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Stress is a triggering factor for anxious and depressive phenotypes. Exercise is known for its action on the central nervous system. This study aimed to evaluate the role of resistance exercise in an anxiety-depression-like dyad in a model of stress. Male Swiss mice (35-day-old) were exercised, three times a week for 4 weeks on nonconsecutive days. The resistance exercise consisted of climbing a 1-m-high ladder 15 times. After mice were subjected to an emotional single prolonged stress (E sps ) protocol. Seven days later, they were subjected to anxiety and depression predictive behavioral tests. The results showed that exercised mice gain less weight than sedentary from weeks 3 to 5. Resistance exercise was effective against an increase in immobility time in the forced swim test and tail suspension test and a decrease in grooming time of mice subjected to E sps. Resistance exercise protected against the decrease in the percentage of open arms time and open arm entries, and the increase in the anxiety index in E sps mice. Four-week resistance exercise did not elicit an antidepressant/anxiolytic phenotype in non-stressed mice. E sps did not alter plasma corticosterone levels but increased the hippocampal glucocorticoid receptor content in mice. Resistance exercise protected against the decrease in hippocampal levels of tropomyosin kinase B (TRκB), the p-Akt/Akt, and the p-mTOR/mTOR ratios of E sps mice. Resistance exercise proved to be effective in decreasing hippocampal neuroinflammation in E sps mice. Resistance exercise protected against the increase in the hippocampal Akt/mTOR pathway and neuroinflammation, and anxiety/depression-like dyad in E sps exposed mice. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-022-03069-x.

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