Early-life Immune Activation Research Articles

High-intensity interval training ameliorates postnatal immune activation-induced mood disorders through KDM6B-regulated glial activation

Postnatal immune activation (PIA) induces persistent glial activation in the brain and causes various neuropathologies in adults. Exercise training improves stress-related mood disorders; however, the role of exercise in psychiatric disorders induced by early-life immune activation and the association between exercise training and glial activation remain unclear. We compared the effects of different exercise intensities on the PIA model, including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Both HIIT and MICT in adolescent mice inhibited neuroinflammation, remodeled synaptic plasticity, and improved PIA-induced mood disorders in adulthood. Importantly, HIIT was superior to MICT in terms of reducing inflammation and increasing body weight. RNA-seq of prefrontal cortex (PFC) tissues revealed a gene expression pattern, confirming that HIIT was more effective than MICT in improving brain glial cell activation through epigenetic modifications of KDM6B. We investigated the role of KDM6B, a specific histone lysine demethylation enzyme — histone 3 lysine 27 demethylase, in inhibiting glial activation against PIA-induced depression and anxiety by regulating the expression of IL-4 and brain-derived neurotrophic factor (BDNF). Overall, our data support the idea that HIIT improves PIA-induced mood disorders by regulating KDM6B-mediated epigenetic mechanisms and indicate that HIIT might be superior to MICT in improving mood disorders with PIA in mice. Our findings provide new insights into the treatment of anxiety and depression disorders.

Early-life immune activation is a vulnerability factor for adult epileptogenesis in neurofibromatosis type 1 in male mice.

Patients with Neurofibromatosis type 1 (NF1), the most common neurocutaneous disorder, can develop several neurological manifestations that include cognitive impairments and epilepsy over their lifetime. It is unclear why certain patients with NF1 develop these conditions while others do not. Early-life immune activation promotes later-life seizure susceptibility, neurocognitive impairments, and leads to spontaneous seizures in some animal models of neurodevelopmental disorders, but the central nervous system immune profile and the enduring consequences of early-life immune activation on the developmental trajectory of the brain in NF1 have not yet been explored. We tested the hypothesis that early-life immune activation promotes the development of spatial memory impairments and epileptogenesis in a mouse model of NF1. Male wild-type (WT) and Nf1+/- mice received systemic lipopolysaccharide (LPS) or saline at post-natal day 10 and were assessed in adulthood for learning and memory deficits in the Barnes maze and underwent EEG recordings to look for spontaneous epileptiform abnormalities and susceptibility to challenge with pentylenetetrazole (PTZ). Whereas early-life immune activation by a single injection of LPS acutely elicited a comparable brain cytokine signature in WT and Nf1+/- mice, it promoted spontaneous seizure activity in adulthood only in the Nf1+/- mice. Early-life immune activation affected susceptibility to PTZ-induced seizures similarly in both WT and Nf1+/-mice. There was no effect on spatial learning and memory regardless of mouse genotype. Our findings suggest second-hit environmental events such as early-life immune activation may promote epileptogenesis in the Nf1+/- mouse and may be a risk-factor for NF1-associated epilepsy.

Combined Effect of Maternal Separation and Early-Life Immune Activation on Brain and Behaviour of Rat Offspring.

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2-14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33-35 and P42-50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52-55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes.

Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function

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.

Effects of a gut-selective integrin-targeted therapy in male mice exposed to early immune activation, a model for the study of autism spectrum disorder

To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (α4β7 mAb), blocking the leukocyte homing into the gut mucosa. EIA is a double-hit variant of the maternal immune-activation (MIA) model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges.In C57BL6/J EIA male adult offspring mice, IL-1β and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4+α4β7+, unstimulated and stimulated IL-17A+ and stimulated IFN-γ+ lymphocytes in MLN and CD4+α4β7+ unstimulated and stimulated IL-17A+ and stimulated IFN-γ+ lymphocytes in the spleen. Treatment with anti-α4β7 mAb in EIA male mice was associated with colonic tissue IL-1β, and IL-17A mRNA content and percentage of CD4+ IL-17A+ and IFN-γ+ lymphocytes in MLN and spleens comparable to control mice. The anti-α4β7 mAb treatment rescue social novelty deficit showed in the three-chamber test by EIA male mice. Increased levels of IL-6 and IL-1β and decreased CD68 and TGF-β mRNAs were also observed in hippocampus and prefrontal cortex of EIA male mice together with a reduction of BDNF mRNA levels in all brain regions examined. Anti-α4β7 mAb treatment restored the expression of BDNF, TGF-β and CD68 in hippocampus and prefrontal cortex.Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first preclinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (α4β7+) lymphocytes expressing IL-17A.

Neonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment

While the precise processes underlying a sex bias in the development of central nervous system (CNS) disorders are unknown, there is growing evidence that an early life immune activation can contribute to the disease pathogenesis. When we mimicked an early systemic viral infection or applied murine cytomegalovirus (MCMV) systemically in neonatal female and male mice, only male adolescent mice presented behavioral deficits, including reduced social behavior and cognition. This was paralleled by an increased amount of infiltrating T cells in the brain parenchyma, enhanced interferon-γ (IFNγ) signaling, and epigenetic reprogramming of microglial cells. These microglial cells showed increased phagocytic activity, which resulted in abnormal loss of excitatory synapses within the hippocampal brain region. None of these alterations were seen in female adolescent mice. Our findings underscore the early postnatal period’s susceptibility to cause sex-dependent long-term CNS deficiencies following infections.

Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: Considerations of timing, severity, individual differences, and sex in human and rodent studies.

Epidemiological evidence suggests that one's risk of being diagnosed with a neurodevelopmental disorder (NDD)-such as autism, ADHD, or schizophrenia-increases significantly if their mother had a viral or bacterial infection during the first or second trimester of pregnancy. Despite this well-known data, little is known about how developing neural systems are perturbed by events such as early-life immune activation. One theory is that the maternal immune response disrupts neural processes important for typical fetal and postnatal development, which can subsequently result in specific and overlapping behavioral phenotypes in offspring, characteristic of NDDs. As such, rodent models of maternal immune activation (MIA) have been useful in elucidating neural mechanisms that may become dysregulated by MIA. This review will start with an up-to-date and in-depth, critical summary of epidemiological data in humans, examining the association between different types of MIA and NDD outcomes in offspring. Thereafter, we will summarize common rodent models of MIA and discuss their relevance to the human epidemiological data. Finally, we will highlight other factors that may interact with or impact MIA and its associated risk for NDDs, and emphasize the importance for researchers to consider these when designing future human and rodent studies. These points to consider include: the sex of the offspring, the developmental timing of the immune challenge, and other factors that may contribute to individual variability in neural and behavioral responses to MIA, such as genetics, parental age, the gut microbiome, prenatal stress, and placental buffering.

Reduced inhibition underlies early life LPS exposure induced-cognitive impairment: Prevention by environmental enrichment

Early life immune activation has negative effects on the development of central nervous system and cognitive function, yet the underlying mechanism remains unclear. Increasing evidence has demonstrated that inflammation induces changes in microglia morphology, which lead to excessive synaptic pruning and improper function of neural circuits. Therefore, we hypothesized that early immune activation induced microglia activation, contributing to synaptic and cognitive impairments in adolescent mice. To establish the animal model of early immune activation, pups received a single intraperitoneal injection of 100 μg/kg lipopolysaccharide (LPS) on postnatal 10 (P10). Environmental enrichment (EE) was conducted four hours per day during P10-P38. Behavioral tests were performed by open field (P39), elevated plus-maze (P40) and Y maze tests (P41). The protein levels of glutamic acid decarboxylas67 (GAD67), parvalbumin (PV), vesicular gaba amino acid transporter (vGAT) and vesicular glutamate transporters (vGLUT1) were determined in the hippocampi and medial prefrontal cortex (mPFC). The protein levels of nuclear factor κB (NF-κB)/p65, NF-κB/p50, interleukin-1β (IL-1β), tumor necrosis factor - ɑ (TNF-ɑ) were determined in the hippocampi. The dendritic spine density was evaluated in the CA1 of the hippocampus. In our study, we showed that early life LPS exposure induced microglia activation and excessive inhibitory synapse engulfment, decreased number of perisomatic puncta on both inhibitory PV interneurons and excitatory neurons, which might contribute to excitation/inhibition imbalance, dendritic spine loss, and cognitive impairment in adolescent mice. Notably, EE rescued most of these abnormalities and improved cognitive impairment. In conclusion, our study demonstrated that reduced inhibition might contribute to early life LPS exposure induced-cognitive impairment. We also provided the possibility of the protective role of EE in rescuing these long-term adverse effects.

Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan.

ABSTRACTAn early-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. Using Drosophila as a model, we find that activation of innate immune pathway Immune deficiency (Imd) signalling in the developing larvae increases adult starvation resistance, decreases food intake and shortens organismal lifespan. Interestingly, lifespan is shortened by Imd activation in the larval gut and fat body, whereas starvation resistance and food intake are altered by that in neurons. The adult flies that developed with Imd activation show sustained Imd activity in the gut, despite complete tissue renewal during metamorphosis. The larval Imd activation increases an immunostimulative bacterial species, Gluconobacter sp., in the gut microbiome, and this dysbiosis is persistent to adulthood. Removal of gut microbiota by antibiotics in the adult fly mitigates intestinal immune activation and rescues the shortened lifespan. This study demonstrates that early-life immune activation triggers long-term physiological changes, highlighted as an irreversible alteration in gut microbiota, prolonged inflammatory intestine and concomitant shortening of the organismal lifespan.

Examining the impact of neuroimmune dysregulation on social behavior of male and female juvenile rats

Many individuals diagnosed with neuropsychiatric disorders, such as autism, attention-deficit/hyperactivity disorder, schizophrenia, and social anxiety disorder, all share a common dimension of aberrant social behavior. Epidemiological data indicate that adverse environmental factors contribute to the risk for neurodevelopmental disorders, including those associated with aberrant social behavior. Early-life exposure to infectious pathogens is one of those adverse environmental factors, suggesting that activation of the immune system during early development may contribute to disease pathology associated with altered social behavior. In the current project, we examined the impact of neonatal infection, with or without juvenile immune activation, on the expression of juvenile social behavior and on the expression of inflammatory cytokines and microglial signaling molecules in the juvenile rat brain. The outcomes of these experiments revealed that neonatal infection significantly decreased juvenile social interaction, but significantly increased juvenile play behavior in male and female rats. Moreover, neonatal infection alone, juvenile immune activation alone, and neonatal infection plus juvenile immune activation all significantly impaired social recognition in juvenile male rats. Juvenile female rats (including controls) did not demonstrate social recognition as measured in our three-chamber social recognition test. Taken together, the behavioral and molecular data presented here support the sensitivity of the developing brain to immune activation, particularly in the expression of age-appropriate social behaviors. These data warrant the design of additional studies to examine the mechanistic relationship between early-life immune activation and aberrant social behavior to develop novel as well as modify existing therapeutic targets and preventative measures to help those who display aberrant social behavior.

The effects of early-life immune activation on microglia-mediated neuronal remodeling and the associated ontogeny of hippocampal-dependent learning in juvenile rats

Many neurodevelopmental disorders and associated learning deficits have been linked to early-life immune activation or ongoing immune dysregulation (Laskaris et al., 2016; O’Connor et al., 2014; Frick et al., 2013). Neuroscientists have begun to understand how the maturation of neural circuits allows for the emergence of cognitive and learning behaviors; yet we know very little about how these developing neural circuits are perturbed by certain events, including risk-factors such as early-life immune activation and immune dysregulation. To answer these questions, we examined the impact of early-life immune activation on the emergence of hippocampal-dependent learning in juvenile male and female rats using a well-characterized hippocampal-dependent learning task and we investigated the corresponding, dynamic multicellular interactions in the hippocampus that may contribute to these learning deficits. We found that even low levels of immune activation can result in hippocampal-depedent learning deficits days later, but only when this activation occurs during a sensitive period of development. The initial immune response and associated cytokine production in the hippocampus resolved within 24 h, several days prior to the observed learning deficit, but notably the initial immune response was followed by altered microglial-neuronal communication and synapse remodeling that changed the structure of hippocampal neurons during this period of juvenile brain development. We conclude that immune activation or dysregulation during a sensitive period of hippocampal development can precipitate the emergence of learning deficits via a multi-cellular process that may be initiated by, but not the direct result of the initial cytokine response. Significance StatementMany neurodevelopmental disorders have been linked to early-life immune activation or immune dysregulation; however, very little is known about how dynamic changes in neuroimmune cells mediate the transition from normal brain function to the early stages of cognitive disorders, or how changes in immune signaling are subsequently integrated into developing neuronal networks. The current experiments examined the consequences of immune activation on the cellular and molecular changes that accompany the emergence of learning deficits during a sensitive period of hippocampal development. These findings have the potential to significantly advance our understanding of how early-life immune activation or dysregulation can result in the emergence of cognitive and learning deficits that are the largest source of years lived with disability in humans.

Reduced Inhibition Underlies Early Life LPS Exposure Induced-Cognitive Impairment: Prevention by Environmental Enrichment

Early life immune activation has negative effects on the development of central nervous system and cognitive function, yet the underlying mechanism remains unclear. Increasing evidence has demonstrated that inflammation induces changes in microglia morphology, which lead to excessive synaptic pruning and improper function of neural circuits. Therefore, we hypothesized that early immune activation induced microglia activation, contributing to synaptic and cognitive impairments in adolescent mice. To establish the animal model of early immune activation, pups received a single intraperitoneal injection of 100 μg/kg lipopolysaccharide (LPS) on postnatal 10 (P10). Environmental enrichment (EE) was conducted four hours per day during P10-P38. Behavioral tests were performed by open field (P39), elevated plus-maze (P40) and Y maze tests (P41). The protein levels of glutamic acid decarboxylas67 (GAD67), parvalbumin (PV), vesicular gaba amino acid transporter (vGAT) and vesicular glutamate transporters (vGLUT1) were determined in the hippocampi and medial prefrontal cortex (mPFC). The dendritic spine density was evaluated in the CA1 of the hippocampus. In our study, we showed that early life LPS exposure induced microglia activation and excessive inhibitory synapse engulfment, decreased number of perisomatic puncta on both inhibitory PV interneurons and excitatory neurons, which might contribute to excitation/inhibition imbalance, dendritic spine loss, and cognitive impairment in adolescent mice. Notably, EE rescued most of these abnormalities and improved cognitive impairment. In conclusion, our study demonstrated that reduced inhibition might contribute to early life LPS exposure induced-cognitive impairment. We also provided the possibility of the protective role of EE in rescuing these long-term adverse effects.

Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females. Here we examined the effects of early-life immune system activation (EIA)—comprising regimens of prenatal, early postnatal, or combined (“two-hit”) immune activation—on the core behavioral features of ASD (decreased social interaction, increased repetitive behavior, and aberrant communication) in C57BL/6J mice. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C) on gestational day 12.5 to produce maternal immune activation (MIA). Some offspring also received lipopolysaccharide (LPS) on postnatal day 9 to produce postnatal immune activation (PIA). EIA produced disruptions in social behavior and increases in repetitive behaviors that were larger in males than in females. Ultrasonic vocalizations (USVs) were altered in both sexes. Molecular studies revealed that EIA also produced prominent sex-specific changes in inflammation-related gene expression in the brain. Whereas both sexes showed increases in pro-inflammatory factors, as reflected by levels of mRNA and protein, expression of anti-inflammatory factors was decreased in males but increased in females. Our findings demonstrate that EIA can produce sex-specific behavioral effects and immune responses in the brain, and identify molecular processes that may contribute to resilience in females.

Affective Behavior Shows Sex Differences in Mid-adulthood Rats Following Postnatal Immune Stimulation

Mid-adulthood represents the critical window period usually associated with the development of age-related diseases. Despite several attempts to delineate the pathological mechanisms underlying postnatal immune challenge and altered brain functions, the role of sex-dependent changes in affective behaviors of middle-aged animals requires more attention. In this study, we sought to investigate behavioral and molecular response patterns at mid-adulthood linked to early-life immune activation. Using affective behavioral test batteries, we showed that lipopolysaccharide (LPS)-induced postnatal immune challenge caused anxiety-like behaviors in both male and female Wistar rats at mid-adulthood, whereas only female rats exhibited depression-like behaviors. Our data further demonstrated a significant increase in microglial complexity and increased levels of tumor necrosis factor (TNFα), nitric oxide (NOx), and lipid peroxidation in the prefrontal cortex of female rats compared to their male counterparts and phosphate-buffered saline (PBS) littermate controls. With these results, we established significant interaction between sex differences and LPS-induced alterations in behavior and associated oxidative and immunohistochemical changes. These findings may provide an insight to better understand the neuroimmunological mechanisms of sex-dependent brain pathological manifestations occurring at mid-adulthood. [Display omitted]

Abstract # 3149 Sex differences in the consequences of early-life immune activation on microglia-neural signaling and the ontogeny of hippocampal-dependent learning in the juvenile rat

Developmental disorders associated with learning deficits, including Autism, have been linked to early-life immune activation, and notably, are male-biased. Microglia are the immune cells of the brain and are in constant communication with neurons, thus, microglia influence the function of surrounding neurons. Recent data indicate that microglia-neuron signaling is necessary for the proper formation of neural circuits during brain development. We determined that immune activation with lipopolysaccharide (LPS; 100ug/ml/kg) on postnatal day (P) 21 produces sex-dependent deficits in the emergence of hippocampal-dependent learning on P24 in rats. Gene expression analysis in the hippocampus at 2-, 4-, 8-, and 24-h following LPS showed sex differences in IL-1 β and IL-6 expression. Males, but not females, have a persistent decrease in BDNF expression starting 4hr post-LPS that persists until 24hr and an increase in C3 expression, an immune molecule that tags synapses for elimination, at 24hr. We are investigating whether we can rescue learning deficits by administering the microglia inhibitor minocycline at the time of LPS. We found a sex difference in the effectiveness of minocycline such that minocycline inhibits microglia in males, but is not as effective in females. Behavioral results following minocycline treatment will be discussed. Our data suggest that changes in microglia-neural communication following early-life immune activation are different in males and females, thus males and females may respond differently to therapies that target microglia.

Abstract # 3106 Sex-biased mitochondrial and behavioral alterations following early-life immune activation

Autism Spectrum Disorders (ASDs) are a collection of complex neurodevelopmental disorders characterized by repetitive behavior and alterations in social interaction/communication. ASD occurs in 1 in 68 children in the US, with a strong sex bias in prevalence ( ∼ 4 males affected to every 1 female). Multiple reports have revealed pervasive immune and mitochondrial abnormalities in ASD patients. Increasing evidence suggests that mitochondrial function is inhibited during proinflammatory microglial activation, although no sex differences remain underexplored. Postmortem analyses of brains from children with ASD revealed significant decreases in expression of mitochondrial electron transport chain (ETC) subunits; however, analyses did not distinguish between cell type or sex. In an early-life immune activation (lipopolysaccharide;LPS) model of ASD, we isolated microglia from prefrontal cortex of PN30 mice. By PCR array, we found that ∼ 96% of mitochondrial ETC genes were strongly diminished by LPS in male microglia, while only ∼ 6% were similarly decreased in females, suggesting that reduced mitochondrial function may be implicated in microglial activation, particularly in males. We show that early-life LPS results in decreased social exploration in both males and females at PN15, but only increased latency to enter stranger bedding in male mice. By PN60, early-life LPS treatment resulted in decreased sociability and social novelty seeking in males only. These data indicate sex-biased deficits in social interaction and anxiety that are related to clinical manifestations of ASD.

Sex- and region-specific differences in microglia phenotype and characterization of the peripheral immune response following early-life infection in neonatal male and female rats

Early-life infection has been shown to have profound effects on the brain and behavior across the lifespan, a phenomenon termed “early-life programming”. Indeed, many neuropsychiatric disorders begin or have their origins early in life and have been linked to early-life immune activation (e.g. autism, ADHD, and schizophrenia). Furthermore, many of these disorders show a robust sex bias, with males having a higher risk of developing early-onset neurodevelopmental disorders. The concept of early-life programming is now well established, however, it is still unclear how such effects are initiated and then maintained across time to produce such a phenomenon. To begin to address this question, we examined changes in microglia, the immune cells of the brain, and peripheral immune cells in the hours immediately following early-life infection in male and female rats. We found that males showed a significant decrease in BDNF expression and females showed a significant increase in IL-6 expression in the cerebellum following E.coli infection on postnatal day 4; however, for most cytokines examined in the brain and in the periphery we were unable to identify any sex differences in the immune response, at least at the time points examined. Instead, neonatal infection with E.coli increased the expression of a number of cytokines in the brain of both males and females similarly including TNF-α, IL-1β, and CD11b (a marker of microglia activation) in the hippocampus and, in the spleen, TNF-α and IL-1β. We also found that protein levels of GRO-KC, MIP-1a, MCP1, IP-10, TNF-α, and IL-10 were elevated 8-hours postinfection, but this response was resolved by 24-hours. Lastly, we found that males have more thin microglia than females on P5, however, neonatal infection had no effect on any of the microglia morphologies we examined. These data show that sex differences in the acute immune response to neonatal infection are likely gene, region, and even time dependent. Future research should consider these factors in order to develop a comprehensive understanding of the immune response in males and females as these changes are likely the initiating agents that lead to the long-term, and often sex-specific, effects of early-life infection.

Early-life sickness may predispose Siberian hamsters to behavioral changes following alterations of the gut microbiome in adulthood

Although it is well-established that the immune system plays an important role in the development of physiology and behavior, the gut microbiome has recently become of interest in the study of developmental origins of behavior. Studies suggest that the effects of early-life immune activation may not occur until a secondary stressor is introduced, though the precise nature and timing of the stressor may be critical in the response. Further, recent work suggests that the microbiome and the immune system develop in parallel, and therefore any perturbations to one of these systems early in life will likely affect the other. Here, we sought to determine whether early-life activation of the immune system had long-term consequences on how the gut microbiome responds to antibiotic treatment in adulthood and whether those changes influence adult same-sex social behavior. In order to test the hypothesis that an early-life immune challenge makes individuals more vulnerable to the effects of antibiotics, we mimicked an early-life infection by injecting pups at postnatal day 3 and 5 with lipopolysaccharide (LPS; cell wall component of gram-negative bacteria) or saline, and subsequently exposed the same animals to antibiotic treatment (known to influence microbial community composition and behavior) or water in adulthood. We tracked physiology across development, and paired males and females with a novel individual of the same age and sex in adulthood to score same-sex behavior (e.g., aggression, investigation, grooming) before antibiotic treatment, immediately following treatment, and after recovery from antibiotics. LPS-treated females exhibited impaired reproductive physiology and function in adulthood (e.g., smaller ovaries and abnormal estrous cycles), and female and male gut microbial communities were strongly affected by antibiotic treatment in adulthood, but only slightly affected by postnatal LPS alone. Interestingly, LPS-treated males exhibited more robust changes in their behavioral response following adult antibiotic treatment, including decreased investigation and increased grooming, suggestive of changes in anxiety-like behaviors. These data suggest that males may be more vulnerable than females to behavioral abnormalities after being predisposed to an immune challenge early in life. Collectively, these results provide novel evidence that some of the sex-specific behavioral consequences of an early-life immune challenge may not transpire until an individual is faced with a secondary challenge, and the context in which an individual is exposed can greatly influence the response.

Early‐Life Sickness May Predispose Individuals to Behavioral Changes Following Gut Dysbiosis in Adulthood

Although it is well‐established that the immune system plays an important role in the development of physiology and behavior, the gut microbiome has recently become of interest in the study of developmental origins of behavior. Some studies suggest that the effects of early‐life immune activation may not occur until a secondary stressor is introduced, though the precise nature and timing of the stressor may be critical in the response. In order to test the hypothesis that early‐life immune stress makes an individual more vulnerable to future insults, we mimicked an early‐life infection by injecting pups at postnatal day 3 and 5 with lipopolysaccharide (LPS; cell wall component of gram‐negative bacteria) or saline, and subsequently exposed the same animals to antibiotic treatment (known to influence microbial community composition ad behavior) or water in adulthood. We tracked physiology across development, and paired males and females with a novel individual of the same sex in adulthood to score behavior before antibiotic treatment, immediately following treatment, and after recovery from antibiotics. LPS‐treated females exhibited impaired reproductive physiology and function in adulthood (e.g., smaller ovaries and abnormal estrous cycles), and female and male gut microbial communities were strongly affected by antibiotic treatment in adulthood, but only slightly affected by postnatal LPS alone. Interestingly, LPS‐treated males exhibited more robust changes in their behavioral response following adult antibiotic treatment, including decreased investigation and increased grooming. These data suggest that males may be more vulnerable than females to behavioral abnormalities after being predisposed to an immune challenge early in life. Collectively, these results provide evidence that some of the sex‐specific behavioral consequences of a stressor may not transpire until an individual is faced with a secondary stressor, and the context in which an individual is exposed can greatly influence the response.Support or Funding InformationNational Institute of Child Health and Human Development (T32HD49336); National Science Foundation, Division of Integrative Organismal Systems (1656414); and Indiana UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Neonatal infection produces sex-specific changes in neuroimmune function with no associated deficits in spatial learning in juvenile rats

Immune activation during early development can have profound effects on later immune function, cognition, and behavior. Epidemiological data indicate a strong correlation between early-life immune activation and later diagnosis of disorders such as autism, schizophrenia, and depression. However, there has been little investigation into the impact of sex or early-life immune activation on the developing immune system or the ontogeny of cognitive processes, such as learning. Microglia are the resident immune cells of the brain and affect neural function and behavior. Male rats have more microglia than female rats in the hippocampus (HP) on postnatal day four (P4), suggesting that males may be more vulnerable to the long- term consequences of early-life immune activation than females. We examined the effect of neonatal immune activation (E.coli; 1 × 106 CFU/0.1 mL/kg) alone, or following a second immune challenge of LPS (Lipopolysaccharide; 25 μg/mL/kg), during late juvenile development on behavior and microglia function in males and females. Neither neonatal infection nor a second immune activation produced learning deficits. However, neonatal infection produced sex-specific alterations in CD11b, IL-β, and IL-6 in the HP, prefrontal cortex (PFC), and cerebellum. Additionally, we found sex-specific alterations in microglial density in CA3, dentate gyrus, and PFC. These data suggest that neonatal infection produces sex-specific changes in cytokine expression and microglia activation in juveniles, but the consequences of these changes may have a delayed effect on behavioral outcomes.