Neonatal overfeeding by small-litter rearing sensitises hippocampal microglial responses to immune challenge:Reversal with neonatal repeated injections of saline or minocycline

The early-life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper-responsive to an immune challenge, as well as hippocampal microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippocampal microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control-fed). We then examined the hippocampal microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippocampus after immune challenge compared to control-fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippocampus and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippocampal immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long-term impact, highlighting the importance of considering these effects when interpreting experimental data

Corrigendum to: Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation (Hippocampus, (2016), 26, (1435–1446), 10.1002/hipo22620)

© 2018 Wiley Periodicals, Inc. Published in Hippocampus 26:1435–1446 (2016) DOI: 10.1002/hipo22620 The authors of this article have notified us that one of the funding agencies was incorrectly acknowledged. The correct citation of the funding body is listed below: This work was supported by a Discovery Project Grant (DP130100508) and a Future Fellowship (FT110100084) from the Australian Research Council as well as an RMIT University Vice Chancellor's Senior Research Fellowship. We apologize for any inconvenience this may have caused

Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation.

Adolescence is a period of significant brain plasticity that can be affected by environmental factors, including the degree of physical activity. Here we hypothesized that adolescent rats would be more sensitive to the beneficial metabolic and anti-inflammatory effects of voluntary exercise than adult rats, whose more mature brains have less capacity for plasticity. We tested this by giving adolescent and adult Wistar rats four weeks' voluntary access to running wheels. At the end of this period we assessed metabolic effects, including weight and circulating leptin and ghrelin, as well as performance in a novel object recognition test of memory and central changes in neuronal proliferation, survival, synaptic density, and inflammatory markers in hippocampus. We found exercise reduced fat mass and circulating leptin levels in both adults and adolescents but suppressed total weight gain and lean mass in adults only. Exercise stimulated neuronal proliferation in the suprapyramidal blade of the dentate gyrus in both adults and adolescents without altering the number of mature neurons during this time frame. Exercise also increased dentate microglial numbers in adolescents alone and microglial numbers in this region were inversely correlated with performance in the novel object recognition test. Together these data suggest that adolescent hippocampal microglia are more sensitive to the effects of exercise than those of adults, but this leads to no apparent improvement in recognition memory. This article is protected by copyright. All rights reserved

Perinatal programming - integration of brain, behaviour and immunity: implications for reproductive fitness

Research Doctorate - Doctor of Philosophy (PhD)Events occurring in early life can induce long-term physiological and behavioural changes through the process of perinatal programming. The concept of perinatal programming has an adaptive value, preparing the foetus for specific extra-uterine demands. As such, early life adversity is thought to enhance an immediate survival via physiological adaptation when the postnatal environment is similar to the prenatal environment. However, under conditions of discrepancy between the early and later life environment, this adaptation may prove disadvantageous, leading to physiological and psychological changes that may predispose the organism to poorer long term health outcomes. Early life adversity, elicited by changes in the nutritional environment, or due to an exposure to stressful and traumatic events, has received increasing recent attention. One model of early life adversity that has been useful in modelling developmental outcomes associated with the early life environment is the model of “neonatal immune challenge”. Specifically, previous research has identified the early microbial environment as a critical factor in the development of mood and behaviour, with increased immune activation during neonatal life having been linked to an emergence of anxiety behaviours in adulthood. The primary aim of the current thesis was to investigate the immediate and long term effects of neonatal immune challenge on the neuroimmune and neuroendocrine pathways, which are proposed to underpin the altered behavioural phenotype. To achieve this aim the Wistar strain rat model was employed. To simulate an immune challenge, these animals were intraperitoneally administered lipopolysaccharide (LPS; Salmonella enterica, serotype enteritidis), on postnatal days (PNDs) 3 and 5 (birth = PND 1). Importantly, an established framework of an anxiety-like phenotype was expanded to encompass a wider range of behavioural changes. Thus, in addition to anxiety-like behaviours, sexual behaviour was examined, along with the underlying regulatory mechanisms of reproductive development and function. The first paper (Sominsky et al., 2012b) in this thesis reported that neonatal LPS exposure is associated with increased microglial activation in the adult brain, corresponding to an increase in anxiety-like behaviours. Given the mediating role of microglia in inflammation-induced psychopathology, the results of this study suggest a neuroimmune pathway which may underpin the long term behavioural changes observed in adulthood following neonatal LPS challenge. Moreover, the increase in microglial activation was specific to the hippocampal areas of the brain, suggesting a susceptibility of this primary HPA axis-regulatory region to neonatal immune challenge and thus supporting previous research which has demonstrated programming of the HPA axis activity by neonatal LPS exposure. The second paper (Sominsky et al., 2013a) investigated the neurocircuitry of the anxiety observed in relation to early life exposure to LPS, specifically by examining the central gene expression in association with peripheral endocrine and autonomic activity. The data indicated that neonatal LPS induces an altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus of adult rats. These changes were associated with a persistent elevation of circulating corticosterone. Furthermore, the long term effects of neonatal LPS exposure were examined for the first time on autonomic function. The data indicate that neonatal LPS exposure results in increased autonomic arousal, as indicated by increased activity of tyrosine hydroxylase in the adrenal glands and increased respiratory rate in response to mild sensory stress. The findings of Paper 2 therefore suggest that neonatal immune challenge produces a prolonged alteration in both central and peripheral measures of the HPA axis activity, associated with a persistent change in autonomic function, and potentially contributing to the anxiety-like phenotype. Given the link between anxiety and reproductive outcomes a subsequent paper further characterised the behavioural and reproductive profile of neonatally treated rats. Sexual behaviour as well as reproductive capacity were assessed in Paper 3 (Walker et al., 2011). Outcomes of this study revealed that neonatally treated rats exhibited impaired mating behaviours, accompanied by persistent HPG suppression. In addition, morphological assessment of the male gonads revealed immediate and long term alterations in the testicular morphology of LPS-treated males. A follow-up Paper 4 (Sominsky et al., 2012a) continued to explore these outcomes with a focussed analysis of reproductive development in the female rat, including ovarian morphology. In addition to alterations in the timing of pubertal onset and endocrine function, diminished ovarian follicular reserve was observed in LPS-treated females when compared to non-treated animals. Taken together the findings of Papers 3 and 4 suggest that neonatally LPS-treated rats demonstrate a subfertile phenotype in adulthood, and this is mediated by functional and morphological changes to the gonads, indicating for the first time a specific susceptibility of the developing gonads to an immune challenge. Therefore the aim of the final Paper 5 (Sominsky et al., 2013b) was to assess whether neonatal LPS may have a direct impact on ovarian development via alteration of the ovarian immune milieu. The results of this paper indicated that neonatal LPS exposure induces activation of inflammatory signalling in the ovary, potentially mediated via increased expression of Toll-like receptor (TLR) 4. Given that common bacterial infections, such as E.Coli and Chlamydia, are associated with increased TLR4 expression in reproductive tissues, which is thought to result in impaired fertility, the findings presented in Paper 5 provide a valuable insight into the link between early life infection and reproductive fitness. Taken together, the papers presented in this thesis demonstrate that neonatal immune challenge contributes to long term programming of physiology and behaviour, fundamentally influencing reproductive fitness and success. The novel insights presented in this thesis, particularly those related to programming of autonomic function and reproductive development, significantly contribute to the understanding of a critical role of the early microbial environment in determining the developmental trajectories of an organism and advance the current knowledge in the perinatal programming field. The observed effects of neonatal immune challenge may be placed into a wider perspective, integrating the continued interaction between the immune system, the brain, the gonads, and the behavioural outcomes of this interaction, reflective of phenotypic plasticity in response to the changing environment

Eating behavior and stress: a pathway to obesity (Review)

Stress causes or contributes to a huge variety of diseases and disorders. Recent evidence suggests obesity and other eating-related disorders may be among these. Immediately after a stressful event is experienced, there is a corticotropin-releasing-hormone (CRH)-mediated suppression of food intake. This diverts the body's resources away from the less pressing need to find and consume food, prioritizing fight, flight, or withdrawal behaviors so the stressful event can be dealt with. In the hours following this, however, there is a glucocorticoid-mediated stimulation of hunger and eating behavior. In the case of an acute stress that requires a physical response, such as a predator-prey interaction, this hypothalamic-pituitary-adrenal (HPA) axis modulation of food intake allows the stressful event to be dealt with and the energy used to be replaced afterward. In the case of ongoing psychological stress, however, chronically elevated glucocorticoids can lead to chronically stimulated eating behavior and excessive weight gain. In particular, stress can enhance the propensity to eat high calorie "palatable" food via its interaction with central reward pathways. Activation of this circuitry can also interact with the HPA axis to suppress its further activation, meaning not only can stress encourage eating behavior, but eating can suppress the HPA axis and the feeling of stress. In this review we will explore the theme of eating behavior and stress and how these can modulate one another. We will address the interactions between the HPA axis and eating, introducing a potential integrative role for the orexigenic hormone, ghrelin. We will also examine early life and epigenetic modulation of the HPA axis and how this can influence eating behavior. Finally, we will investigate the clinical implications of changes to HPA axis function and how this may be contributing to obesity in our society

The Role of Early Life Programming in Vulnerability and Resilience in Relation to HIV

Despite significant advances in HIV/AIDS research, the disease still impacts millions of people worldwide. The psychosocial environment of the patient plays an important role in the disease progression. Psychological stress, mental health issues and lack of social support contribute to a poor prognosis, particularly in those patients with prior exposure to these risk factors. Early life stress is known to affect mental health and modulate neuroendocrine and immune function long term, influencing individual's vulnerability to adult stress and compromised health status. This increased susceptibility to the adverse effects of stress may in turn promote the rate of HIV disease progression. Understanding the possible interactions between early life experiences of an infected individual and their ability to cope with the diagnosis and health consequences of HIV infection may shed light on the underlying biological mechanisms contributing to the disease progression and, thus, to improve current therapeutic strategies

Neuroinflammation and behaviour

No abstract availabl