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Physical activity has been correlated with a reduced risk of cognitive decline, including that associated with vascular dementia, mild cognitive impairment (MCI) and Alzheimer's disease (AD); recent literature suggests this may in part result from benefits to the cerebrovascular network. Using a transgenic (Tg) mouse model of AD, we evaluated the effect of running on cortical and hippocampal vascular morphology, cerebral amyloid angiopathy, amyloid plaque load, and spatial memory. TgCRND8 mice present with progressive amyloid pathology, advancing from the cortex to the hippocampus in a time-dependent manner. We postulated that the characteristic progression of pathology could lead to differential, time-dependent effects of physical activity on vascular morphology in these brain regions at 6 months of age. We used two-photon fluorescent microscopy and 3D vessel tracking to characterize vascular and amyloid pathology in sedentary TgCRND8 mice compared those who have a history of physical activity (unlimited access to a running wheel, from 3 to 6 months of age). In sedentary TgCRND8 mice, capillary density was found to be lower in the cortex and higher in the hippocampus compared to non-transgenic (nonTg) littermates. Capillary length, vessel branching, and non-capillary vessel tortuosity were also higher in the hippocampus of sedentary TgCRND8 compared to nonTg mice. Three months of voluntary running resulted in normalizing cortical and hippocampal microvascular morphology, with no significant difference between TgCRND8 and nonTg mice. The benefits of physical activity on cortical and hippocampal vasculature in 6-month old TgCRND8 mice were not paralleled by significant changes on parenchymal and cerebral amyloid pathology. Short-term spatial memory— as evaluated by performance in the Y-maze— was significantly improved in running compared to sedentary TgCRND8 mice. These results suggest that long-term voluntary running contributes to the maintenance of vascular morphology and spatial memory in TgCRND8 mice, even in the absence of an effect on amyloid pathology.

Although the antidepressant effects of running exercise have been widely reported, further research is still needed to determine the structural bases for these effects. Astrocyte processes physically contact many synapses and directly regulate the numbers of synapses, but it remains unclear whether running exercise can modulate astrocyte morphological complexity and astrocyte-contacted synapses in the hippocampus of the mice with depressive-like behavior. Male C57BL/6 J mice underwent four weeks of running exercise after four weeks of chronic unpredictable stress (CUS). The sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess anhedonia in mice. Western blotting was used to measure the expression of astrocyte- and synapse-related proteins. Immunofluorescence and 3D reconstruction were used to quantify the density and morphology of astrocytes, and astrocyte-contacted synapses in each hippocampal subregion. Four weeks of running exercise alleviated depressive-like symptoms in mice. The expression of astrocyte- and synapse-related proteins in the hippocampus; astrocyte process lengths, process numbers, and dendritic arborization; and the number of astrocyte-contacted PSD95 positive synapses in the CA2-3 and DG regions were significantly decreased in the mice with depressive-like behavior, and running exercise successfully reserved these changes. Running exercise improved the decreases in astrocyte morphological complexity and astrocyte-contacted PSD95 positive synapses in the CA2-3 and DG regions of the mice with depressive-like behavior, suggesting that the physical interactions between astrocytes and synapses can be increased by running exercise, which might be an important structural basis for the antidepressant effects of running exercise., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The aim of this study is to investigate the impact of running exercise training protocols (ETPs) with varying intensities on inflammatory responses, with a specific focus on the interactions between inflammatory mediators, cytokines, and Leydig cell steroidogenic activity, as well as testosterone secretion. To this end, 24 Wistar rats were subdivided into sedentary control, low (LICT), moderate (MICT), and high (HICT) intensity continuous running ETP groups. After 8 weeks, the expression levels of Toll-like receptor-4 (TLR-4), nuclear factor-kappa-B (NF-KB), interleukin-6 (IL-6), interleukin-10 (IL-10), Tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the testicular nitric oxide (NO) content were assessed and compared between groups. Moreover, the mean distributions of Leydig cells/mm 2 of interstitial connective tissue, their steroidogenic activity, and serum level of testosterone were assessed. The LICT did not show any significant (p > 0.05) change in the expression levels of all aforementioned biomarkers. In contrast, both the MICT and HICT groups demonstrated a significant (p < 0.05) increase in the expression levels of TLR-4, NFK-B, IL-6, TNF-α, iNOS, and COX-2 at both the mRNA and protein levels. The testicular NO has increased in HICT and MICT groups. Despite a decrease in the distribution of Leydig cells in both the MICT and HICT groups, the HICT group exhibited a significant (p < 0.05) reduction in Leydig cell steroidogenic activity and serum testosterone levels. In conclusion, our findings revealed that ETPs can influence Leydig cell steroidogenic activity and testosterone secretion, contingent on their intensity. These effects are attributed to alterations in the expression levels of pro-inflammatory mediators and cytokines., Competing Interests: Declaration of competing interest Not applicable., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Persistent cognitive and mood impairments in Gulf War Illness (GWI) are associated with chronic neuroinflammation, typified by hypertrophied astrocytes, activated microglia, and increased proinflammatory mediators in the brain. Using a rat model, we investigated whether a simple lifestyle change such as moderate voluntary physical exercise would improve cognitive and mood function in GWI. Because veterans with GWI exhibit fatigue and post-exertional malaise, we employed an intermittent voluntary running exercise (RE) regimen, which prevented exercise-induced stress. The GWI rats were provided access to running wheels three days per week for 13 weeks, commencing ten weeks after the exposure to GWI-related chemicals and stress (GWI-RE group). Groups of age-matched sedentary GWI rats (GWI-SED group) and naïve rats were maintained parallelly. Interrogation of rats with behavioral tests after the 13-week RE regimen revealed improved hippocampus-dependent object location memory and pattern separation function and reduced anxiety-like behavior in the GWI-RE group compared to the GWI-SED group. Moreover, 13 weeks of RE in GWI rats significantly reversed activated microglia with short and less ramified processes into non-inflammatory/antiinflammatory microglia with highly ramified processes and reduced the hypertrophy of astrocytes. Moreover, the production of new neurons in the hippocampus was enhanced when examined eight weeks after the commencement of RE. Notably, increased neurogenesis continued even after the cessation of RE. Collectively, the results suggest that even a moderate, intermittent physical exercise has the promise to improve brain function in veterans with GWI in association with suppression of neuroinflammation and enhancement of hippocampal neurogenesis., (Published by Elsevier Inc.)