Astrogenesis in the murine dentate gyrus is a life-long and dynamic process.

Astrocytes are highly abundant in the mammalian brain, and their functions are of vital importance for all aspects of development, adaption, and aging of the central nervous system (CNS). Mounting evidence indicates the important contributions of astrocytes to a wide range of neuropathies. Still, our understanding of astrocyte development significantly lags behind that of other CNS cells. We here combine immunohistochemical approaches with genetic fate-mapping, behavioural paradigms, single-cell transcriptomics, and in vivo two-photon imaging, to comprehensively assess the generation and the proliferation of astrocytes in the dentate gyrus (DG) across the life span of a mouse. Astrogenesis in the DG is initiated by radial glia-like neural stem cells giving rise to locally dividing astrocytes that enlarge the astrocyte compartment in an outside-in-pattern. Also in the adult DG, the vast majority of astrogenesis is mediated through the proliferation of local astrocytes. Interestingly, locally dividing astrocytes were able to adapt their proliferation to environmental and behavioral stimuli revealing an unexpected plasticity. Our study establishes astrocytes as enduring plastic elements in DG circuits, implicating a vital contribution of astrocyte dynamics to hippocampal plasticity.

Cardioprotection of voluntary exercise against breast cancer-induced cardiac injury via STAT3.

Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

A meta-analysis of whole-body and heart mass effect sizes from a long-term artificial selection experiment for high voluntary exercise.

Selection experiments play an increasingly important role in comparative and evolutionary physiology. However, selection experiments can be limited by relatively low statistical power, in part because replicate line is the experimental unit for analyses of direct or correlated responses (rather than number of individuals measured). One way to increase the ability to detect correlated responses is through a meta-analysis of studies for a given trait across multiple generations. To demonstrate this, we applied meta-analytic techniques to two traits (body mass and heart ventricle mass, with body mass as a covariate) from a long-term artificial selection experiment for high voluntary wheel-running behavior. In this experiment, all 4 replicate High Runner (HR) lines reached apparent selection limits around generations 17-27, running approximately 2.5-3-fold more revolutions/day than the 4 non-selected Control (C) lines. Although both traits would also be expected to change in HR lines (relative heart size expected to increase, expected direction for body mass is less clear), the statistical significance has varied, despite repeated measurements. We compiled information from 33 unique studies and calculated a measure of effect size (Pearson's R). Our results indicate that, despite a lack of statistical significance in most generations, HR mice have evolved larger hearts and smaller bodies relative to Controls. Moreover, plateaus in effect sizes for both traits coincides with the generational range during which the selection limit for wheel-running behavior was reached. Finally, since the selection limit, absolute effect sizes for body mass and heart ventricle mass have gotten smaller (i.e., closer to 0).

Maternal voluntary physical exercise in the adult rat: evidence of exercise-associated differences in maternal food intake, and in brain effects on the progeny.

Objectives: Maternal physical activity may impact behavioral and electrophysiological aspects of brain function, with short- and long-term effects on pre- and postnatal neurodevelopment of the offspring. This study evaluated in the rat the effects of maternal voluntary physical activity (MVPA) on food intake and weight gain in the dams, as well as anxiety-like behavior, short-term memory and the brain excitability-related phenomenon known as cortical spreading depression (CSD) on the mother-pup dyad.Methods: Female Wistar rats (n=33) were individually housed in cages containing a running wheel for a 30-days adaptation period before mating. Rats were classified as inactive (I); active (A) or very active (VA) according to the distance spontaneously travelled daily. During gestation, the dams continued to have access to the running wheel. Mothers and their respective pups (1 pup per mother) were evaluated in the open field test (OFT), object recognition test (ORT), elevated plus maze test (EPMT) and the CSD propagation features.Results: MVPA was directly associated with increased food intake and weight gain during gestation, and maternal anxiolytic-like behavioral responses in the OFT. Pups from VA mothers showed a high discrimination index for shape recognition memory (ORT) and decreased propagation velocities of CSD, when compared with the inactive group.Discussion: The data suggest that MVPA during the gestational period induces neuroplasticity and may modulate the brain functions in the mother-infant dyad in the rat.

Effects of voluntary exercise and electrical muscle stimulation on reaction time in the Go/No-Go task.

INTRODUCTION: Acute exercise improves cognitive performance. However, it remains unclear what triggers cognitive improvement. Electrical muscle stimulation (EMS) facilitates the examination of physiological changes derived from peripheral muscle contraction during exercise. Thus, we compared the effects of EMS and voluntary exercise at low- or moderate-intensity on reaction time (RT) in a cognitive task to understand the contribution of central and peripheral physiological factors to RT improvement. METHODS: Twenty-four young, healthy male participants performed a Go/No-Go task before and after EMS/exercise. In the EMS condition, EMS was applied to the lower limb muscles. In the low-intensity exercise condition, the participants cycled an ergometer while maintaining their heart rate (HR) at the similar level during EMS. In the moderate-intensity exercise condition, exercise intensity corresponded to ratings of perceived exertion of 13/20. The natural log-transformed root mean square of successive differences between adjacent inter-beat (R-R) intervals (LnRMSSD), which predominantly reflects parasympathetic HR modulation, was calculated before and during EMS/exercise. RESULTS: RT improved following moderate-intensity exercise (p = 0.002, Cohen' d = 0.694), but not following EMS (p = 0.107, Cohen' d = 0.342) and low-intensity exercise (p = 0.076, Cohen' d = 0.380). Repeated measures correlation analysis revealed that RT was correlated with LnRMSSD (Rrm(23) = 0.599, p = 0.002) in the moderate-intensity exercise condition. CONCLUSION: These findings suggest that the amount of central neural activity and exercise pressor reflex may be crucial for RT improvement. RT improvement following moderate-intensity exercise may, at least partly, be associated with enhanced sympathetic nervous system activity.

Exercise Rescues Obesogenic-Related Genes in the Female Hypothalamic Arcuate Nucleus: A Potential Role of miR-211 Modulation.

Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent or combat obesity. This study investigates how voluntary exercise mitigates abnormal gene expression in the hypothalamic arcuate nucleus (ARC) of diet-induced obese (DIO) rats. Using a transcriptomic approach, novel genes in the ARC affected by voluntary wheel running were assessed alongside physiology, pharmacology, and bioinformatics analysis to evaluate the role of miR-211 in reversing obesity. Exercise curbed weight gain and fat mass, and restored ARC gene expression. High-fat diet (HFD) consumption can dysregulate satiety/hunger mechanisms in the ARC. Transcriptional clusters revealed that running altered gene expression patterns, including inflammation and cellular structure genes. To uncover regulatory mechanisms governing gene expression in DIO attenuation, we explored miR-211, which is implicated in systemic inflammation. Exercise ameliorated DIO overexpression of miR-211, demonstrating its pivotal role in regulating inflammation in the ARC. Further, in vivo central administration of miR-211-mimic affected the expression of immunity and cell cycle-related genes. By cross-referencing exercise-affected and miR-211-regulated genes, potential candidates for obesity reduction through exercise were identified. This research suggests that exercise may rescue obesity through gene expression changes mediated partially through miR-211.

Nonphotic entrainment of central and peripheral circadian clocks in mice by scheduled voluntary exercise under constant darkness.

In mammals, the central circadian pacemaker in the suprachiasmatic nucleus (SCN) entrains to an environmental light-dark (LD) cycle and organizes the temporal order of circadian rhythms in physiology and behavior. Previously, some studies have demonstrated that scheduled exercise could entrain the free-running behavior rhythm in nocturnal rodents. However, it remains unknown whether entrainment by scheduled exercise alters the internal temporal order of the behavioral circadian rhythms or clock gene expression in the SCN, extra-SCN brain regions, and peripheral organs when mice are entrained to the scheduled exercise under constant darkness (DD). In the present study, we examined circadian rhythms in locomotor activity and clock gene Per1 expression by bioluminescence reporter (Per1-luc) in the SCN, arcuate nucleus (ARC), liver, and skeletal muscle of mice entrained to an LD cycle, mice free-running under DD, and mice entrained to daily exposure to a new cage with a running wheel (NCRW) under DD. All mice showed a steady-state entrainment of behavioral circadian rhythms to NCRW exposure under DD in parallel with shortening of the α when compared with that under DD. The temporal order of behavioral circadian rhythms and the Per1-luc rhythms in the SCN and peripheral tissues but not in the ARC were maintained in the mice entrained to the NCRW and LD cycles; in contrast, the temporal order was altered in the mice under DD. The present findings reveal that the SCN entrains to daily exercise, and daily exercise reorganizes the internal temporal order of behavioral circadian rhythms and clock gene expression in the SCN and peripheral tissues.

Sodium butyrate and voluntary exercise through activating VEGF-A downstream signaling pathway improve heart angiogenesis in type 2 diabetes.

BACKGROUND: Inadequate angiogenesis in patients with type 2 diabetic heart could result in deprived collateral formation. Herein, we aimed to investigate the effects of sodium butyrate (NaB) along with voluntary exercise simultaneously on the mechanisms acting on cardiac angiogenesis. MATERIALS AND METHODS: Animals were divided into the following five groups: control (Con), diabetic rats (Dia), diabetic rats treated with NaB (200 mg/kg, i.p.) (Dia-NaB), diabetic rats receiving voluntary exercise (Dia-Exe), and diabetic rats treated with NaB and exercise simultaneously (Dia-NaB-Exe). After an eight-week duration, NO metabolites levels were measured using Griess method, the VEGF-A and VEGFR2 expressions was examined by PCR, the expressions of VEGF-A and VEGFR2 proteins was investigated by western blot, and ELISA method was used for Akt, ERK1/2 expression. RESULTS: Cardiac VEGF-A and VEGFR2 expressions were higher in the Dia-Exe and Dia-NaB-Exe groups compared to the Dia group. However, a combination of exercise and NaB enhanced the VEGF-A expression in cardiac tissue compared to the Dia-NaB and Dai-Exe groups. Heart NOx concentration was higher in the treated groups compared to the Dia group. The expression of cardiac Akt levels increased in both the Dia-Exe and Dia-NaB-Exe groups compared to the Dia groups. In addition, cardiac ERK1/2 expression was found to be higher in the Dia-NaB-Exe group compared to the Dia group. CONCLUSION: The findings of this study showed the therapeutic potential of a novel combination therapy of sodium butyrate and voluntary exercise in improving cardiac angiogenesis with the enhanced involvement mechanism in high fat/STZ-induced type 2 diabetic rats.

Hippocampal, Whole Midbrain, Red Nucleus, and Ventral Tegmental Area Volumes Are Increased by Selective Breeding for High Voluntary Wheel-Running Behavior.

Uncovering relationships between neuroanatomy, behavior, and evolution are important for understanding the factors that control brain function. Voluntary exercise is one key behavior that both affects, and may be affected by, neuroanatomical variation. Moreover, recent studies suggest an important role for physical activity in brain evolution. We used a unique and ongoing artificial selection model in which mice are bred for high voluntary wheel-running behavior, yielding four replicate lines of high runner (HR) mice that run ∼3-fold more revolutions per day than four replicate nonselected control (C) lines. Previous studies reported that, with body mass as a covariate, HR mice had heavier whole brains, non-cerebellar brains, and larger midbrains than C mice. We sampled mice from generation 66 and used high-resolution microscopy to test the hypothesis that HR mice have greater volumes and/or cell densities in nine key regions from either the midbrain or limbic system. In addition, half of the mice were given 10 weeks of wheel access from weaning, and we predicted that chronic exercise would increase the volumes of the examined brain regions via phenotypic plasticity. We replicated findings that both selective breeding and wheel access increased total brain mass, with no significant interaction between the two factors. In HR compared to C mice, adjusting for body mass, both the red nucleus (RN) of the midbrain and the hippocampus (HPC) were significantly larger, and the whole midbrain tended to be larger, with no effect of wheel access nor any interactions. Linetype and wheel access had an interactive effect on the volume of the periaqueductal gray (PAG), such that wheel access increased PAG volume in C mice but decreased volume in HR mice. Neither linetype nor wheel access affected volumes of the substantia nigra, ventral tegmental area, nucleus accumbens, ventral pallidum (VP), or basolateral amygdala. We found no main effect of either linetype or wheel access on neuronal densities (numbers of cells per unit area) for any of the regions examined. Taken together, our results suggest that the increased exercise phenotype of HR mice is related to increased RN and hippocampal volumes, but that chronic exercise alone does not produce such phenotypes.

Interplay between Learning and Voluntary Wheel Running in Male C57BL/6NCrl Mice.

Exercise is shown to improve cognitive function in various human and animal studies. Laboratory mice are often used as a model to study the effects of physical activity and running wheels provide a voluntary and non-stressful form of exercise. The aim of the study was to analyze whether the cognitive state of a mouse is related to its wheel-running behavior. Twenty-two male C57BL/6NCrl mice (9.5 weeks old) were used in the study. The cognitive function of group-housed mice (n = 5-6/group) was first analyzed in the IntelliCage system followed by individual phenotyping with the PhenoMaster with access to a voluntary running wheel. The mice were divided into three groups according to their running wheel activity: low, average, and high runners. The learning trials in the IntelliCage showed that the high-runner mice exhibited a higher error rate at the beginning of learning trials but improved their outcome and learning performance more compared to the other groups. The high-runner mice ate more compared to the other groups in the PhenoMaster analyses. There were no differences in the corticosterone levels between the groups, indicating similar stress responses. Our results demonstrate that high-runner mice exhibit enhanced learning capabilities prior to access to voluntary running wheels. In addition, our results also show that individual mice react differently when introduced to running wheels, which should be taken into consideration when choosing animals for voluntary endurance exercise studies.

Voluntary Exercise to Reduce Anxiety Behaviour in Traumatic Brain Injury Shown to Alleviate Inflammatory Brain Response in Mice.

Traumatic brain injury is a leading cause of neuroinflammation and anxiety disorders in young adults. Immune-targeted therapies have garnered attention for the amelioration of TBI-induced anxiety. A previous study has indicated that voluntary exercise intervention following TBI could reduce neuroinflammation. It is essential to determine the effects of voluntary exercise after TBI on anxiety via inhibiting neuroinflammatory response. Mice were randomly divided into four groups (sham, TBI, sham + voluntary wheel running (VWR), and TBI + VWR). One-week VWR was carried out on the 2nd day after trauma. The neurofunction of TBI mice was assessed. Following VWR, anxiety behavior was evaluated, and neuroinflammatory responses in the perilesional cortex were investigated. Results showed that after one week of VWR, neurofunctional recovery was enhanced, while the anxiety behavior of TBI mice was significantly alleviated. The level of pro-inflammatory factors decreased, and the level of anti-inflammatory factors elevated. Activation of nucleotide oligomerization domain-like thermal receptor protein domain associated protein 3 (NLRP3) inflammasome was inhibited significantly. All these alterations were consistent with reduced microglial activation at the perilesional site and positively correlated with the amelioration of anxiety behavior. This suggested that timely rehabilitative exercise could be a useful therapeutic strategy for anxiety resulting from TBI by targeting neuroinflammation.

Effects of Diabetes and Voluntary Exercise on IgA Concentration and Polymeric Immunoglobulin Receptor Expression in the Submandibular Gland of Rats.

Background and Objectives: Patients with diabetes are more susceptible to upper respiratory tract infections (URTIs) because they are easily infected. Salivary IgA (sali-IgA) levels play a major role in transmitting URTIs. Sali-IgA levels are determined by salivary gland IgA production and polymeric immunoglobulin receptor (poly-IgR) expression. However, it is unknown whether salivary gland IgA production and poly-IgR expression are decreased in patients with diabetes. While exercise is reported to increase or decrease the sali-IgA levels, it is unclear how exercise affects the salivary glands of patients with diabetes. This study aimed to determine the effects of diabetes and voluntary exercise on IgA production and poly-IgR expression in the salivary glands of diabetic rats. Materials and Methods: Ten spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats (eight-week-old) were divided into two groups of five rats each: a non-exercise group (OLETF-C) and a voluntary wheel-running group (OLETF-E). Five Long-Evans Tokushima Otsuka (LETO) rats without diabetes were bred under the same conditions as the OLETF-C. Sixteen weeks after the study began, the submandibular glands (SGs) were collected and analyzed for IgA and poly-IgR expression levels. Results: IgA concentrations and poly-IgR expression levels in SGs were lower in OLETF-C and OLETF-E than in LETO (p < 0.05). These values did not differ between the OLETF-C and OLETF-E. Conclusions: Diabetes decreases IgA production and poly-IgR expression in the salivary glands of rats. Moreover, voluntary exercise increases sali-IgA levels but does not increase IgA production and poly-IgR expression in the salivary glands of diabetic rats. Increasing IgA production and poly-IgR expression in the salivary glands, which is reduced in diabetes, might require slightly higher-intensity exercise than voluntary exercise under the supervision of a doctor.

The Combination of Intestinal Alkaline Phosphatase Treatment with Moderate Physical Activity Alleviates the Severity of Experimental Colitis in Obese Mice via Modulation of Gut Microbiota, Attenuation of Proinflammatory Cytokines, Oxidative Stress Biomarkers and DNA Oxidative Damage in Colonic Mucosa.

Inflammatory bowel diseases (IBD) are commonly considered as Crohn's disease and ulcerative colitis, but the possibility that the alterations in gut microbiota and oxidative stress may affect the course of experimental colitis in obese physically exercising mice treated with the intestinal alkaline phosphatase (IAP) has been little elucidated. Mice fed a high-fat-diet (HFD) or normal diet (ND) for 14 weeks were randomly assigned to exercise on spinning wheels (SW) for 7 weeks and treated with IAP followed by intrarectal administration of TNBS. The disease activity index (DAI), grip muscle strength test, oxidative stress biomarkers (MDA, SOD, GSH), DNA damage (8-OHdG), the plasma levels of cytokines IL-2, IL-6, IL-10, IL-12p70, IL-17a, TNF-α, MCP-1 and leptin were assessed, and the stool composition of the intestinal microbiota was determined by next generation sequencing (NGS). The TNBS-induced colitis was worsened in obese sedentary mice as manifested by severe colonic damage, an increase in DAI, oxidative stress biomarkers, DNA damage and decreased muscle strength. The longer running distance and weight loss was observed in mice given IAP or subjected to IAP + SW compared to sedentary ones. Less heterogeneous microbial composition was noticed in sedentary obese colitis mice and this effect disappeared in IAP + SW mice. Absence of Alistipes, lower proportion of Turicibacter, Proteobacteria and Faecalibacterium, an increase in Firmicutes and Clostridium, a decrease in oxidative stress biomarkers, 8-OHdG content and proinflammatory cytokines were observed in IAP + SW mice. IAP supplementation in combination with moderate physical activity attenuates the severity of murine colitis complicated by obesity through a mechanism involving the downregulation of the intestinal cytokine/chemokine network and oxidative stress, the modulation of the gut microbiota and an improvement of muscle strength.

Central command-related increases in blood velocity of anterior cerebral artery and prefrontal oxygenation at the onset of voluntary tapping.

The anterior cerebral artery (ACA) supplies blood predominantly to the frontal lobe including the prefrontal cortex. Our laboratory reported that prefrontal oxygenated-hemoglobin concentration (Oxy-Hb) increased before and at exercise onset, as long as exercise is arbitrarily started. Moreover, the increased prefrontal oxygenation seems independent of both exercise intensity and muscle mass. If so, mean blood velocity of the ACA (ACABV) should increase with "very light motor effort," concomitantly with the preexercise and initial increase in prefrontal Oxy-Hb. This study aimed to examine the responses in ACABV and vascular conductance index (ACAVCI) of the ACA as well as prefrontal Oxy-Hb during arbitrary or cued finger tapping in 12 subjects, an activity with a Borg scale perceived exertion rating of 7 (median). With arbitrary start, ACABV increased at tapping onset (14 ± 9%) via an elevation in ACAVCI. Likewise, prefrontal Oxy-Hb increased at the onset of tapping with a time course resembling that of ACABV. A positive cross correlation between the initial changes in ACABV and prefrontal Oxy-Hb was found significant in 67% of subjects, having a time lag of 2 s, whereas a positive linear regression between them was significant in 75% of subjects. When tapping was forced to start by cue, the initial increases in ACABV, ACAVCI, and prefrontal Oxy-Hb were delayed and blunted as compared with an arbitrary start. Thus, active vasodilatation of the ACA vascular bed occurs at tapping onset, as long as tapping is arbitrarily started, and contributes to immediate increases in blood flow and prefrontal oxygenation.NEW & NOTEWORTHY Anterior cerebral artery blood velocity and vascular conductance index along with prefrontal oxygenated-hemoglobin concentration all increased at the onset of finger tapping, peaking immediately after tapping onset, as long as tapping was arbitrarily started. Positive cross correlation and linear regression between the increases in ACABV and prefrontal Oxy-Hb were significant in 67%-75% of subjects. Active vasodilatation of the ACA vascular bed occurs with arbitrary tapping onset and contributes to increased ACABV and prefrontal oxygenation.

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer's Disease.

Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer's disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice.

Plastic changes in amygdala subregions by voluntary running contribute to exercise-induced hypoalgesia in neuropathic pain model mice.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic pain, but exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. Since a growing body of evidence implicated the amygdala (Amyg) as a critical node in emotional affective aspects of chronic pain, we hypothesized that the Amyg may play important roles to produce EIH effects. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of voluntary running (VR) on the basal amygdala (BA) and the central nuclei of amygdala (CeA). The present study indicated that VR significantly improved heat hyperalgesia which was exacerbated in PSL-Sedentary mice, and that a significant positive correlation was detected between total running distances after PSL-surgery and thermal withdrawal latency. The number of activated glutamate (Glu) neurons in the medal BA (medBA) was significantly increased in PSL-Runner mice, while those were increased in the lateral BA in sedentary mice. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, but these numbers were significantly decreased in PSL-Runner mice. In addition, a tracer experiment demonstrated a marked increase in activated Glu neurons in the medBA projecting into the nucleus accumbens lateral shell in runner mice. Thus, our results suggest that VR may not only produce suppression of the negative emotion such as fear and anxiety closely related with pain chronification, but also promote pleasant emotion and hypoalgesia. Therefore, we conclude that EIH effects may be produced, at least in part, via such plastic changes in the Amyg.

Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease.

BACKGROUND: Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer's disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. METHODS: Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aß) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. RESULTS: Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aß plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aß plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. CONCLUSIONS: Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.

Physical Exercise Ameliorates the Cognitive Function and Attenuates the Neuroinflammation of Alzheimer's Disease via miR-129-5p.

INTRODUCTION: Physical exercise has a significant neuroprotective role in Alzheimer's disease (AD), but the underlying mechanisms remain elusive. OBJECTIVE: This study aimed to explore the molecular mechanisms of physical exercise by analyzing the role of microRNA-129-5p (miR-129-5p) in AD mice and patients. METHODS: AD mice and patients were treated with 4-week and 3-month physical exercise, respectively. The expression of miR-129-5p was measured using quantitative real-time PCR. The Morris water-maze test was used for cognition evaluation, and enzyme-linked immunosorbent assay was used for inflammation analysis. RESULTS: In both AD mice and patients, the expression of miR-129-5p was elevated by physical exercise. By in vivoregulation of miR-129-5p, we found that the improved cognitive function and reduced inflammatory responses were reversed by the knockdown of miR-129-5p. In patients with AD, the serum expression of miR-129-5p was further found to be correlated with the serum levels of cognitive function markers and proinflammatory cytokines. CONCLUSION: All data indicated that the expression of miR-129-5p in AD mice and patients is significantly upregulated by physical exercise. The knockdown of miR-129-5p can abrogate the neuroprotective effect of exercise on cognition and neuroinflammation in AD mice. This study provides a novel insight into the molecular mechanisms underlying the neuroprotective effect of physical exercise in AD, and miR-129-5p may provide a novel therapeutic target for AD treatment.

Estrogen and voluntary exercise attenuate cardiometabolic syndrome and hepatic steatosis in ovariectomized rats fed a high-fat high-fructose diet.

The prevalence of cardiometabolic syndrome (CMS) is increased in women after menopause. While hormone replacement therapy has been prescribed to relieve several components of CMS in postmenopausal women, some aspects of cardiometabolic dysfunction cannot be completely restored. The present study examined the effectiveness of estrogen replacement alone and in combination with exercise by voluntary wheel running (VWR) for alleviating the risks of CMS, insulin-mediated skeletal muscle glucose transport, and hepatic fat accumulation in ovariectomized Sprague-Dawley rats fed a high-fat high-fructose diet (OHFFD). We compared a sham-operated group with OHFFD rats that were subdivided into a sedentary, estradiol replacement (E2), and E2 plus VWR for 12 wk. E2 prevented the development of insulin resistance in skeletal muscle glucose transport and decreased hepatic fat accumulation in OHFFD rats. Furthermore, E2 treatment decreased visceral fat mass and low-density lipoprotein (LDL)-cholesterol in OHFFD rats, while VWR further decreased LDL-cholesterol and increased the ratio of high-density lipoprotein-cholesterol to total cholesterol to a greater extent. Although E2 treatment alone did not reduce serum triglyceride levels in OHFFD rats, the combined intervention of E2 and VWR lowered serum triglycerides in E2-treated OHFFD rats. The addition of VWR to E2-treated OHFFD rats led to AMPK activation and upregulation of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α and PPARδ in skeletal muscle along with increased fatty acid oxidation and suppressed fatty acid synthesis in the liver. Collectively, our findings indicate that, to achieve greater health benefits, physical exercise is required for E2-treated individuals under ovarian hormone deprivation with high-energy consumption.

Protective neuroendocrine effects of environmental enrichment and voluntary exercise against social isolation: evidence for mediation by limbic structures.

Previous research indicates that loneliness and social isolation may contribute to behavioral disorders and neurobiological dysfunction. Environmental enrichment (EE), including both cognitive and physical stimulation, may prevent some behavioral, endocrine, and cardiovascular consequences of social isolation; however, specific neural mechanisms for these benefits are still unclear. Therefore, this study examined potential neuroendocrine protective effects of both EE and exercise. Adult female prairie voles were randomly assigned to one of four experimental conditions: paired control, social isolation/sedentary, social isolation/EE, and social isolation/voluntary exercise. All isolated animals were housed individually for 8 weeks, while paired animals were housed with their respective sibling for 8 weeks. Animals in the EE and voluntary exercise conditions received EE items (including a running wheel) and a running wheel only, respectively, at week 4 of the isolation period. At the end of the experiment, plasma and brains were collected from all animals for corticosterone and FosB and delta FosB (FosB/ΔFosB) - immunoreactivity in stress-related brain regions. Overall, social isolation increased neuroendocrine stress responses, as reflected by the elevation of corticosterone levels and increased FosB/ΔFosB-immunoreactivity in the basolateral amygdala (BLA) compared to paired animals; EE and voluntary exercise attenuated these increases. EE and exercise also increased FosB/ΔFosB-immunoreactivity in the medial prefrontal cortex (mPFC) compared to other conditions. Limbic structures statistically mediated hypothalamic immunoreactivity in EE and exercise animals. This research has translational value for socially isolated individuals by informing our understanding of neural mechanisms underlying responses to social stressors. Highlights Prolonged social isolation increased basal corticosterone levels and basolateral amygdala immunoreactivity. Environmental enrichment and exercise buffered corticosterone elevations and basolateral amygdala hyperactivity. Protective effects of environmental enrichment and exercise may be mediated by medial prefrontal cortex and limbic structures.