Microglial response to sleep deprivation depends on the hippocampal region and paradigm used in adult male mice

With the current society's focus on high productivity and performance, impaired sleep regimen has become prevalent, affecting as much as 25% of the adult population. Sleep loss can lead to many detrimental consequences, including cognitive impairments. In the brain, the hippocampus is one of the regions most vulnerable to sleep deprivation (SD), often displaying neuronal connectivity changes and reduced synaptic density. Strikingly, acute SD induces brain region- and subregion-specific changes in synaptic plasticity in adult mice, suggesting localized mechanisms of vulnerability. Microglia, the brain's immune cells, are important contributors to synaptic plasticity, and their functions are affected by various paradigms of acute SD, while exhibiting regional and environmental heterogeneity. We thus aimed to compare 2 commonly used but experientially distinct SD paradigms, and explore possible differences in microglial properties across hippocampal subregions, hypothesizing that microglia contribute to the region-specific modulation of synaptic plasticity. We exposed adult male mice to 6 h of SD through the paradigms of gentle handling or novelty exposure. We observed a decreased microglial density with novelty exposure compared to control and gentle handling in the CA1 <i>SR</i>, but not the CA3 <i>SR</i>. Regarding morphological changes, microglial soma area, perimeter, and morphological index were reduced with novelty exposure in both the CA1 and CA3 <i>SR</i> <i>,</i> suggesting a more reactive microglial state. Microglial arborization circularity and solidity were also reduced, and microglial arborization perimeter increased after novelty exposure, only in the CA1 <i>SR</i>, indicating increased surveillance activity. Moreover, we measured in microglia an increased number of puncta positive for cluster of differentiation 68, a marker of phagolysosomal activity, after novelty exposure, only in the CA1 <i>SR</i>. Lastly, using advanced scanning electron microscopy, we observed decreased microglial cytoplasm circularity and solidity, and an increased number of fully digested phagosomes within microglia following novelty exposure, only in the CA1 <i>SR</i>, further supporting increased phagocytic activity. Overall, our results indicate that microglial density, distribution, morphology, and phagocytic activity are altered by SD depending on the hippocampal region, specifically in the CA1 <i>SR</i>, and more so in SD by novelty exposure, thereby reinforcing that 'it matters what keeps you awake at night'. Therefore, care should be taken concerning SD procedures as they can directly impact the conclusions.