Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

Outrunning a bad diet: Interactions between exercise and a Western-style diet for adolescent mental health, metabolism and microbes.

Adolescence is a period of biological, psychological and social changes, and the peak time for the emergence of mental health problems. During this life stage, brain plasticity including hippocampal neurogenesis is increased, which is crucial for cognitive functions and regulation of emotional responses. The hippocampus is especially susceptible to environmental and lifestyle influences, mediated by changes in physiological systems, resulting in enhanced brain plasticity but also an elevated risk for developing mental health problems. Indeed, adolescence is accompanied by increased activation of the maturing hypothalamic-pituitary-adrenal axis, sensitivity to metabolic changes due to increased nutritional needs and hormonal changes, and gut microbiota maturation. Importantly, dietary habits and levels of physical activity significantly impact these systems. In this review, the interactions between exercise and Western-style diets, which are high in fat and sugar, on adolescent stress susceptibility, metabolism and the gut microbiota are explored. We provide an overview of current knowledge on implications of these interactions for hippocampal function and adolescent mental health, and speculate on potential mechanisms which require further investigation.

Stress during puberty exerts sex-specific effects on depressive-like behavior and monoamine neurotransmitters in adolescence and adulthood.

Psychiatric disorders including major depression are twice as prevalent in women compared to men. This sex difference in prevalence only emerges after the onset of puberty, suggesting that puberty may be a sensitive period during which sex-associated vulnerability to stress-related depression might become established. Thus, this study investigated whether stress occurring specifically during the pubertal window of adolescence may be responsible for this sex difference in depression vulnerability. Male and female rats were exposed to a three-day stress protocol during puberty (postnatal days 35-37 in females, 45-47 in males) and underwent behavioral tests in adolescence or adulthood measuring anhedonia, anxiety-like behavior, locomotor activity and antidepressant-like behavior. Brainstem and striatum tissue were collected from a separate cohort of behavioral test-naïve rats in adolescence or adulthood to quantify the effect of pubertal stress on monoamine neurotransmitters. Pubertal stress increased immobility behavior in the forced swim test in both sexes in adolescence and adulthood. In adolescence, pubertal stress altered escape-oriented behaviors in a sex-specific manner: decreasing climbing in males but not females and decreasing swimming in females but not males. Pubertal stress decreased adolescent brainstem noradrenaline specifically in females and had opposing effects in adolescent males and females on brainstem serotonin turnover. Pubertal stress induced anhedonia in the saccharin preference test in adult males but not females, an effect paralleled by a male-specific decrease in striatal dopamine turnover. Pubertal stress did not significantly impact anxiety-like behavior or locomotor activity in any sex at either age. Taken together, these data suggest that although pubertal stress did not preferentially increase female vulnerability to depressive-like behaviors compared to males, stress during puberty exerts sex-specific effects on depressive-like behavior and anhedonia, possibly through discrete neurotransmitter systems.

Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis.

The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract, collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota's ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment.

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

GABAB Receptors: Anxiety and Mood Disorders.

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, acts at the ionotropic GABAA and GABAC receptors, and the metabotropic GABAB receptor. This chapter summarizes the studies that have investigated the role of the GABAB receptor in stress-related psychiatric disorders including anxiety and mood disorders. Overall, clinical and preclinical evidences strongly suggest that the GABAB receptor is a therapeutic candidate for depression and anxiety disorders. However, the clinical development of GABAB receptor-based drugs to treat these disorders has been hampered by their potential side-effects, particularly those of agonists. Nevertheless, the discovery of novel GABAB receptor allosteric modulators, and increasing understanding of the influence of specific intracellular GABAB receptor-associated proteins on GABAB receptor activity, may now pave the way towards GABAB receptor therapeutics in the treatment of mood and anxiety disorders.

Prior maternal separation stress alters the dendritic complexity of new hippocampal neurons and neuroinflammation in response to an inflammatory stressor in juvenile female rats.

Stress during critical periods of neurodevelopment is associated with an increased risk of developing stress-related psychiatric disorders, which are more common in women than men. Hippocampal neurogenesis (the birth of new neurons) is vulnerable to maternal separation (MS) and inflammatory stressors, and emerging evidence suggests that hippocampal neurogenesis is more sensitive to stress in the ventral hippocampus (vHi) than in the dorsal hippocampus (dHi). Although research into the effects of MS stress on hippocampal neurogenesis is well documented in male rodents, the effect in females remains underexplored. Similarly, reports on the impact of inflammatory stressors on hippocampal neurogenesis in females are limited, especially when female bias in the prevalence of stress-related psychiatric disorders begins to emerge. Thus, in this study we investigated the effects of MS followed by an inflammatory stressor (lipopolysaccharide, LPS) in early adolescence on peripheral and hippocampal inflammatory responses and hippocampal neurogenesis in juvenile female rats. We show that MS enhanced an LPS-induced increase in the pro-inflammatory cytokine IL-1ß in the vHi but not in the dHi. However, microglial activation was similar following LPS alone or MS alone in both hippocampal regions, while MS prior to LPS reduced microglial activation in both dHi and vHi. The production of new neurons was unaffected by MS and LPS. MS and LPS independently reduced the dendritic complexity of new neurons, and MS exacerbated LPS-induced reductions in the complexity of distal dendrites of new neurons in the vHi but not dHi. These data highlight that MS differentially primes the physiological response to LPS in the juvenile female rat hippocampus.

Juvenile stress exerts sex-independent effects on anxiety, antidepressant-like behaviours and dopaminergic innervation of the prelimbic cortex in adulthood and does not alter hippocampal neurogenesis.

Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the neurobiology underpinning sex differences in the long-term consequences of childhood stress remains unknown. Thus, the aim of this study was to determine whether stress applied during the prepubertal juvenile period (postnatal day 27-29) in rats induces sex-specific changes in anxiety-like behaviour, anhedonia, and antidepressant-like behaviour in adulthood in males and females. The impact of juvenile stress on two systems in the brain associated with these behaviours and that develop during the juvenile period, the mesocorticolimbic dopaminergic system and hippocampal neurogenesis, were also investigated. Juvenile stress altered escape-oriented behaviours in the forced swim test in both sexes, decreased latency to drink a palatable substance in a novel environment in the novelty-induced hypophagia test in both sexes, and decreased open field supported rearing behavior in females. These behavioural changes were accompanied by stress-induced increases in tyrosine hydroxylase immunoreactivity in the prefrontal cortex of both sexes, but not other regions of the mesocorticolimbic dopaminergic system. Juvenile stress did not impact anhedonia in adulthood as measured by the saccharin preference test and had no effect hippocampal neurogenesis across the longitudinal axis of the hippocampus. These results suggest that juvenile stress has long-lasting impacts on antidepressant-like and reward-seeking behaviour in adulthood and these changes may be due to alterations to catecholaminergic innervation of the medial prefrontal cortex.

Specific sub-regions of the longitudinal axis of the hippocampus mediate behavioural responses to chronic psychosocial stress.

Accumulating evidence suggests that the hippocampus is functionally segregated along its longitudinal axis into a dorsal (dHi) sub-region, shown to play roles in learning & memory and a ventral sub-region (vHi), involved in anxiety and antidepressant action. Recent studies also suggest that the intermediate hippocampus (iHi) might be functionally independent, but it has received relatively little attention. We recently found that the iHi is involved in the behavioural effects of chronic treatment with the antidepressant fluoxetine in the forced swim test. However, the roles of specific sub-regions of the longitudinal axis of the hippocampus in the response to chronic stress, a risk factor for depression and anxiety disorders, has not yet been investigated. Therefore, we used excitotoxic lesions of the dHi, iHi or vHi in male C57BL/6 mice to investigate the roles of these sub-regions in the behavioural (anxiety, anhedonia, depression) responses to chronic psychosocial stress. We found that stress-induced increases in anxiety in the novelty-induced hypophagia and marble burying tests were prevented by each of the sub-region lesions, but only vHi lesions attenuated stress-induced anxiety in the open field test. Stress-induced anhedonia was reduced in dHi- and vHi- but not iHi-lesioned mice. In stressed mice, only vHi lesions induced an antidepressant-like effect in the forced swim test and prolonged latency to adopt a defeat posture during social defeat, suggesting an increase in stress resilience. Interestingly, iHi lesions increased stress-induced social avoidance in the social interaction test. In summary, we found that all hippocampal sub-regions are involved in the anxiogenic effects of chronic stress but that the iHi plays a predominant role in stress-induced social avoidance and the vHi has a predominant role in active coping behaviours and antidepressant-like behaviour following chronic stress.

Specific sub-regions along the longitudinal axis of the hippocampus mediate antidepressant-like behavioral effects.

Current antidepressants are suboptimal due incomplete understanding of the neurobiology underlying their behavioral effects. However, imaging studies suggest the hippocampus is a key brain region underpinning antidepressant action. There is increasing attention on the functional segregation of the hippocampus into a dorsal region (dHi) predominantly involved in spatial learning and memory, and a ventral region (vHi) which regulates anxiety, a symptom often co-morbid with depression. However, little is known about the roles of these hippocampal sub-regions in the antidepressant response. Moreover, the area between them, the intermediate hippocampus (iHi), has received little attention. Here, we investigated the impact of dHi, iHi or vHi lesions on anxiety- and depressive-like behaviors under baseline or antidepressant treatment conditions in male C57BL/6 mice (n = 8-10). We found that in the absence of fluoxetine, vHi lesions reduced anxiety-like behavior, while none of the lesions affected other antidepressant-sensitive behaviors. vHi lesions prevented the acute antidepressant-like behavioral effects of fluoxetine in the tail suspension test and its anxiolytic effects in the novelty-induced hypophagia test. Intriguingly, only iHi lesions prevented the antidepressant effects of chronic fluoxetine treatment in the forced swim test. dHi lesions did not impact any behaviors either in the absence or presence of fluoxetine. In summary, we found that vHi plays a key role in anxiety-like behavior and its modulation by fluoxetine, while both iHi and vHi play distinct roles in fluoxetine-induced antidepressant-like behaviors.

Microbiota from young mice counteracts selective age-associated behavioral deficits.

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.

Adult-born neurons from the dorsal, intermediate, and ventral regions of the longitudinal axis of the hippocampus exhibit differential sensitivity to glucocorticoids.

Hippocampal neurogenesis has been shown to play roles in learning, memory, and stress responses. These diverse roles may be related to a functional segregation of the hippocampus along its longitudinal axis. Indeed, the dorsal hippocampus (dHi) plays a predominant role in spatial learning and memory, while the ventral hippocampus (vHi) is predominantly involved in the regulation of anxiety, a behaviour impacted by stress. Recent studies suggest that the area between them, the intermediate hippocampus (iHi) may also be functionally independent. In parallel, it has been reported that chronic stress reduces neurogenesis preferentially in the vHi rather the dHi. We thus aimed to determine whether such stress-induced changes in neurogenesis could be related to differential intrinsic sensitivity of neural progenitor cells (NPCs) from the dHi, iHi, or vHi to the stress hormone, corticosterone, or the glucocorticoid receptor (GR) agonist, dexamethasone. Long-term exposure of rat NPCs to corticosterone or dexamethasone decreased neuronal differentiation in the vHi but not the dHi, while iHi cultures showed an intermediate response. A similar gradient-like response on neuronal differentiation and maturation was observed with dexamethasone treatment. This gradient-like effect was also observed on GR nuclear translocation in response to corticosterone or dexamethasone. Long-term exposure to corticosterone or dexamethasone treatment also tended to induce a greater downregulation of GR-associated genes in vHi-derived neurons compared to those from the dHi and iHi. These data suggest that increased intrinsic sensitivity of vHi NPC-derived neurons to chronic glucocorticoid exposure may underlie the increased vulnerability of the vHi to chronic stress-induced reductions in neurogenesis.

Chronic intrahippocampal interleukin-1ß overexpression in adolescence impairs hippocampal neurogenesis but not neurogenesis-associated cognition.

Both neuroinflammation and adult hippocampal neurogenesis (AHN) are implicated in many neurodegenerative disorders as well as in neuropsychiatric disorders, which often become symptomatic during adolescence. A better knowledge of the impact that chronic neuroinflammation has on the hippocampus during the adolescent period could lead to the discovery of new therapeutics for some of these disorders. The hippocampus is particularly vulnerable to altered concentrations of the pro-inflammatory cytokine interleukin-1ß (IL-1ß), with elevated levels implicated in the aetiology of neurodegenerative disorders such as Alzheimer's and Parkinson's, and stress-related disorders such as depression. The effect of acutely and chronically elevated concentrations of hippocampal IL-1ß have been shown to reduce AHN in adult rodents. However, the effect of exposure to chronic overexpression of hippocampal IL-1ß during adolescence, a time of increased vulnerability, hasn't been fully interrogated. Thus, in this study we utilized a lentiviral approach to induce chronic overexpression of IL-1ß in the dorsal hippocampus of adolescent male Sprague Dawley rats for 5 weeks, during which time its impact on cognition and hippocampal neurogenesis were examined. A reduction in hippocampal neurogenesis was observed along with a reduced level of neurite branching on hippocampal neurons. However, there was no effect of IL-1ß overexpression on performance in pattern separation, novel object recognition or spontaneous alternation in the Y maze. Our study has highlighted that chronic IL-1ß overexpression in the hippocampus during the adolescent period exerts a negative impact on neurogenesis independent of cognitive performance, and suggests a degree of resilience of the adolescent hippocampus to inflammatory insult.

Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome.

Depression remains one of the most prevalent psychiatric disorders, with many patients not responding adequately to available treatments. Chronic or early-life stress is one of the key risk factors for depression. In addition, a growing body of data implicates chronic inflammation as a major player in depression pathogenesis. More recently, the gut microbiota has emerged as an important regulator of brain and behavior and also has been linked to depression. However, how this holy trinity of risk factors interact to maintain physiological homeostasis in the brain and body is not fully understood. In this review, we integrate the available data from animal and human studies on these three factors in the etiology and progression of depression. We also focus on the processes by which this microbiota-immune-stress matrix may influence centrally mediated events and on possible therapeutic interventions to correct imbalances in this triune.

Nigral overexpression of α-synuclein in a rat Parkinson's disease model indicates alterations in the enteric nervous system and the gut microbiome.

BACKGROUND: A hallmark feature of Parkinson's disease (PD) is the build-up of α-synuclein protein aggregates throughout the brain; however α-synuclein is also expressed in enteric neurons. Gastrointestinal (GI) symptoms and pathology are frequently reported in PD, including constipation, increased intestinal permeability, glial pathology, and alterations to gut microbiota composition. α-synuclein can propagate through neuronal systems but the site of origin of α-synuclein pathology, whether it be the gut or the brain, is still unknown. Physical exercise is associated with alleviating symptoms of PD and with altering the composition of the gut microbiota. METHODS: This study investigated the effects of bilateral nigral injection of adeno-associated virus (AAV)-α-synuclein on enteric neurons, glia and neurochemistry, the gut microbiome, and bile acid metabolism in rats, some of whom were exposed to voluntary exercise. KEY RESULTS: Nigral overexpression of α-synuclein resulted in significant neuronal loss in the ileal submucosal plexus with no change in enteric glia. In contrast, the myenteric plexus showed a significant increase in glial expression, while neuronal numbers were maintained. Concomitant alterations were observed in the gut microbiome and related bile acid metabolism. Voluntary running protected against neuronal loss, increased enteric glial expression, and modified gut microbiome composition in the brain-injected AAV-α-synuclein PD model. CONCLUSIONS AND INFERENCES: These results show that developing nigral α-synuclein pathology in this PD model exerts significant alterations on the enteric nervous system (ENS) and gut microbiome that are receptive to modification by exercise. This highlights brain to gut communication as an important mechanism in PD pathology.

Differential effects of adolescent and adult-initiated exercise on cognition and hippocampal neurogenesis.

Adolescence is a critical period for postnatal brain maturation and thus a time when environmental influences may affect cognitive processes in later life. Exercise during adulthood has been shown to increase hippocampal neurogenesis and enhance cognition. However, the impact of exercise initiated in adolescence on the brain and behavior in adulthood is not fully understood. The aim of this study was to compare the impact of voluntary exercise that is initiated during adolescence or early adulthood on cognitive performance in hippocampal-dependent and -independent processes using both object-based and touchscreen operant paradigms. Adult (8 week) and adolescent (4 week) male Sprague-Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for 4 weeks prior to behavioral testing and for the duration of the experiment. Results from touchscreen-based tasks showed that reversal learning was enhanced by both adult and adolescent-initiated exercise, while only exercise that began in adolescence induced a subtle but transient increase in performance on a location discrimination task. Spontaneous alternation in the Y-maze was impaired following adolescent onset exercise, while object memory was unaffected by either adult or adolescent-initiated exercise. Adolescent-initiated exercise increased the number of hippocampal DCX cells, an indicator of neurogenesis. It also promoted the complexity of neurites on DCX cells, a key process for synaptic integration, to a greater degree than adult-initiated exercise. Together the data here show that exercise during the adolescent period compared to adulthood differentially affects cognitive processes and the development of new hippocampal neurons in later life.

Enduring effects of muscarinic receptor activation on adult hippocampal neurogenesis, microRNA expression and behaviour.

The cholinergic system is one of the most important neurotransmitter systems in the brain with key roles in autonomic control and the regulation of cognitive and emotional responses. However, the precise mechanism by which the cholinergic system influences behaviour is unclear. Adult hippocampal neurogenesis (AHN) is a potential mediator in this context based on evidence, which has identified this process as putative mechanism of antidepressant action. More recently, post-transcriptional regulation by microRNAs is another candidate mechanism based on its involvement in the regulation of AHN and neurotransmission. Taking into account this background, we evaluated the behavioural effects of a non-convulsant dose of pilocarpine - a non-selective muscarinic receptor (mAChR) agonist - in adult Wistar rats. Furthermore, we quantified the expression of different microRNAs implicated in the regulation of AHN. Our results suggests that pilocarpine treatment increases AHN in the granular cell layer but also induced ectopic neurogenesis. Pilocarpine treatment reduced immobility time in forced swimming test but did not affect fear conditioning response, sucrose preference or novelty supressed feeding behaviour. In addition, treatment with pilocarpine down-regulated the expression of 6 microRNAs implicated in the regulation of neurotrophin signalling and axon guidance pathways. Therefore, we suggest that the low-dose stimulation of the cholinergic system is sufficient to alter AHN of rats through post-transcriptional mechanisms, which might contribute to long-lasting behavioural effects.

Differential effects of adolescent and adult-initiated voluntary exercise on context and cued fear conditioning.

Adolescence is a critical period for postnatal brain maturation and a time during which there is increased susceptibility to developing emotional and cognitive-related disorders. Exercise during adulthood has been shown to increase hippocampal plasticity and enhance cognition. However, the impact of exercise initiated in adolescence, on brain and behaviour in adulthood is not yet fully explored or understood. The aim of this study was to compare the impact of voluntary exercise that was initiated either during adolescence or early adulthood on cognitive performance in hippocampal and amygdala-dependent fear conditioning tasks in adulthood. Adult (eight weeks old) and adolescent (four weeks old) male Sprague Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for seven weeks. Adult-initiated exercise enhanced both contextual and cued fear conditioning, while conversely, exercise that began in adolescence did not affect performance in these tasks. These behaviours were accompanied by differential expression of plasticity-related genes in the hippocampus and amygdala in adulthood. Specifically, adolescent-initiated exercise increased the expression of an array of plasticity related genes in the hippocampus including BDNF, synaptophysin, Creb, PSD-95, Arc, TLX and DCX, while adult-initiated exercise did not affect hippocampal plasticity related genes. Together results show that exercise initiated during adolescence has a differential effect on hippocampal and amygdala-dependent behaviour and neuronal plasticity compared to when exercise was initiated in adulthood. These findings reinforce adolescence as a period during which environmental influences have a distinct impact on neuronal plasticity and cognition. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Programming Bugs: Microbiota and the Developmental Origins of Brain Health and Disease.

It has been nearly 30 years since Dr. David Barker first highlighted the importance of prenatal factors in contributing to the developmental origins of adult disease. This concept was later broadened to include postnatal events. It is clear that the interaction between genetic predisposition and early life environmental exposures is key in this regard. However, recent research has also identified another important factor in the microbiota-the trillions of microorganisms that inhabit key body niches, including the vagina and gastrointestinal tract. Because the composition of these maternal microbiome sites has been linked to maternal metabolism and is also vertically transmitted to offspring, changes in the maternal microbiota are poised to significantly affect the newborn. In fact, several lines of evidence show that the gut microbiota interacts with diet, drugs, and stress both prenatally and postnatally and that these exogenous factors could also affect the dynamic changes in the microbiota composition occurring during pregnancy. Animal models have shown great utility in illuminating how these disruptions result in behavioral and brain morphological phenotypes reminiscent of psychiatric disorders (anxiety, depression, schizophrenia, and autism spectrum disorders). Increasing evidence points to critical interactions among the microbiota, host genetics, and both the prenatal and postnatal environments to temporally program susceptibility to psychiatric disorders later in life. Sex-specific phenotypes may be programmed through the influence of the microbiota on the hypothalamic-pituitary-adrenal axis and neuroimmune system.

Chronic interleukin-1ß in the dorsal hippocampus impairs behavioural pattern separation.

Understanding the long-term consequences of chronic inflammation in the hippocampus may help to develop therapeutic targets for the treatment of cognitive disorders related to stress, ageing and neurodegeneration. The hippocampus is particularly vulnerable to increases in the pro-inflammatory cytokine interleukin-1ß (IL-1ß), a mediator of neuroinflammation, with elevated levels implicated in the aetiology of neurodegenerative diseases such as Alzheimer's and Parkinson's, and in stress-related disorders such as depression. Acute increases in hippocampal IL-1ß have been shown to impair cognition and reduce adult hippocampal neurogenesis, the birth of new neurons. However, the impact of prolonged increases in IL-1ß, as evident in clinical conditions, on cognition has not been fully explored. Therefore, the present study utilized a lentiviral approach to induce long-term overexpression of IL-1ß in the dorsal hippocampus of adult male Sprague Dawley rats and examine its impact on cognition. Following three weeks of viral integration, pattern separation, a process involving hippocampal neurogenesis, was impaired in IL-1ß-treated rats in both object-location and touchscreen operant paradigms. This was coupled with a decrease in the number and neurite complexity of immature neurons in the hippocampus. Conversely, tasks involving the hippocampus, but not sensitive to disruption of hippocampal neurogenesis, including spontaneous alternation, novel object and location recognition were unaffected. Touchscreen operant visual discrimination, a cognitive task involving the prefrontal cortex, was largely unaffected by IL-1ß overexpression. In conclusion, these findings suggest that chronically elevated IL-1ß in the hippocampus selectively impairs pattern separation. Inflammatory-mediated disruption of adult hippocampal neurogenesis may contribute to the cognitive decline associated with neurodegenerative and stress-related disorders.