Polyinosinic:polycytidylic acid (poly I:C), an agonist for TLR3, induces type-I interferons and o... more Polyinosinic:polycytidylic acid (poly I:C), an agonist for TLR3, induces type-I interferons and other inflammatory mediators such as TNF-alpha, IL-6 and to a lesser extent IL-1beta. Poly I:C induces sickness behaviour in mice and it is known that type-I interferons impact on behaviour and CNS function. Here we assess the role of type-I interferons in pI:C-induced sickness behaviour. Type-I interferon receptor 1 knockout (IFNAR1À/À) and WT C57BL/6 mice were challenged with pI:C (12 mg/kg i.p). IFNAR1À/Àanimals displayed reduced sickness behaviour compared to WT mice and only WT animals displayed a significant hypothermic response. All mice showed a reduction in weight 28 h post-challenge but full recovery was more rapid in IFNAR1À/Àmice. In addition to this, 3 h post-challenge, WT mice showed decreased activity in the open field with respect to IFNAR1À/À. As expected, the interferon responsive genes PKR and IRF7 were not induced by pI:C in IFNAR1À/Àmice. While IL-1beta and TNF-alpha responses to pI:C were equivalent in KO and WT in blood, hippocampus and hypothalamus, there was no synthesis of IL-6 in IFNAR1À/Àin either blood or brain. These results demonstrate a role for type-I interferons in the sickness behaviour response to pI:C and in the induction of IL-6 responses. Further investigations will examine whether the IL-6 deficiency seen in IFNAR1À/Àmice is responsible for the reduced pI:C-induced sickness behaviour.
Glia, including astrocytes and microglia, can profoundly modulate neuronal function and behavior;... more 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. 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. 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. 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. 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.
The microbiome is now widely recognized as being important in health and disease, and makes up a ... more 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...
Environmental chemical exposures during critical windows of development may contribute to the esc... more 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 VEHexposed 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-1b response to an LPS challenge at postnatal day (P)30, whereas their central IL-1b 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. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.2 J.L. Bolton et al. / Brain, Behavior, and Immunity xxx (2013) xxx-xxx Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.
Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments f... more 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. ...
Proceedings of The Royal Society B: Biological Sciences, 2002
Symptoms of infection, such as fever, anorexia and lethargy, are ubiquitous among vertebrates. Ra... more 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
Neonatal infection has enduring effects on the brain, both at the cellular and behavioral levels.... more 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 fr...
Accumulating evidence suggests that outdoor air pollution may have a significant impact on centra... more 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.
Differential allocation of energy to reproduction versus host defense is assumed to drive the sea... more Differential allocation of energy to reproduction versus host defense is assumed to drive the seasonal antiphase relation be- tween peak reproductive function and immunocompetence; however, evidence supporting this assumption is only correla- tional. 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
Bilbo, Staci D., and Randy J. Nelson. Sex steroid hor-mones enhance immune function in male and f... more Bilbo, Staci D., and Randy J. Nelson. Sex steroid hor-mones enhance immune function in male and female Sibe-rian hamsters. Am J Physiol Regulatory Integrative Comp Physiol 280: R207卤R213, 2001.DImmune function is better in females than in males of many vertebrate species, and this dimorphism has been attributed to the presence of immuno-suppressive androgens in males. We investigated the in炉u-ence of
Proceedings of The National Academy of Sciences, 2002
Environmental conditions influence the onset and severity of infection and disease. Stressful con... more 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
Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked... more 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 long-term 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 (e.g., interleukin [IL]-6, IL-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (e.g., 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.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 9, 2013
Recent evidence indicates that inflammatory insults in neonates significantly influenced white ma... more 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 h...
The field of autism research is currently divided based on a fundamental question regarding the n... more 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. 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 a...
In addition to marked seasonal changes in reproductive, metabolic, and other physiological functi... more 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.
Several lines of evidence support the view that autism is a typical member of a large family of i... more 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.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2003
Changes in day length affect several measures of immunity in seasonally breeding mammals. In Sibe... more 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.
An immune challenge during the neonatal period can significantly affect the development of the ne... more 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 24 h 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.
Polyinosinic:polycytidylic acid (poly I:C), an agonist for TLR3, induces type-I interferons and o... more Polyinosinic:polycytidylic acid (poly I:C), an agonist for TLR3, induces type-I interferons and other inflammatory mediators such as TNF-alpha, IL-6 and to a lesser extent IL-1beta. Poly I:C induces sickness behaviour in mice and it is known that type-I interferons impact on behaviour and CNS function. Here we assess the role of type-I interferons in pI:C-induced sickness behaviour. Type-I interferon receptor 1 knockout (IFNAR1À/À) and WT C57BL/6 mice were challenged with pI:C (12 mg/kg i.p). IFNAR1À/Àanimals displayed reduced sickness behaviour compared to WT mice and only WT animals displayed a significant hypothermic response. All mice showed a reduction in weight 28 h post-challenge but full recovery was more rapid in IFNAR1À/Àmice. In addition to this, 3 h post-challenge, WT mice showed decreased activity in the open field with respect to IFNAR1À/À. As expected, the interferon responsive genes PKR and IRF7 were not induced by pI:C in IFNAR1À/Àmice. While IL-1beta and TNF-alpha responses to pI:C were equivalent in KO and WT in blood, hippocampus and hypothalamus, there was no synthesis of IL-6 in IFNAR1À/Àin either blood or brain. These results demonstrate a role for type-I interferons in the sickness behaviour response to pI:C and in the induction of IL-6 responses. Further investigations will examine whether the IL-6 deficiency seen in IFNAR1À/Àmice is responsible for the reduced pI:C-induced sickness behaviour.
Glia, including astrocytes and microglia, can profoundly modulate neuronal function and behavior;... more 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. 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. 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. 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. 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.
The microbiome is now widely recognized as being important in health and disease, and makes up a ... more 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...
Environmental chemical exposures during critical windows of development may contribute to the esc... more 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 VEHexposed 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-1b response to an LPS challenge at postnatal day (P)30, whereas their central IL-1b 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. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.2 J.L. Bolton et al. / Brain, Behavior, and Immunity xxx (2013) xxx-xxx Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.
Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments f... more 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. ...
Proceedings of The Royal Society B: Biological Sciences, 2002
Symptoms of infection, such as fever, anorexia and lethargy, are ubiquitous among vertebrates. Ra... more 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
Neonatal infection has enduring effects on the brain, both at the cellular and behavioral levels.... more 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 fr...
Accumulating evidence suggests that outdoor air pollution may have a significant impact on centra... more 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.
Differential allocation of energy to reproduction versus host defense is assumed to drive the sea... more Differential allocation of energy to reproduction versus host defense is assumed to drive the seasonal antiphase relation be- tween peak reproductive function and immunocompetence; however, evidence supporting this assumption is only correla- tional. 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
Bilbo, Staci D., and Randy J. Nelson. Sex steroid hor-mones enhance immune function in male and f... more Bilbo, Staci D., and Randy J. Nelson. Sex steroid hor-mones enhance immune function in male and female Sibe-rian hamsters. Am J Physiol Regulatory Integrative Comp Physiol 280: R207卤R213, 2001.DImmune function is better in females than in males of many vertebrate species, and this dimorphism has been attributed to the presence of immuno-suppressive androgens in males. We investigated the in炉u-ence of
Proceedings of The National Academy of Sciences, 2002
Environmental conditions influence the onset and severity of infection and disease. Stressful con... more 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
Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked... more 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 long-term 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 (e.g., interleukin [IL]-6, IL-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (e.g., 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.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 9, 2013
Recent evidence indicates that inflammatory insults in neonates significantly influenced white ma... more 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 h...
The field of autism research is currently divided based on a fundamental question regarding the n... more 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. 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 a...
In addition to marked seasonal changes in reproductive, metabolic, and other physiological functi... more 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.
Several lines of evidence support the view that autism is a typical member of a large family of i... more 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.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2003
Changes in day length affect several measures of immunity in seasonally breeding mammals. In Sibe... more 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.
An immune challenge during the neonatal period can significantly affect the development of the ne... more 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 24 h 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.
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Papers by Staci Bilbo