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1.  A model for the induction of autism in the ecosystem of the human body: the anatomy of a modern pandemic? 
Microbial Ecology in Health and Disease  2015;26:10.3402/mehd.v26.26253.
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
PMCID: PMC4310853  PMID: 25634608
microbiome; fauna; autism; pandemic
2.  A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia 
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.
doi:10.1007/s11481-011-9299-y
PMCID: PMC3267003  PMID: 21822589
3.  FACS analysis of neuronal-glial interactions in the Nucleus Accumbens following morphine administration 
Psychopharmacology  2013;230(4):525-535.
Rationale
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 non-specific glial inhibitor, ibudilast, has no effect on the initial rewarding properties of morphine, but completely prevents the relapse of drug-seeking behavior months later.
Objectives
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.
Methods
We used fluorescence-activated cell sorting (FACS) 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.
Results
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.
Conclusions
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.
doi:10.1007/s00213-013-3180-z
PMCID: PMC4134011  PMID: 23793269
microglia; astrocytes; chemokines; opioid; dopamine
4.  Is Autism a Member of a Family of Diseases Resulting from Genetic/Cultural Mismatches? Implications for Treatment and Prevention 
Autism Research and Treatment  2012;2012:910946.
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.
doi:10.1155/2012/910946
PMCID: PMC3420574  PMID: 22928103
5.  Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms 
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.
PMCID: PMC4214174  PMID: 25364282
anxiety; cognition; epigenetics; maternal high-fat diet; maternal obesity; microglia; neuroinflammation; perinatal programming; placenta
6.  BACTERIAL INFECTION EARLY IN LIFE PROTECTS AGAINST STRESSOR-INDUCED DEPRESSIVE-LIKE SYMPTOMS IN ADULT RATS 
Psychoneuroendocrinology  2008;33(3):261-269.
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 E. 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
PMCID: PMC2274778  PMID: 18164556
postnatal; cytokines; depression; sucrose preference; social exploration; corticosterone
7.  Stressor-Specific Alterations in Corticosterone and Immune Responses in Mice 
Brain, behavior, and immunity  2007;22(1):105-113.
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°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.
doi:10.1016/j.bbi.2007.07.012
PMCID: PMC2175078  PMID: 17890050
Restraint; Glucocorticoids; Low Temperature; Stressors; Stress; Isolation; Mice; Delayed-type Hypersensitivity
8.  Early-Life Programming of Later-Life Brain and Behavior: A Critical Role for the Immune System 
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)α, interleukin [IL]-1β, 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.
doi:10.3389/neuro.08.014.2009
PMCID: PMC2737431  PMID: 19738918
cytokines; memory; infection; microglia; interleukin-1; depression; anxiety; schizophrenia
9.  FRANK A. BEACH AWARD: Programming of Neuroendocrine Function by Early-Life Experience: A Critical Role for the Immune System 
Hormones and behavior  2013;63(5):684-691.
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 E. 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.
doi:10.1016/j.yhbeh.2013.02.017
PMCID: PMC3667966  PMID: 23474365
neonate; infection; microglia; development; learning; memory; Interleukin (IL)-1β; obesity; TLR4
10.  Neonatal E. Coli Infection Causes Neuro-Behavioral Deficits Associated with Hypomyelination and Neuronal Sequestration of Iron 
The Journal of Neuroscience  2013;33(41):16334-16345.
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.
doi:10.1523/JNEUROSCI.0708-13.2013
PMCID: PMC3792468  PMID: 24107964
11.  The Outdoor Air Pollution and Brain Health Workshop 
Neurotoxicology  2012;33(5):972-984.
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.
doi:10.1016/j.neuro.2012.08.014
PMCID: PMC3726250  PMID: 22981845
Air pollution; brain; particulate matter; ozone; central nervous system; susceptibility; epidemiology; neuroinflammation; neurotoxicity; behavior
12.  The Immune System and Developmental Programming of Brain and Behavior 
Frontiers in neuroendocrinology  2012;33(3):267-286.
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.
doi:10.1016/j.yfrne.2012.08.006
PMCID: PMC3484177  PMID: 22982535
microglia; cytokines; chemokines; cognition; hippocampus; Toll-like Receptors; infection; sensitive periods
13.  Maternal Stress and Effects of Prenatal Air Pollution on Offspring Mental Health Outcomes in Mice 
Environmental Health Perspectives  2013;121(9):1075-1082.
Background: 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.
Objectives: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Citation: Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL, Bilbo SD. 2013. Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environ Health Perspect 121:1075–1082; http://dx.doi.org/10.1289/ehp.1306560
doi:10.1289/ehp.1306560
PMCID: PMC3764088  PMID: 23823752
14.  Sex, Glia, and Development: interactions in health and disease 
Hormones and behavior  2012;62(3):243-253.
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 be 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.
doi:10.1016/j.yhbeh.2012.02.018
PMCID: PMC3374064  PMID: 22387107
15.  Adolescent Morphine Exposure Affects Long-Term Microglial Function and Later-Life Relapse Liability in a Model of Addiction 
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 sub-chronic 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 following drug re-exposure in adulthood. This effect was not seen in rats pre-treated with a sub-chronic 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 (NAcc) of these rats and determined that rats exposed to morphine during adolescence had a significant increase in Toll-like Receptor (TLR) 4 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.
doi:10.1523/JNEUROSCI.2516-12.2013
PMCID: PMC3713715  PMID: 23325235
16.  Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus 
Brain, Behavior, and Immunity  2012;26(3):500-510.
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.
doi:10.1016/j.bbi.2012.01.003
PMCID: PMC3294275  PMID: 22281279
17.  Sex differences in microglial colonization of the developing rat brain 
Journal of Neurochemistry  2012;120(6):948-963.
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.
doi:10.1111/j.1471-4159.2011.07630.x
PMCID: PMC3296888  PMID: 22182318
male; female; glia; cytokines; chemokines
18.  LPS Elicits a Much Larger and Broader Inflammatory Response than E. coli Infection within the Hippocampus of Neonatal Rats 
Neuroscience letters  2011;497(2):110-115.
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 hours 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.
doi:10.1016/j.neulet.2011.04.042
PMCID: PMC3103622  PMID: 21536105
neonate; E.coli infection; lipopolysaccharide; hippocampus; cytokines; chemokines
19.  Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression 
The Journal of Neuroscience  2011;31(49):17835-17847.
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 X 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
PMCID: PMC3259856  PMID: 22159099
20.  Microglia and Memory: Modulation by Early-life Infection 
The pro-inflammatory cytokine interleukin (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 prior to 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 to controls. However, an exaggerated IL-1β response in vivo requires LPS prior to 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.
doi:10.1523/JNEUROSCI.3688-11.2011
PMCID: PMC3224817  PMID: 22031897
cytokines; synaptic plasticity; hippocampus; early-life programming; microglia
21.  Early-life Infection is a Vulnerability Factor for Aging-Related Glial Alterations and Cognitive Decline 
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 E. coli, and then tested for learning & memory at 2 or 16 month of age, using 2 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 16 month. There were no differences in anxiety between groups. Neonatally-infected rats also exhibited greater aging-induced increases in glial markers (CD11b and MHC II 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.
doi:10.1016/j.nlm.2010.04.001
PMCID: PMC2881165  PMID: 20388544
22.  Neonatal E. coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats 
Neuroscience letters  2010;474(1):52-57.
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 (15 mg/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.
doi:10.1016/j.neulet.2010.03.006
PMCID: PMC2865898  PMID: 20223277
Amphetamine; Cytokines; Glia; Neonatal Infection; Adolescence; RT-PCR
23.  Enduring Consequences of Early-Life Infection on Glial and Neural Cell Genesis Within Cognitive Regions of the Brain 
Brain, behavior, and immunity  2009;24(3):329-338.
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 pre-frontal 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.
doi:10.1016/j.bbi.2009.09.012
PMCID: PMC2826544  PMID: 19782746
24.  Short day lengths attenuate the symptoms of infection in Siberian hamsters. 
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
PMCID: PMC1690914  PMID: 11886635

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