Sustained microglial activation and accelerated elimination of dendritic spines during acute sleep deprivation and restoration

Abstract

<p>Sleep is a fundamental physiological condition strongly regulated by a variety of neuroanatomical and neurochemical systems. Recent studies have indicated that catch-up sleep falls short of effectiveness to counteract the negative consequences of sleep debt however, the underlying mechanisms remain poorly understood. In this study, by using various transgenic fluorescent mouse models as well as techniques including intravital two-photon imaging and immunofluorescence staining of brain sections, we have documented morphological and functional changes of microglia during acute sleep deprivation (ASD) and subsequent short-term recovery sleep (RS). In these cerebral resident immune cells, we observed sustained microglial de-ramification, reduction of process motility and enhancement of microglial phagocytosis across brain regions. Given the intimate connections between microglia activity and neuronal plasticity, we also investigated synaptic plasticity and demonstrated an accelerated elimination of dendritic spines during both ASD and subsequent RS. Furthermore, untargeted metabolomic analyses revealed extensive whole-brain metabolic changes during ASD, and that a substantial number of metabolites and pathways failed to recover within a short period of RS. It is tempting to speculate that the disturbed cerebral metabolic homeostasis contributes to the sustained microglial activation and accelerated elimination of dendritic spines during this process. This study reveals the adverse effects of sleep loss on neuroimmunomodulation and neuronal plasticity, and implicates potential mechanisms underlying how irregular sleep schedules lead to neurological disorders.</p>