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Genetic and neurobiological factors mitigating the negative consequences of sleep deficits


Sleep is an incredibly multifaceted phenomenon affecting and affected by numerous biological processes. We have only begun to understand the breadth of its functions in disease, however; sleep disruption has been robustly demonstrated to have myriad negative consequences on human health and cognition. Here, we explore the etiology of both cellular and genetics feature which putatively protect the brain from the effects of sleep deprivation.

First, we identify characteristics of resilience to neurodegenerative losses in genetic natural short sleeper mice. A major concern affecting Alzheimer’s disease patients worldwide is poor or diminished sleep, as sleep disruption can accelerate cognitive decline. Natural short sleepers are individuals with a genetic predisposition towards a lifelong reduction in nightly sleep duration, yet the majority of them age without experiencing severe neurodegeneration. We investigate the effects of two mutations causing short sleep duration on the progression of two correlates of Alzheimer’s Disease: Tau and Amyloid Beta pathology, using common physiological and molecular metrics of disease burden for these proteins in multiple tissues, as well as behavioral and cognitive assays. We find mice with the DEC2P384R and Npsr1Y206H mutations crossed with PS19 mice display much milder tangle pathology than WT PS19 mice. Further, the DEC2P384R line (but not Npsr1Y206H) exhibited significantly less amyloid plaques. These results suggest that some natural short sleep mutations may grant resilience to the pathological progression of AD and that different natural short sleep mutations may offer these protections through different mechanisms.

We also elucidate a novel protective role for microglia, an innate immune cell found in the brain, to cognitive losses following sleep deprivation. Sleep deprivation can generate inflammatory responses in the central nervous system. In turn, this inflammation increases sleep drive, leading to a rebound in sleep duration. Microglia, have previously been found to release inflammatory signals and exhibit altered characteristics in response to sleep deprivation. Together, this suggests that microglia may be partially responsible for the brain’s response to sleep deprivation through their inflammatory activity. In this study, we ablated microglia from the mouse brain and assessed resulting sleep, circadian, and sleep deprivation phenotypes. Mice were assessed for learning ability following sleep deprivation, resulting in the identification of a severe memory deficit in mice without microglia in this context. Conversely, EEG measurement and analysis found that microglia are dispensable for both homeostatic sleep and circadian function and the sleep rebound response to sleep deprivation. Further physiological assessment of synaptic density attributed the negative learning phenotype in sleep deprived mice to altered spine morphology and processing by microglia during this period. Overall we uncover a phenomenon by which microglia appear to be essential for the protection of synapses and associated memories formed during a period of sleep deprivation, further expanding the list of known functions for microglia in synaptic modulation.

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