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Molecular Mechanisms and Behavioral Outcomes in Bmal1 Muscle Overexpression Mice


Sleep deprivation has consistently been shown to have negative impacts on the health, wellbeing, and memory consolidation of organisms. Recent studies reveal that the overexpression of Bmal1 in skeletal muscle reduces homeostatic sleep responses to acute sleep loss. In this study, we examine the molecular mechanisms by which Bmal1 in the skeletal muscle is modulated by the sleep homeostatic response, and if Bmal1 muscle overexpression mice are protected against the cognitive impacts of sleep deprivation. Our primary targets for the molecular mechanism were the Peroxisome Proliferator-Activated Receptor-γ Coactivator (PGC-1α), and the Brain-Derived Neurotropic Factor (BDNF). Both have been shown to interact with the circadian clock and both have been shown to modulate sleep-wake architecture. We found that while sleep deprivation significantly decreased BMAL1 protein levels, it did not have a significant effect on BDNF and PGC-1α levels. However, female mice had significantly increased BDNF and PGC-1α levels compared to male mice. We examined memory via two behavioral tests — the Novel Object Recognition Test, which measures recognition memory, and the Novel Location Recognition test, which measures spatial memory. In the Novel Object Recognition test, we found that 6 hours of sleep deprivation was unable to disrupt novel object recognition in either Bmal1 muscle overexpression mice or wild-type littermates. However, we found that 12 hours of sleep restriction immediately after memory acquisition disrupted novel object recognition during the testing phase in wild types, but significantly improved novel objection recognition in Bmal1 muscle overexpression mice. In the Novel Location Recognition test, sleep deprivation significantly increased novel location recognition. Posthoc analysis revealed a significant improvement in sleep-deprived wild-types but not in sleep-deprived Bmal1 muscle overexpression mice. These results suggest that skeletal muscle Bmal1 confers resistance to recognition memory deficits caused by sleep deprivation, but not spatial memory deficits.

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