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Sleep Deprivation Alters Microglial Homeostasis and the Strategy to Prevent Its Negative Effects
Sleep deprivation,adolescent,microglia,synaptic pruning,neuroinflammation,voluntary exercise,
|Publication Year :||2020|
The neurological impacts of sleep insufficiency have been extensively explored. However, only a few studies have addressed this issue in adolescents. Adequate sleep is essential for adolescents’ physical function and mental health. Most importantly, since adolescence is a critical period for brain development, emerging evidence revealed that insufficient sleep has detrimental effects on the developmental trajectories in the adolescent brains. Yet, the detailed mechanisms underpinning the interplays between sleep loss and brain development are still expecting disclosure.
Microglia, the resident immune cells and professional phagocytes in the central nervous system (CNS), respond to the pathologic conditions and disrupted homeostasis by increased cytokines secretion, phagocytose pathogens or cellular debris, and rapid morphological changes. Previous studies suggested that sleep loss induces microglial activation and subsequent neuroinflammatory responses. However, microglia also contribute to the maturating process of the nervous system. One of the prominent functions of microglia is to modulate synaptic refinement and maturation during postnatal development. A growing number of studies have highlighted the dysfunctions of microglia during the critical period of neural circuits development lead to aberrant synaptic functions and neural wiring. Therefore, due to the importance of microglia in the maintenance of CNS homeostasis as well as the neurodevelopmental trajectories, the current study aimed to uncover the adverse consequence of sleep loss in respect of microglial functions.
In the first part of our study, we examined and compared the effects of 72 h paradoxical sleep deprivation (SD) on adolescent (five-week-old) and adult (~twelve-week-old) mice. Following 72 h of SD, induced by a modified multiple-platform method, mice were subjected to behavioral, histological and neurochemical examinations. In both adolescent and adult mice, SD adversely affected short-term memory in a novel object recognition test. Compared with normal-sleep controls, sleep-deprived adolescent mice had an increased density of excitatory synapses in the granule cells (GCs) of the dentate gyrus (DG), but no such pattern was observed in the adult group. The engulfment of postsynaptic components within the microglia after SD was reduced in adolescents but not in adults, suggesting an impaired microglia-mediated synaptic pruning in adolescent SD mice. Possible contributing factors included the decreases in CX3CR1, CD11b, and P2Y12, closely associated with the synaptic pruning via microglial phagocytosis. In adult SD mice, microglia-associated inflammatory reactions were noted. In summary, sleep deprivation induces age-dependent microglial reactions in adolescent and adult mice, respectively, yet results in similar defects in short-term recognition memory. Sufficient sleep is indispensable for both adolescents and adults.
While adolescents at large are facing the problem of sleep insufficiency, there is an urgent need to prevent the detrimental effects of sleep loss. Physical exercise has been demonstrated to counteract the harmful consequences of various stress or neurodegenerative models by modulating microglial function. For that reason, in the second part of our study, we investigated the hypothesis that physical exercise might serve as a preventive intervention to rescue the failure of synaptic pruning and microglial function after SD in adolescent mice.
Three-week-old C57/BL6 male mice were randomly assigned into the voluntary exercise (VE) group in which a running wheel was provided or the sedentary control group. In each group, mice were further divided into 72 h SD or home cage (HC) normal sleep groups. After 72 h SD or normal sleep, four groups (HC, VE+HC, SD, VE+SD) of mice were subjected to a short-term memory test or sacrificed for further examination. Our result indicated that SD-induced impairments in short-term memory and an increase in the neural activity index were prevented by the preceding VE. Furthermore, the increased dendritic spine density in the SD group was not observed in the VE+SD group, implying that VE prevented SD-induced synaptic pruning deficits. We also observed greater microglial phagocytic capacity, characterized by increased internalized postsynaptic materials and lysosomal structure within individual microglia, in the VE+SD group than in the SD group. mRNA expression levels of microglia-specific receptors critical to developmental synaptic refinement were found to be upregulated in both the VE+HC and VE+SD groups.
Here, we provided evidence featuring a substantial effect of VE that significantly alleviated the SD-induced deficits in short-term memory and microglia-mediated synaptic pruning. Physical exercise could be a beneficial health practice for adolescents to cope with the adverse influence of inevitable sleep insufficiency.
|Appears in Collections:||解剖學暨細胞生物學科所|
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