Slechta and DA and Costa, D and Diaz Sanchez and D and Dorman, DC and Gold, DR and Gray, K and Jeng, HA and Kaufman, JD and Kleinman, MT and Kirshner, A and Lawler, C and Miller, DS and Nadadur, SS and Ritz, B and Semmens, EO and Tonelli, LH and Veronesi, B and Wright, RO and Wright, RJ}, Title = {The outdoor air pollution and brain health workshop.}, Journal = {Neurotoxicology}, Volume = {33}, Number = {5}, Pages = {972-984}, Year = {2012}, Month = {October}, ISSN = {1872-9711}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22981845}, Abstract = {Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.}, Language = {eng}, Doi = {10.1016/j.neuro.2012.08.014}, Key = {fds250829} } @article{fds250824, Author = {Schwarz, JM and Bilbo, SD}, Title = {Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction.}, Journal = {J Neurosci}, Volume = {33}, Number = {3}, Pages = {961-971}, Year = {2013}, Month = {January}, ISSN = {1529-2401}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23325235}, Keywords = {Age Factors • Animals • Conditioning, Operant • Disease Models, Animal • Drug-Seeking Behavior • Microglia • Minocycline • Morphine • Narcotics • Nucleus Accumbens • Opioid-Related Disorders • Pyridines • Rats • Rats, Sprague-Dawley • Recurrence • Toll-Like Receptor 4 • drug effects • drug effects* • genetics • immunology • immunology* • metabolism • pharmacology • pharmacology* • physiology}, Abstract = {Adolescence in humans represents a unique developmental time point associated with increased risk-taking behavior and experimentation with drugs of abuse. We hypothesized that exposure to drugs of abuse during adolescence may increase the risk of addiction in adulthood. To test this, rats were treated with a subchronic regimen of morphine or saline in adolescence, and their preference for morphine was examined using conditioned place preference (CPP) and drug-induced reinstatement in adulthood. The initial preference for morphine did not differ between groups; however, rats treated with morphine during adolescence showed robust reinstatement of morphine CPP after drug re-exposure in adulthood. This effect was not seen in rats pretreated with a subchronic regimen of morphine as adults, suggesting that exposure to morphine specifically during adolescence increases the risk of relapse to drug-seeking behavior in adulthood. We have previously established a role for microglia, the immune cells of the brain, and immune molecules in the risk of drug-induced reinstatement of morphine CPP. Thus, we examined the role of microglia within the nucleus accumbens of these rats and determined that rats exposed to morphine during adolescence had a significant increase in Toll-like receptor 4 (TLR4) mRNA and protein expression specifically on microglia. Morphine binds to TLR4 directly, and this increase in TLR4 was associated with exaggerated morphine-induced TLR4 signaling and microglial activation in rats previously exposed to morphine during adolescence. These data suggest that long-term changes in microglial function, caused by adolescent morphine exposure, alter the risk of drug-induced reinstatement in adulthood.}, Language = {eng}, Doi = {10.1523/JNEUROSCI.2516-12.2013}, Key = {fds250824} } @article{fds250796, Author = {Bilbo, SD}, Title = {Frank A. Beach award: programming of neuroendocrine function by early-life experience: a critical role for the immune system.}, Journal = {Hormones and behavior}, Volume = {63}, Number = {5}, Pages = {684-691}, Year = {2013}, Month = {May}, ISSN = {1095-6867}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23474365}, Abstract = {Many neuropsychiatric disorders are associated with a strong dysregulation of the immune system, and several have a striking etiology in development as well. Our recent evidence using a rodent model of neonatal Escherichia coli infection has revealed novel insight into the mechanisms underlying cognitive deficits in adulthood, and suggests that the early-life immune history of an individual may be critical to understanding the relative risk of developing later-life mental health disorders in humans. A single neonatal infection programs the function of immune cells within the brain, called microglia, for the life of the rodent such that an adult immune challenge results in exaggerated cytokine production within the brain and associated cognitive deficits. I describe the important role of the immune system, notably microglia, during brain development, and discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, and cognition.}, Language = {eng}, Doi = {10.1016/j.yhbeh.2013.02.017}, Key = {fds250796} } @article{fds250797, Author = {Williamson, LL and Bilbo, SD}, Title = {Chemokines and the hippocampus: a new perspective on hippocampal plasticity and vulnerability.}, Journal = {Brain, behavior, and immunity}, Volume = {30}, Pages = {186-194}, Year = {2013}, Month = {May}, ISSN = {0889-1591}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23376170}, Keywords = {Animals • Chemokines • Conditioning (Psychology) • Cytokines • Hippocampus • Learning • Memory • Neurogenesis • Neuronal Plasticity • Neurons • metabolism* • physiology • physiology*}, Abstract = {The hippocampus is critical for several aspects of learning and memory and is unique among other cortical regions in structure, function and the potential for plasticity. This remarkable region recapitulates development throughout the lifespan with enduring neurogenesis and well-characterized plasticity. The structure and traits of the hippocampus that distinguish it from other brain regions, however, may be the same reasons that this important brain region is particularly vulnerable to insult and injury. The immune system within the brain responds to insult and injury, and the hippocampus and the immune system are extensively interconnected. Immune signaling molecules, cytokines and chemokines (chemotactic cytokines), are well known for their functions during insult or injury. They are also increasingly implicated in normal hippocampal neurogenesis (e.g., CXCR4 on newborn neurons), cellular plasticity (e.g., interleukin-6 in LTP maintenance), and learning and memory (e.g., interleukin-1β in fear conditioning). We provide evidence from the small but growing literature that neuroimmune interactions and immune signaling molecules, especially chemokines, may be a primary underlying mechanism for the coexistence of plasticity and vulnerability within the hippocampus. We also highlight the evidence that the hippocampus exhibits a remarkable resilience in response to diverse environmental events (e.g., enrichment, exercise), which all may converge onto common neuroimmune mechanisms.}, Language = {eng}, Doi = {10.1016/j.bbi.2013.01.077}, Key = {fds250797} } @article{fds250793, Author = {Bolton, JL and Huff, NC and Smith, SH and Mason, SN and Foster, WM and Auten, RL and Bilbo, SD}, Title = {Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice.}, Journal = {Environmental health perspectives}, Volume = {121}, Number = {9}, Pages = {1075-1082}, Year = {2013}, Month = {September}, ISSN = {1552-9924}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23823752}, Abstract = {<h4>Background</h4>Low socioeconomic status is consistently associated with reduced physical and mental health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting with parental stress have been proposed to explain health disparities in respiratory disease, but the impact of such interactions on mental health is unknown.<h4>Objectives</h4>We aimed to determine whether prenatal air pollution exposure and stress during pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent neurocognitive disorders in adulthood.<h4>Methods</h4>Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with standard housing or nest material restriction (NR; a novel model of maternal stress) during the last third of gestation.<h4>Results</h4>Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and NR) displayed increased anxiety, but only male offspring of this group had impaired cognition. Furthermore, maternal DEP exposure increased proinflammatory interleukin (IL)-1β levels within the brains of adult males but not females, and maternal DEP and NR both decreased anti-inflammatory IL-10 in male, but not female, brains. Similarly, only DEP/NR males showed increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its downstream effector, caspase-1.<h4>Conclusions</h4>These results show that maternal stress during late gestation increases the susceptibility of offspring-particularly males-to the deleterious effects of prenatal air pollutant exposure, which may be due to a synergism of these factors acting on innate immune recognition genes and downstream neuroinflammatory cascades within the developing brain.}, Language = {eng}, Doi = {10.1289/ehp.1306560}, Key = {fds250793} } @article{fds250792, Author = {Lieblein-Boff, JC and McKim, DB and Shea, DT and Wei, P and Deng, Z and Sawicki, C and Quan, N and Bilbo, SD and Bailey, MT and McTigue, DM and Godbout, JP}, Title = {Neonatal E. coli infection causes neuro-behavioral deficits associated with hypomyelination and neuronal sequestration of iron.}, Journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, Volume = {33}, Number = {41}, Pages = {16334-16345}, Year = {2013}, Month = {October}, ISSN = {1529-2401}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24107964}, Abstract = {Recent evidence indicates that inflammatory insults in neonates significantly influenced white matter development and caused behavioral deficits that manifest in young adulthood. The mechanisms underlying these developmental and behavioral complications, however, are not well understood. We hypothesize that acute brain inflammation caused by neonatal infection reduces the bioavailability of iron required for oligodendrocyte maturation and white matter development. Here, we confirm that peripheral Escherichia coli infection in neonates at postnatal day 3 (P3) caused acute brain inflammation that was resolved within 72 h. Nonetheless, transient early life infection (ELI) profoundly influenced behavior, white matter development, and iron homeostasis in the brain. For instance, mice exposed to E. coli as neonates had increased locomotor activity and impaired motor coordination as juveniles (P35) and young adults (P60). In addition, these behavioral deficits were associated with marked hypomyelination and a reduction of oligodendrocytes in subcortical white matter and motor cortex. Moreover, ELI altered transcripts related to cellular sequestration of iron in the brain including hepcidin, ferroportin, and L-ferritin. For example, ELI increased hepcidin mRNA and decreased ferroportin mRNA and protein in the brain at P4, which preceded increased L-ferritin mRNA at P12. Consistent with the mRNA results, L-ferritin protein was robustly increased at P12 specifically in neurons of E. coli infected mice. We interpret these data to indicate that neonatal infection causes significant neuronal sequestration of iron at a time point before myelination. Together, these data indicate a possible role for aberrant neuronal iron storage in neonatal infection-induced disturbances in myelination and behavior.}, Language = {eng}, Doi = {10.1523/jneurosci.0708-13.2013}, Key = {fds250792} } @article{fds250795, Author = {Schwarz, JM and Smith, SH and Bilbo, SD}, Title = {FACS analysis of neuronal-glial interactions in the nucleus accumbens following morphine administration.}, Journal = {Psychopharmacology}, Volume = {230}, Number = {4}, Pages = {525-535}, Year = {2013}, Month = {December}, ISSN = {0033-3158}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23793269}, Abstract = {<h4>Rationale</h4>Glia, including astrocytes and microglia, can profoundly modulate neuronal function and behavior; however, very little is known about the signaling molecules that govern neuronal-glial communication and in turn affect behavior. Morphine treatment activates microglia and astrocytes in the nucleus accumbens (NAcc) to induce the synthesis of cytokines and chemokines, and this has important implications for addictive behavior. Blocking morphine-induced glial activation using the nonspecific glial inhibitor, ibudilast, has no effect on the initial rewarding properties of morphine, but completely prevents the relapse of drug-seeking behavior months later.<h4>Objectives</h4>We sought to determine the cellular source of these cytokines and chemokines in the NAcc in response to morphine, and the cell-type-specific expression pattern of their receptors to determine whether neurons have the capacity to respond to these immune signals directly.<h4>Methods</h4>We used fluorescence-activated cell sorting of neurons (Thy1+), astrocytes (GLT1+), and microglia (CD11b+) from the NAcc for the analysis of cell type specific gene expression following morphine or saline treatment.<h4>Results</h4>The results indicate that microglia and neurons each produce a subset of chemokines in response to morphine and that neurons have the capacity to respond directly to a select group of these chemokines via their receptors. In addition, we provide evidence that microglia are capable of responding directly to dopamine release in the NAcc.<h4>Conclusions</h4>Future studies will examine the mechanism(s) by which neurons respond to these immune signals produced by microglia in an effort to understand their effect on addictive behaviors.}, Language = {eng}, Doi = {10.1007/s00213-013-3180-z}, Key = {fds250795} } @article{fds250788, Author = {Bolton, JL and Auten, RL and Bilbo, SD}, Title = {Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring}, Journal = {Brain, Behavior, and Immunity}, Volume = {37}, Pages = {30-44}, Year = {2014}, ISSN = {0889-1591}, url = {http://dx.doi.org/10.1016/j.bbi.2013.10.029}, Keywords = {Adipose tissue • Anxiety • Diesel exhaust particles • Fetal programming • High-fat diet • Hippocampus • Hypothalamus • Insulin resistance • Macrophages • Microglia}, Abstract = {HASH(0xcfc2fa8)}, Language = {ENG}, Doi = {10.1016/j.bbi.2013.10.029}, Key = {fds250788} } @article{fds250786, Author = {Bilbo, SD and Williamson, LL and Parker, W}, Title = {Early-Life Programming of Neuroendocrine Function by the Immune System: Plasticity or Autoimmunity due to Biome Depletion?}, Journal = {INTEGRATIVE AND COMPARATIVE BIOLOGY}, Volume = {54}, Pages = {E19-E19}, Publisher = {OXFORD UNIV PRESS INC}, Year = {2014}, Month = {January}, ISSN = {1540-7063}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000333049500074&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Key = {fds250786} } @article{fds250785, Author = {Bolton, JL and Smith, SH and Huff, NC and Ian Gilmour and M and Michael Foster, W and Auten, RL and Bilbo, SD}, Title = {Erratum: Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner (FASEB Journal (2012) 26 (4743-4754) DOI:10.1096/fj.12-210989)}, Journal = {FASEB Journal}, Volume = {28}, Number = {6}, Pages = {2737-2738}, Year = {2014}, Month = {January}, ISSN = {0892-6638}, url = {http://dx.doi.org/10.1096/fj.12-210989ERR}, Doi = {10.1096/fj.12-210989ERR}, Key = {fds250785} } @article{fds250791, Author = {Bolton, JL and Auten, RL and Bilbo, SD}, Title = {Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring.}, Journal = {Brain, behavior, and immunity}, Volume = {37}, Pages = {30-44}, Year = {2014}, Month = {March}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24184474}, Abstract = {Environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood. Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle (VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet (LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEH-exposed dams, whereas female offspring did not differ according to prenatal treatment. Furthermore, HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes, but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus, whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second experiment, DEP male offspring mounted an exaggerated peripheral IL-1β response to an LPS challenge at postnatal day (P)30, whereas their central IL-1β response did not differ from VEH male offspring, which is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution exposure "programs" offspring for increased susceptibility to diet-induced metabolic, behavioral, and neuroinflammatory changes in adulthood in a sexually dimorphic manner.}, Doi = {10.1016/j.bbi.2013.10.029}, Key = {fds250791} } @article{fds250789, Author = {Williamson, LL and Bilbo, SD}, Title = {Neonatal infection modulates behavioral flexibility and hippocampal activation on a Morris Water Maze task.}, Journal = {Physiology & behavior}, Volume = {129}, Pages = {152-159}, Year = {2014}, Month = {April}, ISSN = {0031-9384}, url = {http://dx.doi.org/10.1016/j.physbeh.2014.02.033}, Abstract = {Neonatal infection has enduring effects on the brain, both at the cellular and behavioral levels. We determined the effects of peripheral infection with Escherichia coli at postnatal day (P) 4 in rats on a water maze task in adulthood, and assessed neuronal activation in the dentate gyrus (DG) following the memory test. Rats were trained and tested on one of 3 distinct water maze task paradigms: 1) minimal training (18 trials/3days), 2) extended training (50 trials/10days) or 3) reversal training (extended training followed by 30 trials/3days with a new platform location). Following a 48h memory test, brains were harvested to assess neuronal activation using activity-regulated cytoskeleton-associated (Arc) protein in the DG. Following minimal training, rats treated neonatally with E. coli had improved performance and paradoxically reduced Arc expression during the memory test compared to control rats treated with PBS early in life. However, neonatally-infected rats did not differ from control rats in behavior or neuronal activation during the memory test following extended training. Furthermore, rats treated neonatally with E. coli were significantly impaired during the 48h memory test for a reversal platform location, unlike controls. Specifically, whereas neonatally-infected rats were able to acquire the new location at the same rate as controls, they spent significantly less time in the target quadrant for the reversal platform during a memory test. However, neonatally-infected and control rats had similar levels of Arc expression following the 48h memory test for reversal. Together, these data indicate that neonatal infection may improve the rate of acquisition on hippocampal-dependent tasks while impairing flexibility on the same tasks; in addition, network activation in the DG during learning may be predictive of future cognitive flexibility on a hippocampal-dependent task.}, Doi = {10.1016/j.physbeh.2014.02.033}, Key = {fds250789} } @article{fds250784, Author = {Bolton, JL and Bilbo, SD}, Title = {Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms.}, Journal = {Dialogues in clinical neuroscience}, Volume = {16}, Number = {3}, Pages = {307-320}, Year = {2014}, Month = {September}, ISSN = {1294-8322}, Abstract = {Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may "program" offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.}, Key = {fds250784} } @article{fds250782, Author = {McKenney, EA and Williamson, L and Yoder, AD and Rawls, JF and Bilbo, SD and Parker, W}, Title = {Alteration of the rat cecal microbiome during colonization with the helminth Hymenolepis diminuta.}, Journal = {Gut Microbes}, Volume = {6}, Number = {3}, Pages = {182-193}, Year = {2015}, ISSN = {1949-0976}, url = {http://dx.doi.org/10.1080/19490976.2015.1047128}, Abstract = {The microbiome is now widely recognized as being important in health and disease, and makes up a substantial subset of the biome within the ecosystem of the vertebrate body. At the same time, multicellular, eukaryotic organisms such as helminths are being recognized as an important component of the biome that shaped the evolution of our genes. The absence of these macroscopic organisms during the early development and life of humans in Western culture probably leads to a wide range of human immunological diseases. However, the interaction between the microbiome and macroscopic components of the biome remains poorly characterized. In this study, the microbiome of the cecum in rats colonized for 2 generations with the small intestinal helminth Hymenolepis diminuta was evaluated. The introduction of this benign helminth, which is of considerable therapeutic interest, led to several changes in the cecal microbiome. Most of the changes were within the Firmicutes phylum, involved about 20% of the total bacteria, and generally entailed a shift from Bacilli to Clostridia species in the presence of the helminth. The results point toward ecological relationships between various components of the biome, with the observed shifts in the microbiome suggesting potential mechanisms by which this helminth might exert therapeutic effects.}, Doi = {10.1080/19490976.2015.1047128}, Key = {fds250782} } @article{fds250783, Author = {Bilbo, SD and Nevison, CD and Parker, W}, Title = {A model for the induction of autism in the ecosystem of the human body: the anatomy of a modern pandemic?}, Journal = {Microb Ecol Health Dis}, Volume = {26}, Pages = {26253}, Year = {2015}, ISSN = {0891-060X}, url = {http://dx.doi.org/10.3402/mehd.v26.26253}, Abstract = {BACKGROUND: The field of autism research is currently divided based on a fundamental question regarding the nature of autism: Some are convinced that autism is a pandemic of modern culture, with environmental factors at the roots. Others are convinced that the disease is not pandemic in nature, but rather that it has been with humanity for millennia, with its biological and neurological underpinnings just now being understood. OBJECTIVE: In this review, two lines of reasoning are examined which suggest that autism is indeed a pandemic of modern culture. First, given the widely appreciated derailment of immune function by modern culture, evidence that autism is strongly associated with aberrant immune function is examined. Second, evidence is reviewed indicating that autism is associated with 'triggers' that are, for the most part, a construct of modern culture. In light of this reasoning, current epidemiological evidence regarding the incidence of autism, including the role of changing awareness and diagnostic criteria, is examined. Finally, the potential role of the microbial flora (the microbiome) in the pathogenesis of autism is discussed, with the view that the microbial flora is a subset of the life associated with the human body, and that the entire human biome, including both the microbial flora and the fauna, has been radically destabilized by modern culture. CONCLUSIONS: It is suggested that the unequivocal way to resolve the debate regarding the pandemic nature of autism is to perform an experiment: monitor the prevalence of autism after normalizing immune function in a Western population using readily available approaches that address the well-known factors underlying the immune dysfunction in that population.}, Doi = {10.3402/mehd.v26.26253}, Key = {fds250783} } @article{fds321833, Author = {Posillico, CK and Terasaki, LS and Bilbo, SD and Schwarz, JM}, Title = {Examination of sex and minocycline treatment on acute morphine-induced analgesia and inflammatory gene expression along the pain pathway in Sprague-Dawley rats.}, Journal = {Biology of sex differences}, Volume = {6}, Pages = {33}, Year = {2015}, Month = {January}, url = {http://dx.doi.org/10.1186/s13293-015-0049-3}, Abstract = {<h4>Background</h4>In addition to its classical effects on opioid receptors, morphine can activate glia and stimulate the production of pro-inflammatory immune molecules which in turn counteract the analgesic properties of morphine. We hypothesized that decreased morphine analgesia in females may be the result of exaggerated microglial activation in brain regions critical for analgesia.<h4>Methods</h4>Male and female rats were treated with morphine and/or minocycline and morphine analgesia was examined using the hot plate. We also examined the expression of microglial and astrocyte markers in the pain pathway.<h4>Results</h4>Males treated with minocycline, a microglial inhibitor, exhibited a significant increase in acute morphine analgesia as previously shown; however, morphine analgesia was not affected by minocycline pretreatment in female rats. Minocycline decreased the expression of glial activation markers in the male spinal cord and periaqueductal gray as expected; however, these same molecules were upregulated in the female.<h4>Conclusions</h4>These data describe a significant difference between males and females in the behavioral effects following co-administration of morphine and minocycline.}, Doi = {10.1186/s13293-015-0049-3}, Key = {fds321833} } @article{fds250781, Author = {Williamson, LL and McKenney, EA and Holzknecht, ZE and Belliveau, C and Rawls, JF and Poulton, S and Parker, W and Bilbo, SD}, Title = {Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection.}, Journal = {Brain Behav Immun}, Volume = {51}, Pages = {14-28}, Year = {2016}, Month = {January}, ISSN = {0889-1591}, url = {http://dx.doi.org/10.1016/j.bbi.2015.07.006}, Abstract = {The incidence of autoimmune and inflammatory diseases has risen dramatically in post-industrial societies. "Biome depletion" - loss of commensal microbial and multicellular organisms such as helminths (intestinal worms) that profoundly modulate the immune system - may contribute to these increases. Hyperimmune-associated disorders also affect the brain, especially neurodevelopment, and increasing evidence links early-life infection to cognitive and neurodevelopmental disorders. We have demonstrated previously that rats infected with bacteria as newborns display life-long vulnerabilities to cognitive dysfunction, a vulnerability that is specifically linked to long-term hypersensitivity of microglial cell function, the resident immune cells of the brain. Here, we demonstrate that helminth colonization of pregnant dams attenuated the exaggerated brain cytokine response of their offspring to bacterial infection, and that combined with post-weaning colonization of offspring with helminths (consistent with their mothers treatment) completely prevented enduring microglial sensitization and cognitive dysfunction in adulthood. Importantly, helminths had no overt impact on adaptive immune cell subsets, whereas exaggerated innate inflammatory responses in splenic macrophages were prevented. Finally, helminths altered the effect of neonatal infection on the gut microbiome; neonatal infection with Escherichia coli caused a shift from genera within the Actinobacteria and Tenericutes phyla to genera in the Bacteroidetes phylum in rats not colonized with helminths, but helminths attenuated this effect. In sum, these data point toward an inter-relatedness of various components of the biome, and suggest potential mechanisms by which this helminth might exert therapeutic benefits in the treatment of neuroinflammatory and cognitive disorders.}, Doi = {10.1016/j.bbi.2015.07.006}, Key = {fds250781} } @article{fds321832, Author = {Kraft, AD and Aschner, M and Cory-Slechta, DA and Bilbo, SD and Caudle, WM and Makris, SL}, Title = {Unmasking silent neurotoxicity following developmental exposure to environmental toxicants.}, Journal = {Neurotoxicology and teratology}, Volume = {55}, Pages = {38-44}, Year = {2016}, Month = {May}, url = {http://dx.doi.org/10.1016/j.ntt.2016.03.005}, Abstract = {Silent neurotoxicity, a term introduced approximately 25years ago, is defined as a persistent change to the nervous system that does not manifest as overt evidence of toxicity (i.e. it remains clinically unapparent) unless unmasked by experimental or natural processes. Silent neurotoxicants can be challenging for risk assessors, as the multifactorial experiments needed to reveal their effects are seldom conducted, and they are not addressed by current study design guidelines. This topic was the focus of a symposium addressing the interpretation and use of silent neurotoxicity data in human health risk assessments of environmental toxicants at the annual meeting of the Developmental Neurotoxicology Society (previously the Neurobehavioral Teratology Society) on June 30th, 2014. Several factors important to the design and interpretation of studies assessing the potential for silent neurotoxicity were discussed by the panelists and audience members. Silent neurotoxicity was demonstrated to be highly specific to the characteristics of the animals being examined, the unmasking agent tested, and the behavioral endpoint(s) evaluated. Overall, the experimental examples presented highlighted a need to consider common adverse outcomes and common biological targets for chemical and non-chemical stressors, particularly when the exposure and stressors are known to co-occur. Risk assessors could improve the evaluation of silent neurotoxicants in assessments through specific steps from researchers, including experiments to reveal the molecular targets and mechanisms that may result in specific types of silent neurotoxicity, and experiments with complex challenges reminiscent of the human situation.}, Doi = {10.1016/j.ntt.2016.03.005}, Key = {fds321832} } @article{fds290504, Author = {Hanamsagar, R and Bilbo, SD}, Title = {Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development.}, Journal = {The Journal of steroid biochemistry and molecular biology}, Volume = {160}, Pages = {127-133}, Year = {2016}, Month = {June}, ISSN = {0960-0760}, url = {http://dx.doi.org/10.1016/j.jsbmb.2015.09.039}, Abstract = {Several neurological conditions are associated with sex differences in prevalence or outcome. For example, autism predominantly affects boys, depression is more common in women, Parkinson's disease more common in men, and multiple sclerosis in women. In the case of stroke, women have a less favorable outcome and suffer from a more precipitous drop in health status compared to men. As a result, treatment of such diseases is difficult and yields variable results. Despite this, sex is rarely considered when making treatment decisions. The mechanisms underlying sex differences in disease progression are not well understood, however a strong link exists between different inflammation states of men and women and their propensity to develop certain diseases. As neuroinflammation is an important component of pathophysiology in many neurological conditions, it can be speculated that any changes in the state of inflammation in the brain during normal development can potentially lead to an increase in susceptibility to neurological and neurodegenerative diseases. Microglia play a crucial role in onset and modulation of inflammation and thus sex differences in microglial function could explain, at least in part, differences observed in susceptibilities and outcomes of neurological disorders in men and women. Understanding the mechanisms behind sex differences could help develop more targeted therapy with higher success rate, especially in diseases where sex differences are most prominent.}, Doi = {10.1016/j.jsbmb.2015.09.039}, Key = {fds290504} } @article{fds321831, Author = {Lacagnina, MJ and Rivera, PD and Bilbo, SD}, Title = {Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {42}, Number = {1}, Pages = {156-177}, Year = {2017}, Month = {January}, url = {http://dx.doi.org/10.1038/npp.2016.121}, Abstract = {Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.}, Doi = {10.1038/npp.2016.121}, Key = {fds321831} } @article{fds326607, Author = {Bolton, JL and Marinero, S and Hassanzadeh, T and Natesan, D and Le, D and Belliveau, C and Mason, SN and Auten, RL and Bilbo, SD}, Title = {Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner.}, Journal = {Frontiers in synaptic neuroscience}, Volume = {9}, Number = {MAY}, Pages = {10}, Year = {2017}, Month = {January}, url = {http://dx.doi.org/10.3389/fnsyn.2017.00010}, Abstract = {Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia <i>in vitro</i> and <i>in vivo</i> in adult rodents. We have demonstrated that <i>prenatal</i> exposure to DEP in mice, i.e., to the pregnant dams throughout gestation, results in a persistent vulnerability to behavioral deficits in adult offspring, especially in males, which is intriguing given the greater incidence of ASD in males to females (∼4:1). Moreover, there is a striking upregulation of toll-like receptor (TLR) 4 gene expression within the brains of the same mice, and this expression is primarily in microglia. Here we explored the impact of gestational exposure to DEP or vehicle on microglial morphology in the developing brains of male and female mice. DEP exposure increased inflammatory cytokine protein and altered the morphology of microglia, consistent with activation or a delay in maturation, only within the embryonic brains of male mice; and these effects were dependent on TLR4. DEP exposure also increased cortical volume at embryonic day (E)18, which switched to decreased volume by post-natal day (P)30 in males, suggesting an impact on the developing neural stem cell niche. Consistent with this hypothesis, we found increased microglial-neuronal interactions in male offspring that received DEP compared to all other groups. Taken together, these data suggest a mechanism by which prenatal exposure to environmental toxins may affect microglial development and long-term function, and thereby contribute to the risk of neurodevelopmental disorders.}, Doi = {10.3389/fnsyn.2017.00010}, Key = {fds326607} } @article{fds325332, Author = {Kopec, AM and Rivera, PD and Lacagnina, MJ and Hanamsagar, R and Bilbo, SD}, Title = {Optimized solubilization of TRIzol-precipitated protein permits Western blotting analysis to maximize data available from brain tissue.}, Journal = {Journal of neuroscience methods}, Volume = {280}, Pages = {64-76}, Year = {2017}, Month = {March}, url = {http://dx.doi.org/10.1016/j.jneumeth.2017.02.002}, Abstract = {<h4>Background</h4>Techniques simultaneously assessing multiple levels of molecular processing are appealing because molecular signaling underlying complex neural phenomena occurs at complementary levels. The TRIzol method isolates RNA and DNA, but protein retrieval is difficult due to inefficient solubilization of precipitated protein pellets.<h4>New method</h4>We optimized a buffer for the efficient solubilization of protein from TRIzol-precipitated brain tissue for Western blotting analysis, which was also more effective at directly homogenizing brain tissue than RIPA buffer.<h4>Results</h4>Protein yield during solubilization, in addition to protein yield via direct homogenization, is increased by optimizing concentrations of chemicals in a standard lysis buffer. Effective incubation parameters for both total protein yield and the analysis of post-translational modifications is remarkably flexible. Importantly, different neural cell types and protein classes are represented in solubilized protein samples. Moreover, we used dissociated mouse brain tissue to isolate microglia from other cell types and successfully resolved cell type-specific proteins from these small and difficult to attain samples.<h4>Comparison with existing method(s)</h4>Solubilization buffers to date have been comprised primarily of SDS or urea; the data herein demonstrate that components common to lysis buffers can also enhance protein solubilization both after direct homogenization and after precipitation.<h4>Conclusions</h4>This method is suitable for assessing gene and protein expression from a single brain sample, allowing for a more comprehensive evaluation of neural phenomena while minimizing the number of subjects.}, Doi = {10.1016/j.jneumeth.2017.02.002}, Key = {fds325332} } @article{fds326354, Author = {Parker, W and Hornik, CD and Bilbo, S and Holzknecht, ZE and Gentry, L and Rao, R and Lin, SS and Herbert, MR and Nevison, CD}, Title = {The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism.}, Journal = {J Int Med Res}, Volume = {45}, Number = {2}, Pages = {407-438}, Year = {2017}, Month = {April}, url = {http://dx.doi.org/10.1177/0300060517693423}, Abstract = {The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.}, Doi = {10.1177/0300060517693423}, Key = {fds326354} } @article{fds326608, Author = {Bilbo, SD}, Title = {Sex differences in microglial appetites during development: Inferences and implications.}, Journal = {Brain, behavior, and immunity}, Volume = {64}, Pages = {9-10}, Year = {2017}, Month = {August}, url = {http://dx.doi.org/10.1016/j.bbi.2017.05.010}, Doi = {10.1016/j.bbi.2017.05.010}, Key = {fds326608} } @article{fds366413, Author = {McCullough, LE and Miller, EE and Calderwood, LE and Shivappa, N and Steck, SE and Forman, MR and A Mendez and M and Maguire, R and Fuemmeler, BF and Kollins, SH and D Bilbo and S and Huang, Z and Murtha, AP and Murphy, SK and Hébert, JR and Hoyo, C}, Title = {Maternal inflammatory diet and adverse pregnancy outcomes: Circulating cytokines and genomic imprinting as potential regulators?}, Journal = {Epigenetics}, Volume = {12}, Number = {8}, Pages = {688-697}, Year = {2017}, Month = {August}, url = {http://dx.doi.org/10.1080/15592294.2017.1347241}, Abstract = {Excessive inflammation during pregnancy alters homeostatic mechanisms of the developing fetus and has been linked to adverse pregnancy outcomes. An anti-inflammatory diet could be a promising avenue to combat the pro-inflammatory state of pregnancy, particularly in obese women, but we lack mechanistic data linking this dietary pattern during pregnancy to inflammation and birth outcomes. In an ethnically diverse cohort of 1057 mother-child pairs, we estimated the relationships between dietary inflammatory potential [measured via the energy-adjusted dietary inflammatory index (E-DII™)] and birth outcomes overall, as well as by offspring sex and maternal pre-pregnancy body mass index (BMI). In a subset of women, we also explored associations between E-DII, circulating cytokines (n = 105), and offspring methylation (n = 338) as potential modulators of these relationships using linear regression. Adjusted regression models revealed that women with pro-inflammatory diets had elevated rates of preterm birth among female offspring [β = -0.22, standard error (SE) = 0.07, P<0.01], but not male offspring (β=0.09, SE = 0.06, P<0.12) (Pinteraction = 0.003). Similarly, we observed pro-inflammatory diets were associated with higher rates of caesarean delivery among obese women (β = 0.17, SE = 0.08, P = 0.03), but not among women with BMI <25 kg/m2 (Pinteraction = 0.02). We observed consistent inverse associations between maternal inflammatory cytokine concentrations (IL-12, IL-17, IL-4, IL-6, and TNFα) and lower methylation at the MEG3 regulatory sequence (P<0.05); however, results did not support the link between maternal E-DII and circulating cytokines. We replicate work by others on the association between maternal inflammatory diet and adverse pregnancy outcomes and provide the first empirical evidence supporting the inverse association between circulating cytokine concentrations and offspring methylation.}, Doi = {10.1080/15592294.2017.1347241}, Key = {fds366413} } @article{fds339557, Author = {Hanamsagar, R and Alter, MD and Block, CS and Sullivan, H and Bolton, JL and Bilbo, SD}, Title = {Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.}, Journal = {Glia}, Volume = {65}, Number = {9}, Pages = {1504-1520}, Year = {2017}, Month = {September}, url = {http://dx.doi.org/10.1002/glia.23176}, Abstract = {Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e., when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer's and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer's Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments.}, Doi = {10.1002/glia.23176}, Key = {fds339557} } @article{fds366411, Author = {Lacagnina, MJ and Kopec, AM and Cox, SS and Hanamsagar, R and Wells, C and Slade, S and Grace, PM and Watkins, LR and Levin, ED and Bilbo, SD}, Title = {Opioid Self-Administration is Attenuated by Early-Life Experience and Gene Therapy for Anti-Inflammatory IL-10 in the Nucleus Accumbens of Male Rats.}, Journal = {Neuropsychopharmacology}, Volume = {42}, Number = {11}, Pages = {2128-2140}, Year = {2017}, Month = {October}, url = {http://dx.doi.org/10.1038/npp.2017.82}, Abstract = {Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement.}, Doi = {10.1038/npp.2017.82}, Key = {fds366411} } @article{fds366412, Author = {Bolton, JL and Wiley, MG and Ryan, B and Truong, S and Strait, M and Baker, DC and Yang, NY and Ilkayeva, O and O'Connell, TM and Wroth, SW and Sánchez, CL and Swamy, G and Newgard, C and Kuhn, C and Bilbo, SD and Simmons, LA}, Title = {Perinatal western-type diet and associated gestational weight gain alter postpartum maternal mood.}, Journal = {Brain Behav}, Volume = {7}, Number = {10}, Pages = {e00828}, Year = {2017}, Month = {October}, url = {http://dx.doi.org/10.1002/brb3.828}, Abstract = {INTRODUCTION: The role of perinatal diet in postpartum maternal mood disorders, including depression and anxiety, remains unclear. We investigated whether perinatal consumption of a Western-type diet (high in fat and branched-chain amino acids [BCAA]) and associated gestational weight gain (GWG) cause serotonin dysregulation in the central nervous system (CNS), resulting in postpartum depression and anxiety (PPD/A). METHODS: Mouse dams were fed one of four diets (high-fat/high BCAA, low-fat/high BCAA, high-fat, and low-fat) prior to mating and throughout gestation and lactation. Postpartum behavioral assessments were conducted, and plasma and brain tissues assayed. To evaluate potential clinical utility, we conducted preliminary human studies using data from an extant sample of 17 primiparous women with high GWG, comparing across self-reported postpartum mood symptoms using the Edinburgh Postnatal Depression Scale (EPDS) for percent GWG and plasma amino acid levels. RESULTS: Mouse dams fed the high-fat/high BCAA diet gained more weight per kcal consumed, and BCAA-supplemented dams lost weight more slowly postpartum. Dams on BCAA-supplemented diets exhibited increased PPD/A-like behavior, decreased dopaminergic function, and decreased plasma tyrosine and histidine levels when assessed on postnatal day (P)8. Preliminary human data showed that GWG accounted for 29% of the variance in EPDS scores. Histidine was also lower in women with higher EPDS scores. CONCLUSIONS: These findings highlight the role of perinatal diet and excess GWG in the development of postpartum mood disorders.}, Doi = {10.1002/brb3.828}, Key = {fds366412} } @article{fds339556, Author = {Hanamsagar, R and Bilbo, SD}, Title = {Environment matters: microglia function and dysfunction in a changing world.}, Journal = {Current opinion in neurobiology}, Volume = {47}, Pages = {146-155}, Year = {2017}, Month = {December}, url = {http://dx.doi.org/10.1016/j.conb.2017.10.007}, Abstract = {The immune system is our interface with the environment, and immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy or the early postnatal period, for example, in response to infection, may disrupt the normal developmental trajectory of microglia and consequently their interactions with neurons, thereby contributing to the risk for neurological disorders. The current article outlines recent findings on the impact of diverse, pervasive environmental challenges, beyond infection, including air pollution and maternal stress; and their impact on microglial development and its broad implications for neural pathologies.}, Doi = {10.1016/j.conb.2017.10.007}, Key = {fds339556} } @article{fds339555, Author = {Bilbo, SD and Block, CL and Bolton, JL and Hanamsagar, R and Tran, PK}, Title = {Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.}, Journal = {Experimental neurology}, Volume = {299}, Number = {Pt A}, Pages = {241-251}, Year = {2018}, Month = {January}, url = {http://dx.doi.org/10.1016/j.expneurol.2017.07.002}, Abstract = {Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD.}, Doi = {10.1016/j.expneurol.2017.07.002}, Key = {fds339555} } @article{fds342607, Author = {Hanamsagar, R and Alter, MD and Block, CS and Sullivan, H and Bolton, JL and Bilbo, SD}, Title = {Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.}, Journal = {Glia}, Volume = {66}, Number = {2}, Pages = {460}, Year = {2018}, Month = {February}, url = {http://dx.doi.org/10.1002/glia.23277}, Doi = {10.1002/glia.23277}, Key = {fds342607} } @article{fds339722, Author = {Bilbo, SD}, Title = {Sex Differences Shape Brain Development and Function, in Health and Disease: Policy Implications}, Journal = {Policy Insights from the Behavioral and Brain Sciences}, Volume = {5}, Number = {1}, Pages = {104-109}, Publisher = {SAGE Publications}, Year = {2018}, Month = {March}, url = {http://dx.doi.org/10.1177/2372732217742673}, Abstract = {Sex differences profoundly impact health and disease. Despite this, the inclusion of females in clinical and fundamental research lags far behind advances in other aspects of medicine, especially in the brain sciences. Regardless of whether neuroscientists are intrinsically interested in sex differences per se, observing a sex disparity in the incidence or presentation of a given neurological disorder provides a significant clue into the neurobiology of that disorder. Autism spectrum disorder (ASD) is one of the most sex-biased disorders, with a 4:1 male-to-female ratio, an important aspect of its etiology and biology that has largely been ignored in the preclinical literature. This article briefly overviews what is known about the sexual differentiation of the developing healthy brain, with a focus on the preclinical literature. This places observed sex differences in neurological disorders such as ASD into the context of known sex differences in neurobiology—along with insight from known sex-specific mechanisms in other systems that impact the brain (e.g., immune system, microbiome). Finally, the article provides recommendations for progress forward.}, Doi = {10.1177/2372732217742673}, Key = {fds339722} } @article{fds366410, Author = {Dozmorov, MG and Bilbo, SD and Kollins, SH and Zucker, N and Do, EK and Schechter, JC and Zhang, JJ and Murphy, SK and Hoyo, C and Fuemmeler, BF}, Title = {Associations between maternal cytokine levels during gestation and measures of child cognitive abilities and executive functioning.}, Journal = {Brain Behav Immun}, Volume = {70}, Pages = {390-397}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1016/j.bbi.2018.03.029}, Abstract = {Preclinical studies demonstrate that environmentally-induced alterations in inflammatory cytokines generated by the maternal and fetal immune system can significantly impact fetal brain development. Yet, the relationship between maternal cytokines during gestation and later cognitive ability and executive function remains understudied. Children (n = 246) were born of mothers enrolled in the Newborn Epigenetic Study - a prospective pre-birth cohort in the Southeastern US. We characterized seven cytokines [IL-1β, IL-4,IL-6, IL-12p70, IL-17A, tumor necrosis factor-α (TNFα), and interferon-γ (IFNγ)] and one chemokine (IL-8) from maternal plasma collected during pregnancy. We assessed children's cognitive abilities and executive functioning at a mean age of 4.5 (SD = 1.1) years. Children's DAS-II and NIH toolbox scores were regressed on cytokines and the chemokine, controlling for maternal age, race, education, body mass index, IQ, parity, smoking status, delivery type, gestational weeks, and child birth weight and sex. Higher IL-12p70 (βIL-12p70 = 4.26, p = 0.023) and IL-17A (βIL-17A = 3.70, p = 0.042) levels were related to higher DAS-II GCA score, whereas higher IL-1β (βIL-1B = -6.07, p = 0.003) was related to lower GCA score. Higher IL-12p70 was related to higher performance on NIH toolbox measures of executive functions related to inhibitory control and attention (βIL-12p70 = 5.20, p = 0.046) and cognitive flexibility (βIL-12p70 = 5.10, p = 0.047). Results suggest that dysregulation in gestational immune activity are associated with child cognitive ability and executive functioning.}, Doi = {10.1016/j.bbi.2018.03.029}, Key = {fds366410} } @article{fds339553, Author = {Bilbo, SD}, Title = {The diverse culinary habits of microglia.}, Journal = {Nature neuroscience}, Volume = {21}, Number = {8}, Pages = {1023-1025}, Year = {2018}, Month = {August}, url = {http://dx.doi.org/10.1038/s41593-018-0196-z}, Doi = {10.1038/s41593-018-0196-z}, Key = {fds339553} } @article{fds339554, Author = {Kopec, AM and Fiorentino, MR and Bilbo, SD}, Title = {Gut-immune-brain dysfunction in Autism: Importance of sex.}, Journal = {Brain research}, Volume = {1693}, Number = {Pt B}, Pages = {214-217}, Year = {2018}, Month = {August}, url = {http://dx.doi.org/10.1016/j.brainres.2018.01.009}, Abstract = {Autism Spectrum Disorder (ASD) is characterized by social behavior deficits, stereotypies, cognitive rigidity, and in some cases severe intellectual impairment and developmental delay. Although ASD is most widely identified by its neurological deficits, gastrointestinal issues are common in ASD. An intimate and complex relationship exists between the gut, the immune system, and the brain, leading to the hypothesis that ASD may be a systems-level disease affecting the gut and immune systems, in addition to the brain. Despite significant advances in understanding the contribution of the gut and immune systems to the etiology of ASD, there is an intriguing commonality among patients that is not well understood: they are predominantly male. Virtually no attention has been given to the potential role of sex-specific regulation of gut, peripheral, and central immune function in ASD, despite the 4:1 male-to-female bias in this disorder. In this review, we discuss recent revelations regarding the impact of gut-immune-brain relationships on social behavior in rodent models and in ASD patients, placing them in the context of known or putative sex specific mechanisms.}, Doi = {10.1016/j.brainres.2018.01.009}, Key = {fds339554} } @article{fds339551, Author = {Kopec, AM and Smith, CJ and Ayre, NR and Sweat, SC and Bilbo, SD}, Title = {Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats.}, Journal = {Nature communications}, Volume = {9}, Number = {1}, Pages = {3769}, Year = {2018}, Month = {September}, url = {http://dx.doi.org/10.1038/s41467-018-06118-z}, Abstract = {Adolescence is a developmental period in which the mesolimbic dopaminergic "reward" circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity. Dopamine D1 receptors (D1rs) in the NAc are critical for social behavior, but how these receptors are regulated during adolescence is not well understood. In this report, we demonstrate that microglia and complement-mediated phagocytic activity shapes NAc development by eliminating D1rs in male, but not female rats, during adolescence. Moreover, immune-mediated elimination of D1rs is required for natural developmental changes in male social play behavior. These data demonstrate for the first time that microglia and complement-mediated immune signaling (i) participate in adolescent brain development in a sex-specific manner, and (ii) are causally implicated in developmental changes in behavior. These data have broad implications for understanding the adolescent critical period of development, the molecular mechanisms underlying social behavior, and sex differences in brain structure and function.}, Doi = {10.1038/s41467-018-06118-z}, Key = {fds339551} } @article{fds339552, Author = {Kentner, AC and Bilbo, SD and Brown, AS and Hsiao, EY and McAllister, AK and Meyer, U and Pearce, BD and Pletnikov, MV and Yolken, RH and Bauman, MD}, Title = {Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {44}, Number = {2}, Pages = {245-258}, Year = {2019}, Month = {January}, url = {http://dx.doi.org/10.1038/s41386-018-0185-7}, Abstract = {The 2017 American College of Neuropychopharmacology (ACNP) conference hosted a Study Group on 4 December 2017, Establishing best practice guidelines to improve the rigor, reproducibility, and transparency of the maternal immune activation (MIA) animal model of neurodevelopmental abnormalities. The goals of this session were to (a) evaluate the current literature and establish a consensus on best practices to be implemented in MIA studies, (b) identify remaining research gaps warranting additional data collection and lend to the development of evidence-based best practice design, and (c) inform the MIA research community of these findings. During this session, there was a detailed discussion on the importance of validating immunogen doses and standardizing the general design (e.g., species, immunogenic compound used, housing) of our MIA models both within and across laboratories. The consensus of the study group was that data does not currently exist to support specific evidence-based model selection or methodological recommendations due to lack of consistency in reporting, and that this issue extends to other inflammatory models of neurodevelopmental abnormalities. This launched a call to establish a reporting checklist focusing on validation, implementation, and transparency modeled on the ARRIVE Guidelines and CONSORT (scientific reporting guidelines for animal and clinical research, respectively). Here we provide a summary of the discussions in addition to a suggested checklist of reporting guidelines needed to improve the rigor and reproducibility of this valuable translational model, which can be adapted and applied to other animal models as well.}, Doi = {10.1038/s41386-018-0185-7}, Key = {fds339552} } @article{fds341510, Author = {Liu, X and Nemeth, DP and McKim, DB and Zhu, L and DiSabato, DJ and Berdysz, O and Gorantla, G and Oliver, B and Witcher, KG and Wang, Y and Negray, CE and Vegesna, RS and Sheridan, JF and Godbout, JP and Robson, MJ and Blakely, RD and Popovich, PG and Bilbo, SD and Quan, N}, Title = {Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities.}, Journal = {Immunity}, Volume = {50}, Number = {2}, Pages = {317-333.e6}, Year = {2019}, Month = {February}, url = {http://dx.doi.org/10.1016/j.immuni.2018.12.012}, Abstract = {Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain's IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.}, Doi = {10.1016/j.immuni.2018.12.012}, Key = {fds341510} } @article{fds339917, Author = {Rivera, PD and Hanamsagar, R and Kan, MJ and Tran, PK and Stewart, D and Jo, YC and Gunn, M and Bilbo, SD}, Title = {Removal of microglial-specific MyD88 signaling alters dentate gyrus doublecortin and enhances opioid addiction-like behaviors.}, Journal = {Brain Behav Immun}, Volume = {76}, Pages = {104-115}, Year = {2019}, Month = {February}, url = {http://dx.doi.org/10.1016/j.bbi.2018.11.010}, Abstract = {Drugs of abuse promote a potent immune response in central nervous system (CNS) via the activation of microglia and astrocytes. However, the molecular mechanisms underlying microglial activation during addiction are not well known. We developed and functionally characterized a novel transgenic mouse (Cx3cr1-CreBTtg/0:MyD88f/f [Cretg/0]) wherein the immune signaling adaptor gene, MyD88, was specifically deleted in microglia. To test the downstream effects of loss of microglia-specific MyD88 signaling in morphine addiction, Cretg/0 and Cre0/0 mice were tested for reward learning, extinction, and reinstatement using a conditioned place preference (CPP) paradigm. There were no differences in drug acquisition, but Cretg/0 mice had prolonged extinction and enhanced reinstatement compared to Cre0/0 controls. Furthermore, morphine-treated Cretg/0 mice showed increased doublecortin (DCX) signal relative to Cre0/0 control mice in the hippocampus, indicative of increased number of immature neurons. Additionally, there was an increase in colocalization of microglial lysosomal marker CD68 with DCX+cells in morphine-treated Cretg/0 mice but not in Cre0/0 or drug-naїve mice, suggesting a specific role for microglial MyD88 signaling in neuronal phagocytosis in the hippocampus. Our results show that MyD88 deletion in microglia may negatively impact maturing neurons within the adult hippocampus and thus reward memories, suggesting a novel protective role for microglia in opioid addiction.}, Doi = {10.1016/j.bbi.2018.11.010}, Key = {fds339917} } @article{fds342606, Author = {Edlow, AG and Glass, RM and Bilbo, SD}, Title = {Sexually-Dimorphic Effects of Maternal Obesity on Microglial Antigen Density in the Embryonic Hippocampus: Implications for Offspring Hippocampal Learning.}, Journal = {REPRODUCTIVE SCIENCES}, Volume = {26}, Pages = {96A-96A}, Publisher = {SAGE PUBLICATIONS INC}, Year = {2019}, Month = {March}, Key = {fds342606} } @article{fds341885, Author = {Liu, X and Nemeth, DP and McKim, DB and Zhu, L and DiSabato, DJ and Berdysz, O and Gorantla, G and Oliver, B and Witcher, KG and Wang, Y and Negray, CE and Vegesna, RS and Sheridan, JF and Godbout, JP and Robson, MJ and Blakely, RD and Popovich, PG and Bilbo, SD and Quan, N}, Title = {Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities.}, Journal = {Immunity}, Volume = {50}, Number = {3}, Pages = {764-766}, Year = {2019}, Month = {March}, url = {http://dx.doi.org/10.1016/j.immuni.2019.02.012}, Abstract = {© 2019 (Immunity 50, 317-333.e1–e6; February 19, 2019) Main Text: In the original version of the published manuscript, the insets of Figure 3F (middle and right panels) were identical to the insets of Figure 3E. This error was generated inadvertently during the revision process of the manuscript. The insets of Figure 3F (middle and right panels) have now been replaced and are consistent with their corresponding images, and the revised version is provided below and has been corrected online. The authors apologize for the error. [Figure presented]}, Doi = {10.1016/j.immuni.2019.02.012}, Key = {fds341885} } @article{fds342359, Author = {Smith, CJ and Bilbo, SD}, Title = {Microglia Sculpt Sex Differences in Social Behavior.}, Journal = {Neuron}, Volume = {102}, Number = {2}, Pages = {275-277}, Year = {2019}, Month = {April}, url = {http://dx.doi.org/10.1016/j.neuron.2019.03.039}, Abstract = {Microglia are increasingly recognized as developmental sculptors of neural circuits. In this issue of Neuron, VanRyzin et al. (2019) demonstrate a novel mechanism by which endocannabinoids drive microglia to phagocytose newborn astrocytes in the medial amygdala of male rats, promoting sex differences in social play behavior.}, Doi = {10.1016/j.neuron.2019.03.039}, Key = {fds342359} } @article{fds342148, Author = {Kopec, AM and Smith, CJ and Bilbo, SD}, Title = {Neuro-Immune Mechanisms Regulating Social Behavior: Dopamine as Mediator?}, Journal = {Trends in neurosciences}, Volume = {42}, Number = {5}, Pages = {337-348}, Year = {2019}, Month = {May}, url = {http://dx.doi.org/10.1016/j.tins.2019.02.005}, Abstract = {Social interactions are fundamental to survival and overall health. The mechanisms underlying social behavior are complex, but we now know that immune signaling plays a fundamental role in the regulation of social interactions. Prolonged or exaggerated alterations in social behavior often accompany altered immune signaling and function in pathological states. Thus, unraveling the link between social behavior and immune signaling is a fundamental challenge, not only to advance our understanding of human health and development, but for the design of comprehensive therapeutic approaches for neural disorders. In this review, we synthesize literature demonstrating the bidirectional relationship between social behavior and immune signaling and highlight recent work linking social behavior, immune function, and dopaminergic signaling in adolescent neural and behavioral development.}, Doi = {10.1016/j.tins.2019.02.005}, Key = {fds342148} } @article{fds342605, Author = {Smith, CJ and Bhanot, A and Norman, E and Mullett, JE and Bilbo, SD and McDougle, CJ and Zürcher, NR and Hooker, JM}, Title = {A Protocol for Sedation Free MRI and PET Imaging in Adults with Autism Spectrum Disorder.}, Journal = {Journal of autism and developmental disorders}, Volume = {49}, Number = {7}, Pages = {3036-3044}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1007/s10803-019-04010-3}, Abstract = {Imaging technologies such as positron emission tomography (PET) and magnetic resonance imaging (MRI) present unparalleled opportunities to investigate the neural basis of autism spectrum disorder (ASD). However, challenges such as deficits in social interaction, anxiety around new experiences, impaired language abilities, and hypersensitivity to sensory stimuli make participating in neuroimaging studies challenging for individuals with ASD. In this commentary, we describe the existent training protocols for preparing individuals with ASD for PET/MRI scans and our own experience developing a training protocol to facilitate the inclusion of low-functioning adults with ASD in PET-MRI studies. We hope to raise awareness of the need for more information exchange between research groups about lessons learned in this context in order to include the entire disease spectrum in neuroimaging studies.}, Doi = {10.1007/s10803-019-04010-3}, Key = {fds342605} } @article{fds339550, Author = {Bordt, EA and Smith, CJ and Demarest, TG and Bilbo, SD and Kingsbury, MA}, Title = {Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response.}, Journal = {Neurotoxicity research}, Volume = {36}, Number = {2}, Pages = {239-256}, Year = {2019}, Month = {August}, url = {http://dx.doi.org/10.1007/s12640-018-9962-7}, Abstract = {Neuroendocrine and immune signaling pathways are activated following insults such as stress, injury, and infection, in a systemic response aimed at restoring homeostasis. Mitochondrial metabolism and function have been implicated in the control of immune responses. Commonly studied along with mitochondrial function, reactive oxygen species (ROS) are closely linked to cellular inflammatory responses. It is also accepted that cells experiencing mitochondrial or endoplasmic reticulum (ER) stress induce response pathways in order to cope with protein-folding dysregulation, in homeostatic responses referred to as the unfolded protein responses (UPRs). Recent reports indicate that the UPRs may play an important role in immune responses. Notably, the homeostasis-regulating hormones oxytocin (OXT) and vasopressin (AVP) are also associated with the regulation of inflammatory responses and immune function. Intriguingly, OXT and AVP have been linked with ER unfolded protein responses (UPR<sup>ER</sup>), and can impact ROS production and mitochondrial function. Here, we will review the evidence for interactions between these various factors and how these neuropeptides might influence mitochondrial processes.}, Doi = {10.1007/s12640-018-9962-7}, Key = {fds339550} } @article{fds340068, Author = {Edlow, AG and Glass, RM and Smith, CJ and Tran, PK and James, K and Bilbo, S}, Title = {Placental Macrophages: A Window Into Fetal Microglial Function in Maternal Obesity.}, Journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, Volume = {77}, Pages = {60-68}, Publisher = {Elsevier BV}, Year = {2019}, Month = {October}, url = {http://dx.doi.org/10.1016/j.ijdevneu.2018.11.004}, Abstract = {Fetal placental macrophages and microglia (resident brain macrophages) have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual's lifetime. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living fetus or neonate is impossible. We sought to test the hypothesis that maternal obesity would prime both placental macrophages and fetal brain microglia to overrespond to an immune challenge, thus providing a window into microglial function using placental cells. Obesity was induced in C57BL/6 J mice using a 60% high-fat diet. On embryonic day 17.5, fetal brain microglia and corresponding CD11b + placental cells were isolated from fresh tissue. Cells were treated with media or lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-α) production by stimulated and unstimulated cells was quantified via ELISA. We demonstrate for the first time that the proinflammatory cytokine production of CD11b + placental cells is strongly correlated with that of brain microglia (Spearman's ρ = 0.73, p = 0.002) in the setting of maternal obesity. Maternal obesity-exposed CD11b + cells had an exaggerated response to LPS compared to controls, with a 5.1-fold increase in TNF-α production in placentas (p = 0.003) and 3.8-fold increase in TNF-α production in brains (p = 0.002). In sex-stratified analyses, only male obesity-exposed brains and placentas had significant increase in TNF-α production in response to LPS. Taken together, these data suggest that maternal obesity primes both placental macrophages and fetal brain microglia to overproduce a proinflammatory cytokine in response to immune challenge. Male brain and placental immune response is more marked than female in this setting. Given that fetal microglial priming may impact neuroimmune function throughout the lifespan, these data could provide insight into the male predominance of certain neurodevelopmental morbidities linked to maternal obesity, including cognitive dysfunction, autism spectrum disorder, and ADHD. Placental CD11b+ macrophages may have the potential to serve as an accessible biomarker of aberrant fetal brain immune activation in maternal obesity. This finding may have broader implications for assaying the impact of other maternal exposures on fetal brain development.}, Doi = {10.1016/j.ijdevneu.2018.11.004}, Key = {fds340068} } @article{fds346774, Author = {Kingsbury, MA and Bilbo, SD}, Title = {The inflammatory event of birth: How oxytocin signaling may guide the development of the brain and gastrointestinal system.}, Journal = {Frontiers in neuroendocrinology}, Volume = {55}, Pages = {100794}, Year = {2019}, Month = {October}, url = {http://dx.doi.org/10.1016/j.yfrne.2019.100794}, Abstract = {The role of oxytocin (OT) as a neuropeptide that modulates social behavior has been extensively studied and reviewed, but beyond these functions, OT's adaptive functions at birth are quite numerous, as OT coordinates many physiological processes in the mother and fetus to ensure a successful delivery. In this review we explore in detail the potential adaptive roles of oxytocin as an anti-inflammatory, protective molecule at birth for the developing fetal brain and gastrointestinal system based on evidence that birth is a potent inflammatory/immune event. We discuss data with relevance for a number of neurodevelopmental disorders, as well as the emerging role of the gut-brain axis for health and disease. Finally, we discuss the potential relevance of sex differences in OT signaling present at birth in the increased male vulnerability to neurodevelopmental disabilities.}, Doi = {10.1016/j.yfrne.2019.100794}, Key = {fds346774} } @article{fds348031, Author = {Bordt, EA and Bilbo, SD}, Title = {Stressed-Out T Cells Fragment the Mind.}, Journal = {Trends in immunology}, Volume = {41}, Number = {2}, Pages = {94-97}, Year = {2020}, Month = {February}, url = {http://dx.doi.org/10.1016/j.it.2019.12.008}, Abstract = {The immune system is increasingly recognized to play an integral role in regulating stress responses. In a recent article in Cell, Fan et al. demonstrate a novel mechanism through which stress drives mitochondrial fragmentation-induced xanthine accumulation in mouse CD4<sup>+</sup> T cells, subsequently acting on oligodendrocytes to induce anxiety-like behaviors.}, Doi = {10.1016/j.it.2019.12.008}, Key = {fds348031} } @article{fds347134, Author = {Bordt, EA and Ceasrine, AM and Bilbo, SD}, Title = {Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors.}, Journal = {Glia}, Volume = {68}, Number = {6}, Pages = {1085-1099}, Year = {2020}, Month = {June}, url = {http://dx.doi.org/10.1002/glia.23753}, Abstract = {Sexual differentiation of the brain during early development likely underlies the strong sex biases prevalent in many neurological conditions. Mounting evidence indicates that microglia, the innate immune cells of the central nervous system, are intricately involved in these sex-specific processes of differentiation. In this review, we synthesize literature demonstrating sex differences in microglial number, morphology, transcriptional state, and functionality throughout spatiotemporal development as well as highlight current literature regarding ontogeny of microglia. Along with vanRyzin et al. in this issue, we explore the idea that differences in microglia imparted by chromosomal or ontogeny-related programming can influence microglial-driven sexual differentiation of the brain, as well as the idea that extrinsic differences in the male and female brain microenvironment may in turn impart sex differences in microglia.}, Doi = {10.1002/glia.23753}, Key = {fds347134} } @article{fds348872, Author = {Hollander, JA and Cory-Slechta, DA and Jacka, FN and Szabo, ST and Guilarte, TR and Bilbo, SD and Mattingly, CJ and Moy, SS and Haroon, E and Hornig, M and Levin, ED and Pletnikov, MV and Zehr, JL and McAllister, KA and Dzierlenga, AL and Garton, AE and Lawler, CP and Ladd-Acosta, C}, Title = {Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease.}, Journal = {Neuropsychopharmacology}, Volume = {45}, Number = {7}, Pages = {1086-1096}, Year = {2020}, Month = {June}, url = {http://dx.doi.org/10.1038/s41386-020-0648-5}, Abstract = {The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.}, Doi = {10.1038/s41386-020-0648-5}, Key = {fds348872} } @article{fds357323, Author = {Bordt, EA and Block, CL and Petrozziello, T and Sadri-Vakili, G and Smith, CJ and Edlow, AG and Bilbo, SD}, Title = {Isolation of Microglia from Mouse or Human Tissue.}, Journal = {STAR protocols}, Volume = {1}, Number = {1}, Pages = {100035}, Year = {2020}, Month = {June}, url = {http://dx.doi.org/10.1016/j.xpro.2020.100035}, Abstract = {Microglia are the innate immune cells of the central nervous system. Although numerous methods have been developed to isolate microglia from the brain, the method of dissociation and isolation can have a profound effect on the function of these highly dynamic cells. Here, we present an optimized protocol to isolate CD11b+ cells (microglia) from mouse or human brain tissue using magnetic bead columns. Isolated microglia can be used to model diseases with neuroinflammatory components for potential therapeutic discoveries. For complete details on the use and execution of this protocol, please refer to Hanamsagar et al. (2017), Rivera et al. (2019), and Edlow et al. (2019).}, Doi = {10.1016/j.xpro.2020.100035}, Key = {fds357323} } @article{fds340827, Author = {Missig, G and Robbins, JO and Mokler, EL and McCullough, KM and Bilbo, SD and McDougle, CJ and Carlezon, WA}, Title = {Sex-dependent neurobiological features of prenatal immune activation via TLR7.}, Journal = {Molecular psychiatry}, Volume = {25}, Number = {10}, Pages = {2330-2341}, Year = {2020}, Month = {October}, url = {http://dx.doi.org/10.1038/s41380-018-0346-4}, Abstract = {Immune activation during pregnancy via infection or autoimmune disease is a risk factor for neuropsychiatric illness. Mouse models of prenatal immune activation often involve maternal administration of agents that activate toll-like receptors (TLRs), a class of pattern recognition receptors that initiate innate immune responses. Such studies have focused primarily on activating the TLR3 or TLR4 subtypes, to mimic immune responses to viral or bacterial infections, respectively. Here, we characterize the effects of prenatal activation of TLR7, which is implicated in the pathogenesis of autoimmune disease. Prenatal TLR7 activation via administration of the selective agonist imiquimod (5.0 mg/kg) induces a phenotype in offspring characterized by reduced anxiety-like behavior, fragmented social behavior, and altered ultrasonic vocalization patterns at 6-12 weeks of age. The characteristics of this phenotype are readily distinguishable from-and in some ways opposite to-those seen following prenatal activation of TLR3 and/or TLR4. Prenatal TLR7-activated mice have normal baseline locomotor activity, but are hyperresponsive to stimuli including social partners, circadian cues, and gonadal hormone fluctuations. These alterations are accompanied by decreases in microglia density but increases in ramifications. RNA-sequencing of dorsal striatum, a region showing profound changes in microglial markers, indicates that prenatal TLR7 activation induces differential expression of hundreds of genes at 13 weeks of age, with virtually no overlap in differentially expressed genes between males and females. Our findings demonstrate that prenatal immune activation can promote a wide range of developmental trajectories, depending on the type and/or pattern of TLR activation and the sex of the offspring.}, Doi = {10.1038/s41380-018-0346-4}, Key = {fds340827} } @article{fds352331, Author = {Smith, CJ and Kingsbury, MA and Dziabis, JE and Hanamsagar, R and Malacon, KE and Tran, JN and Norris, HA and Gulino, M and Bordt, EA and Bilbo, SD}, Title = {Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number.}, Journal = {Brain, behavior, and immunity}, Volume = {90}, Pages = {332-345}, Year = {2020}, Month = {November}, url = {http://dx.doi.org/10.1016/j.bbi.2020.08.013}, Abstract = {Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1β) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, largely independent of microglial inflammatory signaling.}, Doi = {10.1016/j.bbi.2020.08.013}, Key = {fds352331} } @article{fds355562, Author = {Smith, CJ and Bilbo, SD}, Title = {Sickness and the Social Brain: Love in the Time of COVID.}, Journal = {Frontiers in psychiatry}, Volume = {12}, Pages = {633664}, Year = {2021}, Month = {January}, url = {http://dx.doi.org/10.3389/fpsyt.2021.633664}, Abstract = {As a highly social species, inclusion in social networks and the presence of strong social bonds are critical to our health and well-being. Indeed, impaired social functioning is a component of numerous neuropsychiatric disorders including depression, anxiety, and substance use disorder. During the current COVID-19 pandemic, our social networks are at risk of fracture and many are vulnerable to the negative consequences of social isolation. Importantly, infection itself leads to changes in social behavior as a component of "sickness behavior." Furthermore, as in the case of COVID-19, males and females often differ in their immunological response to infection, and, therefore, in their susceptibility to negative outcomes. In this review, we discuss the many ways in which infection changes social behavior-sometimes to the benefit of the host, and in some instances for the sake of the pathogen-in species ranging from eusocial insects to humans. We also explore the neuroimmune mechanisms by which these changes in social behavior occur. Finally, we touch upon the ways in which the social environment (group living, social isolation, etc.) shapes the immune system and its ability to respond to challenge. Throughout we emphasize how males and females differ in their response to immune activation, both behaviorally and physiologically.}, Doi = {10.3389/fpsyt.2021.633664}, Key = {fds355562} } @article{fds361153, Author = {Bordt, EA and Shook, LL and Atyeo, C and Pullen, KM and De Guzman and RM and Meinsohn, M-C and Chauvin, M and Fischinger, S and Yockey, LJ and James, K and Lima, R and Yonker, LM and Fasano, A and Brigida, S and Bebell, LM and Roberts, DJ and Pépin, D and Huh, JR and Bilbo, SD and Li, JZ and Kaimal, A and Schust, D and Gray, KJ and Lauffenburger, D and Alter, G and Edlow, AG}, Title = {Sexually dimorphic placental responses to maternal SARS-CoV-2 infection.}, Journal = {bioRxiv}, Year = {2021}, Month = {March}, url = {http://dx.doi.org/10.1101/2021.03.29.437516}, Abstract = {There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.}, Doi = {10.1101/2021.03.29.437516}, Key = {fds361153} } @article{fds357322, Author = {Kemény, LV and Robinson, KC and Hermann, AL and Walker, DM and Regan, S and Yew, YW and Lai, YC and Theodosakis, N and Rivera, PD and Ding, W and Yang, L and Beyer, T and Loh, Y-HE and Lo, JA and van der Sande, AAJ and Sarnie, W and Kotler, D and Hsiao, JJ and Su, MY and Kato, S and Kotler, J and Bilbo, SD and Chopra, V and Salomon, MP and Shen, S and Hoon, DSB and Asgari, MM and Wakeman, SE and Nestler, EJ and Fisher, DE}, Title = {Vitamin D deficiency exacerbates UV/endorphin and opioid addiction.}, Journal = {Science advances}, Volume = {7}, Number = {24}, Pages = {eabe4577}, Year = {2021}, Month = {June}, url = {http://dx.doi.org/10.1126/sciadv.abe4577}, Abstract = {The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.}, Doi = {10.1126/sciadv.abe4577}, Key = {fds357322} } @article{fds354527, Author = {Maguire, RL and House, JS and Lloyd, DT and Skinner, HG and Allen, TK and Raffi, AM and Skaar, DA and Park, SS and McCullough, LE and Kollins, SH and Bilbo, SD and Collier, DN and Murphy, SK and Fuemmeler, BF and Gowdy, KM and Hoyo, C}, Title = {Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort.}, Journal = {Pediatr Obes}, Volume = {16}, Number = {7}, Pages = {e12763}, Year = {2021}, Month = {July}, url = {http://dx.doi.org/10.1111/ijpo.12763}, Abstract = {BACKGROUND: Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. OBJECTIVES: In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. METHODS: In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1β, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. RESULTS: After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24). CONCLUSIONS: Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.}, Doi = {10.1111/ijpo.12763}, Key = {fds354527} } @article{fds358768, Author = {Ceasrine, AM and Bilbo, SD}, Title = {Primetime for microglia: When stress and infection collide.}, Journal = {Neuron}, Volume = {109}, Number = {16}, Pages = {2503-2505}, Year = {2021}, Month = {August}, url = {http://dx.doi.org/10.1016/j.neuron.2021.07.023}, Abstract = {Inflammation during critical windows of development contributes to behavioral affect later in life. In this of Neuron, Cao et al. (2021) demonstrate a novel mechanism through which early life Tlr4-dependent inflammation in microglia permanently alters neuronal function and leaves male mice susceptible to stress-induced depressive-like behaviors.}, Doi = {10.1016/j.neuron.2021.07.023}, Key = {fds358768} } @article{fds358813, Author = {Figueroa, C and Yang, H and DiSpirito, J and Bourgeois, JR and Kalyanasundaram, G and Doshi, I and Bilbo, SD and Kopec, AM}, Title = {Morphine exposure alters Fos expression in a sex-, age-, and brain region-specific manner during adolescence.}, Journal = {Developmental psychobiology}, Volume = {63}, Number = {6}, Pages = {e22186}, Year = {2021}, Month = {September}, url = {http://dx.doi.org/10.1002/dev.22186}, Abstract = {Data in both humans and preclinical animal models clearly indicate drug exposure during adolescence, when the "reward" circuitry of the brain develops, increases the risk of substance use and other mental health disorders later in life. Human data indicate that different neural and behavioral sequelae can be observed in early versus late adolescence. However, most studies with rodent models examine a single adolescent age compared to a mature adult age, and often only in males. Herein, we sought to determine whether the acute response to the opioid morphine would also differ across adolescence, and by sex. By quantifying Fos positive cells, a proxy for neural activity, at different stages during adolescence (pre-, early, mid-, and late adolescence) and in multiple reward regions (prefrontal cortex, nucleus accumbens, caudate/putamen), we determined that the neural response to acute morphine is highly dependent on adolescent age, sex, and brain region. These data suggest that heterogeneity in the consequences of adolescent opioid exposure may be due to age- and sex-specific developmental profiles in individual reward processing regions. In future studies, it will be important to add age within adolescence as an independent variable for a holistic view of healthy or abnormal reward-related neural development.}, Doi = {10.1002/dev.22186}, Key = {fds358813} } @article{fds359680, Author = {Bordt, EA and Shook, LL and Atyeo, C and Pullen, KM and De Guzman and RM and Meinsohn, M-C and Chauvin, M and Fischinger, S and Yockey, LJ and James, K and Lima, R and Yonker, LM and Fasano, A and Brigida, S and Bebell, LM and Roberts, DJ and Pépin, D and Huh, JR and Bilbo, SD and Li, JZ and Kaimal, A and Schust, DJ and Gray, KJ and Lauffenburger, D and Alter, G and Edlow, AG}, Title = {Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses.}, Journal = {Sci Transl Med}, Volume = {13}, Number = {617}, Pages = {eabi7428}, Year = {2021}, Month = {October}, url = {http://dx.doi.org/10.1126/scitranslmed.abi7428}, Abstract = {There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.}, Doi = {10.1126/scitranslmed.abi7428}, Key = {fds359680} } @article{fds365998, Author = {Ceasrine, AM and Devlin, BA and Bolton, JL and Green, LA and Jo, YC and Huynh, C and Patrick, B and Washington, K and Sanchez, CL and Joo, F and Brayan Campos-Salazar and A and Lockshin, ER and Kuhn, C and Murphy, SK and Simmons, LA and Bilbo, SD}, Title = {Maternal diet disrupts the placenta-brain axis in a sex-specific manner}, Year = {2021}, Month = {November}, url = {http://dx.doi.org/10.1101/2021.11.12.468408}, Abstract = {<jats:title>SUMMARY</jats:title><jats:p>High maternal weight is associated with a number of detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression, and communicative disorders (e.g. autism spectrum disorders)<jats:sup>1–8</jats:sup>. Despite widespread acknowledgement of sex-biases in the prevalence, incidence, and age of onset of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we use a mouse model to demonstrate how maternal high-fat diet, one contributor to overweight, causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation influences sex-specific behavioral outcomes in offspring. In male high-fat diet offspring, increased macrophage toll like receptor 4 signaling results in excess phagocytosis of serotonin neurons in the developing dorsal raphe nucleus, decreasing serotonin bioavailability in the fetal and adult brain. Bulk sequencing from a large cohort of matched first trimester human fetal brain, placenta, and maternal decidua samples reveals sex-specific transcriptome-wide changes in placenta and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, we find that fetal brain serotonin levels decrease as maternal dietary fat intake increases in males only. These findings uncover a microglia-dependent mechanism through which maternal diet may impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.</jats:p>}, Doi = {10.1101/2021.11.12.468408}, Key = {fds365998} } @article{fds359903, Author = {Petrozziello, T and Bordt, EA and Mills, AN and Kim, SE and Sapp, E and Devlin, BA and Obeng-Marnu, AA and Farhan, SMK and Amaral, AC and Dujardin, S and Dooley, PM and Henstridge, C and Oakley, DH and Neueder, A and Hyman, BT and Spires-Jones, TL and Bilbo, SD and Vakili, K and Cudkowicz, ME and Berry, JD and DiFiglia, M and Silva, MC and Haggarty, SJ and Sadri-Vakili, G}, Title = {Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis.}, Journal = {Molecular neurobiology}, Volume = {59}, Number = {1}, Pages = {683-702}, Year = {2022}, Month = {January}, url = {http://dx.doi.org/10.1007/s12035-021-02557-w}, Abstract = {Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer's disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach. Our findings demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro. Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS. As previously reported, electron microscopy revealed a significant decrease in mitochondria density and length in ALS mCTX. Lastly, reducing tau levels with QC-01-175, a selective tau degrader, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS. pTau-S396 mis-localizes to synapses in ALS. ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. Reducing tau with a selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro.}, Doi = {10.1007/s12035-021-02557-w}, Key = {fds359903} } @article{fds359042, Author = {Dziabis, JE and Bilbo, SD}, Title = {Microglia and Sensitive Periods in Brain Development.}, Journal = {Current topics in behavioral neurosciences}, Volume = {53}, Pages = {55-78}, Year = {2022}, Month = {January}, url = {http://dx.doi.org/10.1007/7854_2021_242}, Abstract = {From embryonic neuronal migration to adolescent circuit refinement, the immune system plays an essential role throughout central nervous system (CNS) development. Immune signaling molecules serve as a common language between the immune system and CNS, allowing them to work together to modulate brain function both in health and disease. As the resident CNS macrophage, microglia comprise the majority of immune cells in the brain. Much like their peripheral counterparts, microglia survey their environment for pathology, clean up debris, and propagate inflammatory responses when necessary. Beyond this, recent studies have highlighted that microglia perform a number of complex tasks during neural development, from directing neuronal and axonal positioning to pruning synapses, receptors, and even whole cells. In this chapter, we discuss this literature within the framework that immune activation during discrete windows of neural development can profoundly impact brain function long-term, and thus the risk of neurodevelopmental and neuropsychiatric disorders. In this chapter, we review three sensitive developmental periods - embryonic wiring, early postnatal synaptic pruning, and adolescent circuit refinement - in order to highlight the diversity of functions that microglia perform in building a brain. In reviewing this literature, it becomes obvious that timing matters, perhaps more so than the nature of the immune activation itself; largely conserved patterns of microglial response to diverse insults result in different functional impacts depending on the stage of brain maturation at the time of the challenge.}, Doi = {10.1007/7854_2021_242}, Key = {fds359042} } @article{fds361152, Author = {Devlin, BA and Smith, CJ and Bilbo, SD}, Title = {Sickness and the Social Brain: How the Immune System Regulates Behavior across Species.}, Journal = {Brain, behavior and evolution}, Volume = {97}, Number = {3-4}, Pages = {197-210}, Year = {2022}, Month = {January}, url = {http://dx.doi.org/10.1159/000521476}, Abstract = {Many instances of sickness critically involve the immune system. The immune system talks to the brain in a bidirectional loop. This discourse affords the immune system immense control, such that it can influence behavior and optimize recovery from illness. These behavioral responses to infection are called sickness behaviors and can manifest in many ways, including changes in mood, motivation, or energy. Fascinatingly, most of these changes are conserved across species, and most organisms demonstrate some form of sickness behaviors. One of the most interesting sickness behaviors, and not immediately obvious, is altered sociability. Here, we discuss how the immune system impacts social behavior, by examining the brain regions and immune mediators involved in this process. We first outline how social behavior changes in response to infection in various species. Next, we explore which brain regions control social behavior and their evolutionary origins. Finally, we describe which immune mediators establish the link between illness and social behavior, in the context of both normal development and infection. Overall, we hope to make clear the striking similarities between the mechanisms that facilitate changes in sociability in derived and ancestral vertebrate, as well as invertebrate, species.}, Doi = {10.1159/000521476}, Key = {fds361152} } @article{fds361813, Author = {Ceasrine, AM and Bilbo, SD}, Title = {Dietary fat: a potent microglial influencer.}, Journal = {Trends in endocrinology and metabolism: TEM}, Volume = {33}, Number = {3}, Pages = {196-205}, Year = {2022}, Month = {March}, url = {http://dx.doi.org/10.1016/j.tem.2021.12.005}, Abstract = {Poor nutrition, lack of exercise, and genetic predisposition all contribute to the growing epidemic of obesity. Overweight/obesity create an environment of chronic inflammation that leads to negative physiological and neurological outcomes, such as diabetes, cardiovascular disease, and anxiety/depression. While the whole body contributes to metabolic homeostasis, the neuroimmune system has recently emerged as a key regulator of metabolism. Microglia, the resident immune cells of the brain, respond both directly and indirectly to dietary fat, and the environment in which microglia develop contributes to their responsiveness later in life. Thus, high maternal weight during pregnancy may have consequences for microglial function in offspring. Here, we discuss the most recent findings on microglia signaling in overweight/obesity with a focus on perinatal programming.}, Doi = {10.1016/j.tem.2021.12.005}, Key = {fds361813} } @article{fds365154, Author = {Block, CL and Eroglu, O and Mague, SD and Smith, CJ and Ceasrine, AM and Sriworarat, C and Blount, C and Beben, KA and Malacon, KE and Ndubuizu, N and Talbot, A and Gallagher, NM and Chan Jo and Y and Nyangacha, T and Carlson, DE and Dzirasa, K and Eroglu, C and Bilbo, SD}, Title = {Prenatal environmental stressors impair postnatal microglia function and adult behavior in males.}, Journal = {Cell Rep}, Volume = {40}, Number = {5}, Pages = {111161}, Year = {2022}, Month = {August}, url = {http://dx.doi.org/10.1016/j.celrep.2022.111161}, Abstract = {Gestational exposure to environmental toxins and socioeconomic stressors is epidemiologically linked to neurodevelopmental disorders with strong male bias, such as autism. We model these prenatal risk factors in mice by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activates the maternal immune system. Only male offspring display long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminish microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Precise inhibition of microglial phagocytosis within the anterior cingulate cortex (ACC) of wild-type (WT) mice during the same critical period mimics the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.}, Doi = {10.1016/j.celrep.2022.111161}, Key = {fds365154} } @article{fds364170, Author = {Smith, CJ and Lintz, T and Clark, MJ and Malacon, KE and Abiad, A and Constantino, NJ and Kim, VJ and Jo, YC and Alonso-Caraballo, Y and Bilbo, SD and Chartoff, EH}, Title = {Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring.}, Journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, Volume = {47}, Number = {10}, Pages = {1755-1763}, Year = {2022}, Month = {September}, url = {http://dx.doi.org/10.1038/s41386-022-01376-4}, Abstract = {The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.}, Doi = {10.1038/s41386-022-01376-4}, Key = {fds364170} } @article{fds367609, Author = {Paolicelli, RC and Sierra, A and Stevens, B and Tremblay, M-E and Aguzzi, A and Ajami, B and Amit, I and Audinat, E and Bechmann, I and Bennett, M and Bennett, F and Bessis, A and Biber, K and Bilbo, S and Blurton-Jones, M and Boddeke, E and Brites, D and Brône, B and Brown, GC and Butovsky, O and Carson, MJ and Castellano, B and Colonna, M and Cowley, SA and Cunningham, C and Davalos, D and De Jager and PL and de Strooper, B and Denes, A and Eggen, BJL and Eyo, U and Galea, E and Garel, S and Ginhoux, F and Glass, CK and Gokce, O and Gomez-Nicola, D and González, B and Gordon, S and Graeber, MB and Greenhalgh, AD and Gressens, P and Greter, M and Gutmann, DH and Haass, C and Heneka, MT and Heppner, FL and Hong, S and Hume, DA and Jung, S and Kettenmann, H and Kipnis, J and Koyama, R and Lemke, G and Lynch, M and Majewska, A and Malcangio, M and Malm, T and Mancuso, R and Masuda, T and Matteoli, M and McColl, BW and Miron, VE and Molofsky, AV and Monje, M and Mracsko, E and Nadjar, A and Neher, JJ and Neniskyte, U and Neumann, H and Noda, M and Peng, B and Peri, F and Perry, VH and Popovich, PG and Pridans, C and Priller, J and Prinz, M and Ragozzino, D and Ransohoff, RM and Salter, MW and Schaefer, A and Schafer, DP and Schwartz, M and Simons, M and Smith, CJ and Streit, WJ and Tay, TL and Tsai, L-H and Verkhratsky, A and von Bernhardi, R and Wake, H and Wittamer, V and Wolf, SA and Wu, L-J and Wyss-Coray, T}, Title = {Microglia states and nomenclature: A field at its crossroads.}, Journal = {Neuron}, Volume = {110}, Number = {21}, Pages = {3458-3483}, Year = {2022}, Month = {November}, url = {http://dx.doi.org/10.1016/j.neuron.2022.10.020}, Abstract = {Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.}, Doi = {10.1016/j.neuron.2022.10.020}, Key = {fds367609} } @article{fds366200, Author = {Ceasrine, AM and Green, LA and Bilbo, SD}, Title = {Protocol to measure endotoxin from opaque tissues in mice using an optimized kinetic limulus amebocyte lysate assay.}, Journal = {STAR protocols}, Volume = {3}, Number = {4}, Pages = {101669}, Year = {2022}, Month = {December}, url = {http://dx.doi.org/10.1016/j.xpro.2022.101669}, Abstract = {Endotoxin accumulation has been widely noted in several pathologies ranging from metabolic dysregulation to bacterial infection. Using limulus amebocyte lysate (LAL) assays to detect endotoxin load has been the only reliable way to assess endotoxin accumulation, but assays optimized for detection in opaque tissues are still lacking. We optimized a sensitive Kinetic LAL assay for endotoxin detection from murine tissues. In this protocol, we describe tissue collection and homogenization, followed by the procedure to run the assay and data analysis. For complete details on the use and execution of this protocol, please refer to Ceasrine et al. (2022).}, Doi = {10.1016/j.xpro.2022.101669}, Key = {fds366200} } @article{fds368398, Author = {Ceasrine, AM and Devlin, BA and Bolton, JL and Green, LA and Jo, YC and Huynh, C and Patrick, B and Washington, K and Sanchez, CL and Joo, F and Campos-Salazar, AB and Lockshin, ER and Kuhn, C and Murphy, SK and Simmons, LA and Bilbo, SD}, Title = {Maternal diet disrupts the placenta-brain axis in a sex-specific manner.}, Journal = {Nat Metab}, Volume = {4}, Number = {12}, Pages = {1732-1745}, Year = {2022}, Month = {December}, url = {http://dx.doi.org/10.1038/s42255-022-00693-8}, Abstract = {High maternal weight is associated with detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression and communicative disorders. Despite widespread acknowledgement of sex biases in the development of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring. In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains. Bulk sequencing from a large cohort of matched first-trimester human samples reveals sex-specific transcriptome-wide changes in placental and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples. These findings uncover a microglia-dependent mechanism through which maternal diet can impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.}, Doi = {10.1038/s42255-022-00693-8}, Key = {fds368398} } @article{fds368470, Author = {Hermann, AL and Fell, GL and Kemény, LV and Fung, CY and Held, KD and Biggs, PJ and Rivera, PD and Bilbo, SD and Igras, V and Willers, H and Kung, J and Gheorghiu, L and Hideghéty, K and Mao, J and Woolf, CJ and Fisher, DE}, Title = {β-Endorphin mediates radiation therapy fatigue.}, Journal = {Science advances}, Volume = {8}, Number = {50}, Pages = {eabn6025}, Year = {2022}, Month = {December}, url = {http://dx.doi.org/10.1126/sciadv.abn6025}, Abstract = {Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. β-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as β-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived β-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma β-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either β-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived β-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.}, Doi = {10.1126/sciadv.abn6025}, Key = {fds368470} } @article{fds369662, Author = {Bilbo, S and Smith, C and Rendina, D and Kingsbury, M and Malacon, K and Nguyen, D and Tran, J and Devlin, B and Raju, R and Clark, M and Burgett, L and Zhang, J and Cetinbas, M and Sadreyev, R and Chen, K and Iyer, M}, Title = {Microbial modulation prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.}, Journal = {Res Sq}, Year = {2023}, Month = {February}, url = {http://dx.doi.org/10.21203/rs.3.rs-2548369/v1}, Abstract = {Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.}, Doi = {10.21203/rs.3.rs-2548369/v1}, Key = {fds369662} } @article{fds370885, Author = {Smith, CJ and Rendina, DN and Kingsbury, MA and Malacon, KE and Nguyen, DM and Tran, JJ and Devlin, BA and Raju, RM and Clark, MJ and Burgett, L and Zhang, JH and Cetinbas, M and Sadreyev, RI and Chen, K and Iyer, MS and Bilbo, SD}, Title = {Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.}, Journal = {Molecular psychiatry}, Volume = {28}, Number = {6}, Pages = {2549-2562}, Year = {2023}, Month = {June}, url = {http://dx.doi.org/10.1038/s41380-023-02108-w}, Abstract = {Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.}, Doi = {10.1038/s41380-023-02108-w}, Key = {fds370885} } @article{fds374234, Author = {Bordt, EA and Moya, HA and Jo, YC and Ravichandran, CT and Bankowski, IM and Ceasrine, AM and McDougle, CJ and Carlezon, WA and Bilbo, SD}, Title = {Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function.}, Journal = {Brain, behavior, and immunity}, Volume = {115}, Pages = {680-695}, Year = {2024}, Month = {January}, url = {http://dx.doi.org/10.1016/j.bbi.2023.11.010}, Abstract = {There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.}, Doi = {10.1016/j.bbi.2023.11.010}, Key = {fds374234} } %% Books @book{fds198766, Author = {J.M. Schwarz and S.D. Bilbo}, Title = {The Immune System and the Developing Brain}, Series = {McCarthy's The Developing Brain Series}, Publisher = {Morgan and Claypool Life Sciences}, Year = {2011}, Key = {fds198766} } %% Chapters in Books @misc{fds365186, Author = {Schwarz, JM and Bilbo, SD}, Title = {Microglia and Neurodevelopment: Programming of Cognition throughout the Lifespan}, Pages = {296-312}, Booktitle = {The Wiley-Blackwell Handbook of Psychoneuroimmunology}, Year = {2013}, Month = {January}, ISBN = {9781119979517}, url = {http://dx.doi.org/10.1002/9781118314814.ch15}, Abstract = {Neuroimmune activation during prenatal or early postnatal development can have profound and long-lasting effects on the brain. This chapter provides an up-to-date review of the long-term effects of early-life immune activation on adult cognition, a current perspective on the long-term mechanisms by which these effects are propagated from development to adulthood, and a brief primer on the techniques and methodology by which the long-term consequences of early-life immune activation on later-life cognition can be investigated in a rodent model. The concept of perinatal programming of the immune system and the potential effects on brain and behavior in adulthood remains relatively unexplored, despite strong evidence that perinatal exposure to infectious agents has a number of influences on later life outcomes including disease susceptibility, and, increased vulnerability to cognitive and/or neuropsychiatric disorders. A minor yet significant shift in microglial function has significant negative consequences for cognition.}, Doi = {10.1002/9781118314814.ch15}, Key = {fds365186} } @misc{fds198784, Author = {J.M. Schwarz and S.D. Bilbo}, Title = {Chapter 15: Microglia and Neurodevelopment}, Booktitle = {The Wiley-Blackwell Handbook of Psychoneuroimmunology}, Publisher = {Wiley-Blackwell}, Editor = {Kusnecov and Anisman}, Year = {2013}, Month = {December}, Key = {fds198784} } @misc{fds362983, Author = {Delage, C and Rendina, DN and Malacon, KE and Tremblay, MÈ and Bilbo, SD}, Title = {Sex differences in microglia as a risk factor for Alzheimer’s disease}, Pages = {79-104}, Booktitle = {Sex and Gender Differences in Alzheimer’s Disease}, Year = {2021}, Month = {January}, ISBN = {9780128193440}, url = {http://dx.doi.org/10.1016/B978-0-12-819344-0.00008-9}, Abstract = {Women are known to have a significantly higher lifetime risk of developing Alzheimer’s disease (AD) and recent research shows that they also appear to suffer greater cognitive deterioration than men at the same disease stage. However, the exact mechanisms underlying this prevalence remain elusive. The purpose of this review is to examine the potential role of neuroinflammation and microglia in driving this sex difference in AD. We first introduce the dual role of microglia in AD, describing their transition from being neuroprotective, in reducing amyloid burden during earlier stages of disease, to their pathological role in exacerbating tau pathology in the later stages. We then describe sex differences in the immune system and in microglial maturation and activities as well as how immune activation in early life may modulate brain function later in life. Lastly, sex differences in microglial function are described in the contexts of aging and AD among other neurodegenerative conditions.}, Doi = {10.1016/B978-0-12-819344-0.00008-9}, Key = {fds362983} } %% Articles Submitted @article{fds220606, Author = {L.L. Williamson and S.D. Bilbo}, Title = {Neonatal infection modulates behavioral accuracy and hippocampal activation on a Morris Water Maze task}, Journal = {Physiology & Behavior}, Year = {2013}, Key = {fds220606} } %% Other @misc{fds69304, Author = {Bilbo, SD and Day, LB and Wilczynski, W}, Title = {An anticholinergic disrupts operant conditioning but not spatial memory in frogs}, Journal = {Society for Neuroethology Abstracts}, Year = {1998}, Key = {fds69304} } @misc{fds69302, Author = {Bilbo, SD and Drazen, DL and Bilu, D and Nelson, RJ}, Title = {Luzindole attenuates the in vitro melatonin enhancement of cell-mediated immunity in C57BL/6J house mice}, Journal = {Society for Neuroscience Abstracts}, Year = {1999}, Key = {fds69302} } @misc{fds69303, Author = {Bilbo, SD and Klein, SL and DeVries, AC and Nelson, RJ}, Title = {Lipopolysaccharide elicits sexually dimorphic partner preference behaviors in monogamous prairie voles}, Journal = {Society for Behavioral Neuroendocrinology Abstracts}, Year = {1999}, Key = {fds69303} } @misc{fds69299, Author = {Bilbo, SD and Nelson, RJ}, Title = {Photoperiod affects immune function and sickness behavior in Siberian hamsters}, Journal = {Society for Research on Biological Rhythms Abstracts}, Year = {2000}, Key = {fds69299} } @misc{fds69300, Author = {Drazen, DL and Bilbo, SD and Nelson, RJ}, Title = {In vitro melatonin enhancement of splenocyte proliferation appears to be mediated directly by melatonin receptor subtype 1B}, Journal = {Society for Behavioral Neuroendocrinology Abstracts}, Year = {2000}, Key = {fds69300} } @misc{fds69301, Author = {Bilbo, SD and Drazen, DL and Nelson, RJ}, Title = {Sickness behavior and energy balance vary as a function of photoperiod in Siberian hamsters}, Journal = {Society for Neuroscience Abstracts}, Year = {2000}, Key = {fds69301} } @misc{fds69298, Author = {Bilbo, SD and Dhabhar, FS and Yellon, SM and Nelson RJ}, Title = {Photoperiodic and stress-induced changes in blood and splenic leukocyte distributions in Siberian hamsters}, Journal = {Society for Neuroscience Abstracts}, Year = {2001}, Key = {fds69298} } @misc{fds69291, Author = {Viswanathan, K and Bilbo, SD and Dhabhar, FS}, Title = {Acute stress administered before primary immunization or before challenge enhances skin delayed type hypersensitivity responses to keyhole limpet hemocyanin (KLH)}, Journal = {PsychoNeuroImmunology Research Society Abstracts}, Year = {2002}, Key = {fds69291} } @misc{fds69293, Author = {Neigh-McCandless, G and Bilbo, SD and Hotchkiss, AH and Nelson, RJ}, Title = {Pyruvate supplementation attenuates stress-evoked immunosuppression}, Journal = {Society for Behavioral Neuroendocrinology Abstracts}, Year = {2002}, Key = {fds69293} } @misc{fds69294, Author = {Hotchkiss, AK and Prendergast, BJ and Bilbo, SD and Nelson, RJ}, Title = {Reproductive costs of immune system activation in juvenile Siberian hamsters}, Journal = {Society for Behavioral Neuroendocrinology Abstracts}, Year = {2002}, Key = {fds69294} } @misc{fds69295, Author = {Bilbo, SD and Dhabhar, FS and Viswanathan, K and Light, A and Nelson, RJ}, Title = {Sex and photoperiodic differences in immune function and stress responses in congeneric hamsters}, Journal = {Society for Neuroscience Abstracts}, Year = {2002}, Key = {fds69295} } @misc{fds69296, Author = {Neigh-McCandless, G and Bilbo, SD and Hotchkiss, AH and Nelson, RJ}, Title = {Pyruvate supplementation ameliorates the effects of chronic stress on immune and endocrine systems}, Journal = {Society for Neuroscience Abstracts}, Year = {2002}, Key = {fds69296} } @misc{fds69297, Author = {Prendergast, BJ and Hotchkiss, AK and Bilbo, SD and Nelson, RJ}, Title = {Circadian and photoperiodic control of immune function in juvenile Siberian hamsters}, Journal = {Society for Neuroscience Abstracts}, Year = {2002}, Key = {fds69297} } @misc{fds69285, Author = {Bilbo, SD and Dhabhar, FS and Viswanathan, K and Prendergast, BJ and Nelson, RJ}, Title = {Sex differences in photoperiodic and stress-induced enhancement of immune function in Siberian hamsters}, Journal = {PsychoNeuroImmunology Research Society Abstracts}, Year = {2003}, Key = {fds69285} } @misc{fds69286, Author = {Bilbo, SD and Nelson, RJ}, Title = {Photoperiod and exercise affect metabolism and delayed type hypersensitivity in Siberian hamsters}, Journal = {Society for Behavioral Neuroendocrinology Abstracts}, Year = {2003}, Key = {fds69286} } @misc{fds69287, Author = {Bowers, SL and Bilbo, SD and Nelson, RJ}, Title = {A comparison of chronic stressors effects on delayed type hypersensitivity in mice}, Journal = {Society for Behavioral Neuroendocrinology Abstracts}, Year = {2003}, Key = {fds69287} } @misc{fds69288, Author = {Bilbo, SD and Neigh, GN and Glasper, ER and DeVries, AC}, Title = {Enhanced delayed-type-hypersensitivity responses in cardiac arrest survivors}, Journal = {Society for Neuroscience Abstracts}, Year = {2003}, Key = {fds69288} } @misc{fds69289, Author = {Prendergast, BJ and Bilbo, SD and Nelson, RJ}, Title = {Day length regulates induction, retention, and retrieval of immunological memory in Siberian hamsters}, Journal = {Society for Neuroscience Abstracts}, Year = {2003}, Key = {fds69289} } @misc{fds69283, Author = {Spataro, LE and Walsh, MG and Levkoff, LH and Wieseler Frank and JL, Frank and MG, Bilbo and SD, Martin and TJ, Maier and SF and Watkins, LR}, Title = {Laparotomy sensitizes dorsal spinal cord glia: Enhanced glial response to later challenge}, Journal = {Society for Neuroscience Abstracts}, Year = {2004}, Key = {fds69283} } @misc{fds69284, Author = {Neigh, GN and Bilbo, SD and Glasper, ER and DeVries, AC}, Title = {Cardiac arrest/cardiopulmonary resuscitation increases the delayed-type-hypersensitivity response and alters hypothalamic-pituitary adrenal axis activity}, Journal = {PsychoNeuroImmunology Research Society Abstracts}, Year = {2004}, Key = {fds69284} } @misc{fds69281, Author = {Bilbo, SD and Levkoff, LH and Mahoney, JH and Rudy, JW and Watkins, LR and Maier, SF}, Title = {Neonatal infection induces memory impairments and cytokine alterations following an immune challenge in adulthood}, Journal = {PsychoNeuroImmunology Research Society Abstracts}, Year = {2004}, Key = {fds69281} } @misc{fds69282, Author = {Bilbo, SD and Mahoney, JH and Rudy, JW and Watkins, LR and Maier, SF}, Title = {Neonatal infection alters hippocampal glia and induces memory impairments and cytokine alterations following an immune challenge in adulthood}, Journal = {Society for Neuroscience Abstracts}, Year = {2004}, Key = {fds69282} } | |
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