Microglial efferocytosis dysfunction contributes to depression-like behaviors and cognitive impairment in aged mice following chronic sleep deprivation.

Abstract

BACKGROUND: Chronic sleep deprivation (CSD), commonly observed in the elderly, is associated with an increased risk of neuroinflammation, depression, and cognitive impairment. Microglial efferocytosis plays a vital role in maintaining neural homeostasis and tissue repair. However, the mechanistic role of microglial efferocytosis in linking CSD to neurobehavioral impairments in aging remains largely undefined. METHODS: A 21-day CSD model was established in aged mice, and depression-like behaviors and cognitive function were evaluated. Hippocampal neuronal injury and neuroinflammation were evaluated using histological staining and immunohistochemistry/immunofluorescence. Microglial efferocytosis was assessed in both hippocampal tissues and an in vitro microglial model. Expression of inflammatory mediators and efferocytosis-related molecules was quantified by qRT-PCR and Western blotting, and TREM2 overexpression was applied to determine its functional contribution to efferocytic capacity and behavioral outcomes. RESULTS: CSD induced significant depression-like behaviors and cognitive impairment in aged mice, accompanied by hippocampal neuronal damage and enhanced neuroinflammation. Importantly, CSD markedly impaired microglial efferocytosis and was associated with selective downregulation of TREM2 expression. Pharmacological inhibition of efferocytosis with Annexin V further exacerbated neuroinflammation and behavioral deficits. In contrast, TREM2 overexpression restored microglial efferocytic activity, attenuated neuroinflammatory responses, and significantly improved depression-like behaviors and cognitive impairment in CSD-treated aged mice. CONCLUSIONS: Our findings reveal that TREM2-mediated impairment of microglial efferocytosis represents a key mechanism underlying CSD-related neuropathology in aging, highlighting TREM2 as a potential therapeutic target for sleep disturbance-related neuropsychiatric disorders.