The gut-brain and gut-macrophage contribution to gastrointestinal dysfunction with systemic inflammation.

The gastrointestinal tract is one of the main organs affected during systemic inflammation and disrupted gastrointestinal motility is a major clinical manifestation. Many studies have investigated the involvement of neuroimmune interactions in regulating colonic motility during localized colonic inflammation, i.e., colitis. However, little is known about how the enteric nervous system and intestinal macrophages contribute to dysregulated motility during systemic inflammation. Given that systemic inflammation commonly results from the innate immune response against bacterial infection, we mimicked bacterial infection by administering lipopolysaccharide (LPS) to rats and assessed colonic motility using ex vivo video imaging techniques. We utilized the Cx3cr1-Dtr rat model of transient depletion of macrophages to investigate the role of intestinal macrophages in regulating colonic motility during LPS infection. To investigate the role of inhibitory enteric neurotransmission on colonic motility following LPS, we applied the nitric oxide synthase inhibitor, Nω-nitro-L-arginine (NOLA). Our results confirmed an increase in colonic contraction frequency during LPS-induced systemic inflammation. However, neither the depletion of intestinal macrophages, nor the suppression of inhibitory enteric nervous system activity impacted colonic motility disruption during inflammation. This implies that the interplay between the enteric nervous system and intestinal macrophages is nuanced, and complex, and further investigation is needed to clarify their joint roles in colonic motility.

Ginsenosides enhance P2X7-dependent cytokine secretion from LPS-primed rodent macrophages.

The activation of P2X7 is a well-known stimulus for the NLRP3-caspase 1 inflammasome and subsequent rapid IL-1ß secretion from monocytes and macrophages. Here we show that positive allosteric modulators of P2X7, ginsenosides, can enhance the release of three important cytokines, IL-1ß, IL-6 and TNF-α from LPS-primed rodent macrophages using the J774 mouse macrophage cell line and primary rat peritoneal macrophages. We compared the immediate P2X7 responses in un-primed and LPS-primed macrophages and found no difference in calcium response amplitude or kinetics. These results suggest that under inflammatory conditions positive allosteric modulators are capable of increasing cytokine secretion at lower concentrations of ATP, thus boosting the initial pro-inflammatory signal. This may be important in the control of intracellular infections.

The role of microglia and monocytes in the generation and resolution of the immune response in female and male rats.

Microglia have long been thought to be responsible for the initiation of the central nervous system (CNS) immune response to pathogen exposure. However, we recently reported that depleting CNS microglia and circulating monocytes does not abrogate the sickness response in male rats or mice to bacterial endotoxin, lipopolysaccharide (LPS). How the central immune response to an endotoxin challenge is initiated and resolved in the absence of microglia and monocytes remains unclear. Here we investigated the role of microglia and monocytes in driving the behavioral, febrile and neuroimmune response to LPS using the Cx3cr1-Dtr rat model of conditional microglia/monocyte depletion, assessed if this role is similar in females and males, and examined how the response to an immune challenge might be initiated in the absence of these cells. We show that depletion of microglia and monocytes exacerbates the response to LPS at each phase of the immune cascade. Our data indicate that the changes in the central response to immune challenge may be an indirect effect of excess neutrophil expansion into the bloodstream and infiltration into peripheral organs stimulating a rapid and exacerbated cytokine and prostaglandin response to the LPS that is not curtailed by the usual negative feedback mechanisms. Thus, we show that a demonstrable immune response can be generated (and resolved) in the near complete absence of microglia and monocytes and that these cells play a regulatory role in the initiation and resolution of the response to an immune challenge, rather than being critical for it to occur.

Exercise regulates shelterin genes and microRNAs implicated in ageing in Thoroughbred horses.

Ageing causes a gradual deterioration of bodily functions and telomere degradation. Excessive telomere shortening leads to cellular senescence and decreases tissue vitality. Six proteins, called shelterin, protect telomere integrity and control telomere length through telomerase-dependent mechanisms. Exercise training appears to maintain telomeres in certain somatic cells, although the underlying molecular mechanisms are incompletely understood. Here, we examined the influence of a single bout of vigorous exercise training on leukocyte telomerase reverse transcriptase (TERT) and shelterin gene expression, and the abundance of three microRNAs (miRNAs) implicated in biological ageing (miRNA-143, -223 and -486-5p) in an elite athlete and large animal model, Thoroughbred horses. Gene and miRNA expression were analysed using primer-based and TaqMan Assay qPCR. Leukocyte TRF1, TRF2 and POT1 expression were all significantly increased whilst miR-223 and miR-486-5p were decreased immediately after vigorous exercise (all p < 0.05), and tended to return to baseline levels 24 h after training. Relative to the young horses (~ 3.9 years old), middle-aged horses (~ 14.8 years old) exhibited reduced leukocyte TERT gene expression, and increased POT1 and miR-223 abundance (all p < 0.05). These data demonstrate that genes transcribing key components of the shelterin-telomere complex are influenced by ageing and dynamically regulated by a single bout of vigorous exercise in a large, athletic mammal - Thoroughbred horses. Our findings also implicate TERT and shelterin gene transcripts as potential targets of miR-223 and miR-486-5p, which are modulated by exercise and may have a role in the telomere maintenance and genomic stability associated with long-term aerobic training.

Examining enteric nervous system function in rat and mouse: an interspecies comparison of colonic motility.

Gastrointestinal motility is crucial to gut health and has been associated with different disorders such as inflammatory bowel diseases and postoperative ileus. Despite rat and mouse being the two animal models most widely used in gastrointestinal research, minimal studies in rats have investigated gastrointestinal motility. Therefore, our study provides a comparison of colonic motility in the mouse and rat to clarify species differences and assess the relative effectiveness of each animal model for colonic motility research. We describe the protocol modifications and optimization undertaken to enable video imaging of colonic motility in the rat. Apart from the broad difference in terms of gastrointestinal diameter and length, we identified differences in the fundamental histology of the proximal colon such that the rat had larger villus height-to-width and villus height-to-crypt depth ratios compared with mouse. Since gut motility is tightly regulated by the enteric nervous system (ENS), we investigated how colonic contractile activity within each rodent species responds to modulation of the ENS inhibitory neuronal network. Here we used Nω-nitro-l-arginine (l-NNA), an inhibitor of nitric oxide synthase (NOS) to assess proximal colon responses to the stimulatory effect of blocking the major inhibitory neurotransmitter, nitric oxide (NO). In rats, the frequency of proximal colonic contractions increased in the presence of l-NNA (vs. control levels) to a greater extent than in mice. This is despite a similar number of NOS-expressing neurons in the myenteric plexus across species. Given this increase in colonic contraction frequency, the rat represents another relevant animal model for investigating how gastrointestinal motility is regulated by the inhibitory neuronal network of the ENS.NEW & NOTEWORTHY Mice and rats are widely used in gastrointestinal research but have fundamental differences that make them important as different models for different questions. We found that mice have a higher villi length-to-width and villi length-to-crypt depth ratio than rat in proximal colon. Using the ex vivo video imaging technique, we observed that rat colon has more prominent response to blockade of major inhibitory neurotransmitter (nitric oxide) in myenteric plexus than mouse colon.

Microglial ablation in rats disrupts the circadian system.

Microglia, the key neuroimmune cells of the central nervous system, are best known for their function in defending an individual from pathogens and injury. Recent findings, including our own, suggest microglia also have several immune-independent roles, including in regulating satiety, promoting memory, and modifying pain responses. Many of these microglia-associated functions are affected by circadian rhythmicity, thus, varying substantially depending upon the time of day. To gain further insight into this link, we used a Cx3cr1-Dtr transgenic Wistar rat model to acutely deplete microglia and examined if this could lead to a disruption in diurnal temperature, metabolism, and activity measures. We also examined if differences in the physiological rhythms corresponded with changes in the expression of key circadian rhythm-regulating genes and proteins. Our data show that in the absence of microglia there is a pronounced disruption of diurnal rhythms in several domains consistent with a shift toward the inactive phase, in conjunction with changes in circadian rhythm-regulating genes and proteins. These data suggest microglia are involved in the regulation of circadian rhythms and indicate an exciting potential to manipulate these cells to improve disrupted circadian rhythms such as with shift-work or jet-lag.

Ovarian follicles are resistant to monocyte perturbations-implications for ovarian health with immune disruption†.

Monocytes and macrophages are the most abundant immune cell populations in the adult ovary, with well-known roles in ovulation and corpus luteum formation and regression. They are activated and proliferate in response to immune challenge and are suppressed by anti-inflammatory treatments. It is also likely they have a functional role in the healthy ovary in supporting the maturing follicle from the primordial through to the later stages; however, this role has been unexplored until now. Here, we utilized a Cx3cr1-Dtr transgenic Wistar rat model that allows a conditional depletion of circulating monocytes, to investigate their role in ovarian follicle health. Our findings show that circulating monocyte depletion leads to a significant depletion of ovarian monocytes and monocyte-derived macrophages. Depletion of monocytes was associated with a transient reduction in circulating anti-Müllerian hormone (AMH) at 5 days postdepletion. However, the 50-60% ovarian monocyte/macrophage depletion had no effect on ovarian follicle numbers, follicle atresia, or apoptosis, within 5-21 days postdepletion. These data reveal that the healthy adult ovary is remarkably resistant to perturbations of circulating and ovarian monocytes despite acute changes in AMH. These data suggest that short-term anti-inflammatory therapies that transiently impact on circulating monocytes are unlikely to disrupt ovarian follicle health, findings that have significant implications for fertility planning relative to the experience of an immune challenge or immunosuppression.

Maternal diet before and during pregnancy modulates microglial activation and neurogenesis in the postpartum rat brain.

The implications of poor maternal diet on offspring metabolic and neuroimmune development are well established. Increasing evidence now suggests that maternal obesity and poor diet can also increase the risk of postpartum mood disorders, but the mechanisms are unknown. Here we investigated the effects of a poor, high-fat-high-sugar diet (HFSD) on peripheral and central inflammation, neurogenesis and postpartum anxiety-like behaviours. We hypothesised that long-term consumption of a HFSD pre- and post-conception would increase the levels of circulating cytokines and induce microglial activation, particularly in the arcuate nucleus of the hypothalamus (ARC), as the primary brain region involved in the integration of satiety signalling; and this would lead to increased anxiety, stress responsivity and disrupted neurogenesis. We further hypothesised that these effects would be ameliorated by consumption of a healthier diet during pregnancy - specifically a diet high in omega-3 polyunsaturated fatty acids (PUFAs). As expected, the HFSD significantly increased pre-conception body weight, elevated circulating cytokines and activated microglia in the ARC, as well as in the basolateral amygdala. The HFSD also significantly increased the numbers of immature (doublecortin (DCX)-positive) neurons in the subgranular/granular region of the hippocampus, a neurogenic response that was, surprisingly, mimicked by consumption of a diet high in omega-3 PUFAs. Despite these effects of peri-pregnancy dietary imbalance, we detected no differences in anxiety-like behaviours or hypothalamic-pituitary-adrenal (HPA) axis reactivity between the groups. A shift to a healthier diet post-conception reversed the peripheral inflammation and alleviated the microglial activation. These novel data indicate the importance of a balanced peri-pregnancy diet and highlight the need for future research into key triggers that alter the neuroimmune balance in the maternal brain.

Emerging roles of extracellular vesicles in the intercellular communication for exercise-induced adaptations.

Complex organisms rely heavily on intercellular communication. The rapidly expanding field of extracellular vesicle biology has made it clear that the necessary intercellular communication occurs partly through their paracrine and endocrine actions. Extracellular vesicles are nanoscale lipid membranes (30-2,000 nm in diameter) that shuttle functional biological material between cells. They are released from numerous tissues and are isolated from nearly all biofluids and cell cultures. Although their biogenesis, cell targeting, and functional roles are incompletely understood, they appear to have crucial roles in physiological and disease processes. Their enormous potential to serve as sensitive biomarkers of disease and also new therapeutic interventions for diseases have gained them considerable attention in recent years. Regular physical exercise training confers systemic health benefits and consequently prevents many age-related degenerative diseases. Many of the molecular mechanisms responsible for the salubrious effects of exercise are known, yet a common underlying mechanism potentially responsible for the holistic health benefits of exercise has only recently been explored (i.e., via extracellular vesicle transport of biological material). Here, we provide an overview of extracellular vesicle biology before outlining the current evidence on the capacity for a single bout and chronic exercise to elicit changes in extracellular vesicle content and modulate their molecular cargo (e.g., small RNAs). We highlight areas for future research and emphasize their potential utility as biomarkers and therapeutic strategies of disease and its prevention.

Glial remodeling enhances short-term memory performance in Wistar rats.

BACKGROUND: Microglia play a key role in neuronal circuit and synaptic maturation in the developing brain. In the healthy adult, however, their role is less clear: microglial hyperactivation in adults can be detrimental to memory due to excessive synaptic pruning, yet learning and memory can also be impaired in the absence of these cells. In this study, we therefore aimed to determine how microglia contribute to short-term memory in healthy adults. METHODS: To this end, we developed a Cx3cr1-Dtr transgenic Wistar rat with a diphtheria toxin receptor (Dtr) gene inserted into the fractalkine receptor (Cx3cr1) promoter, expressed on microglia and monocytes. This model allows acute microglial and monocyte ablation upon application of diphtheria toxin, enabling us to directly assess microglia's role in memory. RESULTS: Here, we show that short-term memory in the novel object and place recognition tasks is entirely unaffected by acute microglial ablation. However, when microglia repopulate the brain after depletion, learning and memory performance in these tasks is improved. This transitory memory enhancement is associated with an ameboid morphology in the newly repopulated microglial cells and increased astrocyte density that are linked with a higher density of mature hippocampal synaptic spines and differences in pre- and post-synaptic markers. CONCLUSIONS: These data indicate that glia play a complex role in the healthy adult animal in supporting appropriate learning and memory and that subtle changes to the function of these cells may strategically enhance memory.

Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats.

BACKGROUND: Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation. METHODS: Depletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion vs. control) × 2 (LPS vs. saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice. RESULTS: Chronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice. CONCLUSIONS: These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.

Consequences of early life overfeeding for microglia - Perspectives from rodent models.

The early life period is crucially important to how the individual develops, and environmental and lifestyle challenges during this time can lead to lasting programming effects on the brain and immune system. In particular, poor diet in early development can lead to long-term negative metabolic and cognitive outcomes, with those who over-eat in early development being at risk of obesity and poor learning and memory throughout their adult lives. Current research has identified a neuroinflammatory component to this metabolic and cognitive programming that can potentially be manipulated to restore a healthy phenotype. Thus, early life over-feeding in a rat model leads to microglial priming and an exacerbated microglial response to immune challenge when the rats reach adulthood. Microglial responses to a learning task are also impaired. To specifically investigate the role of microglia in these programming effects our group has developed a novel transgenic rat with a diphtheria toxin receptor insertion in the promoter region for the Cx3cr1 gene, expressed on microglia and monocytes; allowing us to conditionally ablate microglia throughout the brain. With this model we reveal that microglia have a direct role in regulating feeding behavior and modifying cognition, but are not likely to be the sole mechanism by which early life overfeeding confers lasting neuroimmune and cognitive effects. Additional work implicates changes to the hypothalamic-pituitary-adrenal axis in this. Together these data highlight the importance of dietary choices in early life and the potential for positive interventions targeting the neuroimmune and neuroendocrine stress systems to reverse such programming damage.

The role of microglia in the second and third postnatal weeks of life in rat hippocampal development and memory.

Microglia are resident immune cells of the central nervous system (CNS). In adulthood they are involved in surveillance and responses to pathogens and injury and prenatally they play a role in brain development. However, the role of microglia during the early postnatal period and how they impact development long-term remains poorly understood. Here, to investigate the specific role of microglia in postnatal development, we used a Cx3cr1-Dtr transgenic Wistar rat model to acutely ablate microglia from either postnatal day (P) 7 or 14. We specifically assessed how transient microglial ablation affected astrocytes and neurons acutely, during the juvenile period, and in adulthood. Hippocampal microglial numbers remained low at P21 in the P7-ablated animals and complexity remained reduced after P14-ablation. This protracted effect on these key immune cells led to a small but significant increase in CA1 mature neuron numbers and a significant increase in astrocyte density in the subgranular dentate gyrus in adults that had their microglia ablated at P14. However, these histological differences were small, and spatial and recognition memory in novel objection and place recognition tests were not affected. Overall, our data reveal for the first time that the transient depletion of microglia during the neonatal period impacts briefly on the brain but that the long-lasting effects are minimal. Neonatal microglia may be dispensable in the establishment of hippocampal brain function. These data also imply that novel therapeutic anti-inflammatories that cross the blood-brain barrier to inhibit microglia are unlikely to have long-term negative consequences if administered in the neonatal period.

Psychoneuroimmunology goes East: Development of the PNIRSChina affiliate and its expansion into PNIRSAsia-Pacific.

The Psychoneuroimmunology Research Society (PNIRS) created an official Chinese regional affiliate in 2012, designated PNIRSChina. Now, just eight years later, the program has been so successful in advancing the science of psychoneuroimmunology that it has expanded to the whole of Asia-Oceania. In 2017, PNIRSChina became PNIRSAsia-Pacific. Between 2012 and 2019, this outreach affiliate of PNIRS organized seven symposia at major scientific meetings in China as well as nine others in Taiwan, Japan, South Korea, Australia and New Zealand. This paper summarizes the remarkable growth of PNIRSAsia-Pacific. Here, regional experts who have been instrumental in organizing these PNIRSAsia-Pacific symposia briefly review and share their views about the past, present and future state of psychoneuroimmunology research in China, Taiwan, Australia and Japan. The newest initiative of PNIRSAsia-Pacific is connecting Asia-Pacific laboratories with those in Western countries through a simple web-based registration system. These efforts not only contribute to the efforts of PNIRS to serve a truly global scientific society but also to answer the imperative call of increasing diversity in our science.

Conditional microglial depletion in rats leads to reversible anorexia and weight loss by disrupting gustatory circuitry.

Microglia are highly sensitive to dietary influence, becoming activated acutely and long-term by high fat diet. However, their role in regulating satiety and feeding in healthy individuals remains unclear. Here we show that microglia are essential for the normal regulation of satiety and metabolism in rats. Short-term microglial depletion in a Cx3cr1-Dtr rat led to a dramatic weight loss that was largely accounted for by an acute reduction in food intake. This weight loss and anorexia were not likely due to a sickness response since the rats did not display peripheral or central inflammation, withdrawal, anxiety-like behavior, or nausea-associated pica. Hormonal and hypothalamic anatomical changes were largely compensatory to the suppressed food intake, which occurred in association with disruption of the gustatory circuitry at the paraventricular nucleus of the thalamus. Thus, microglia are important in supporting normal feeding behaviors and weight, and regulating preference for palatable food. Inhibiting this circuitry is able to over-ride strong compensatory drives to eat, providing a potential target for satiety control.

Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production.

BACKGROUND: It is well established that lung pathology and inflammation are more severe during respiratory infections complicated by the presence of both bacteria and viruses. Whilst co-infection can result in invasive pneumococcal disease and systemic inflammation, the neuroinflammatory consequences of co-infection are poorly characterised. METHODS: In this study, we utilised a mouse co-infection model involving Streptococcus pneumoniae (S. pneumoniae) and influenza A virus (IAV) lung infection, and we also isolated microglia for ex vivo stimulation with pneumococcus or serum amyloid A (SAA). RESULTS: Co-infection but not S. pneumoniae or IAV alone significantly increased the number of amoeboid-shaped microglia and expression of pro-inflammatory cytokines including tumour necrosis factor α (TNFα), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and C-C motif chemokine ligand-2 (CCL-2) in the hypothalamus. Pneumococcus was only detected in the hypothalamus of co-infected mice. In addition, the systemic inflammatory cytokines TNFα, IL-1ß and IL-6 were not elevated in co-infected mice relative to IAV-infected mice, whereas SAA levels were markedly increased in co-infected mice (p < 0.05). SAA and its functional receptor termed formyl peptide receptor 2 (Fpr2) transcript expression were also increased in the hypothalamus. In mouse primary microglia, recombinant SAA but not S. pneumoniae stimulated TNFα, IL-1ß, IL-6 and CCL-2 expression, and this response was completely blocked by the pro-resolving Fpr2 agonist aspirin-triggered resolvin D1 (AT-RvD1). CONCLUSIONS: In summary, lung co-infection increased the number of 'activated' amoeboid-shaped microglia and inflammatory cytokine expression in the hypothalamus. Whilst persistent pneumococcal brain infection was observed, SAA proved to be a much more potent stimulus of microglia than pneumococci, and this response was potently suppressed by the anti-inflammatory AT-RvD1. Targeting Fpr2 with pro-resolving eicosanoids such as AT-RvD1 may restore microglial homeostasis during severe respiratory infections.

Acylated ghrelin suppresses the cytokine response to lipopolysaccharide and does so independently of the hypothalamic-pituitary-adrenal axis.

Ghrelin, one of the major metabolic hormones involved in controlling energy balance, has recently been shown to have other properties including regulating the hypothalamic-pituitary-adrenal (HPA) axis response to psychological stress and being a potent anti-inflammatory agent. Ghrelin's HPA axis and anti-inflammatory actions have previously been identified as principally due to the acylated form (AG). However, our recent work has also suggested a role for des-acylated ghrelin (DAG) in these functions. Here we hypothesized ghrelin's anti-inflammatory activity is mediated by the HPA axis and this effect is differentially executed by AG and DAG. We gave adult male Wistar rats a concomitant injection of AG or DAG and lipopolysaccharide (LPS) and measured their effects on circulating cytokines, stress hormones and neuronal activation of the paraventricular nucleus of the hypothalamus (PVN). AG, but not DAG significantly suppressed the pro- and anti-inflammatory cytokine response induced by LPS in vivo. DAG also had no effects on any components of the HPA axis. AG, despite stimulating neuronal activation in the PVN in vivo and stimulating ACTH release from the pituitary in vitro, did not affect the HPA axis response to LPS. These findings suggest AG's anti-inflammatory effects are independent of its actions on the HPA axis and have implications for the potential use of this peptide for treatment of inflammatory conditions without compromising HPA axis activity.

Perinatal programming by inflammation.

Since Levine and then Barker's seminal work mid to late last century demonstrating the importance of early life environment, intensive research has revealed the plasticity, vulnerability and resilience of the developing brain to environmental challenges. In particular, early exposure to infectious pathogens and inflammatory stimuli has a lasting impact on brain and behavior. These data establish clear effects on vulnerability to later disease and neuroinflammatory injury, cognitive function and emotionality, and even responses to pain and susceptibility to metabolic disorders. They also highlight the issues with defining rodent models of complex diseases like autism spectrum disorders and schizophrenia, as well as the complexity of experimental design, for instance when deciding the appropriate allocation of subjects to experimental groups when dealing with whole-litter manipulations in rodents. The studies presented in this special issue of Brain Behavior and Immunity are a collection of the very latest advances in the science of perinatal inflammation and its implications for perinatal programming of brain and behavior.

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. © 2016 Wiley Periodicals, Inc.