The niacin receptor HCAR2 prevents sleep deprivation-induced cognitive impairment by inhibiting microglia-mediated neuroinflammation in mice

Sleep loss has become a common occurrence nowadays, posing significant concerns to public health by increasing risks of various diseases. Studies have shown that sleep loss can cause neuroinflammation and cognitive decline, yet its exact mechanisms and reliable prevention strategies remain unclear. Hydroxycarboxylic acid receptor 2 (HCAR2) is a G protein-coupled receptor expressed in various immune cells, and its activation shows beneficial anti-inflammatory effects in some peripheral and central inflammatory diseases. In this study, we aimed to employ a sleep deprivation (SD) mouse model, combined with genetic and pharmacological manipulation, behavioral tests, biochemical assays and proteomics analysis, to investigate whether activation of HCAR2 could improve SD-induced neuroinflammation and cognitive impairment in mice. We observed that SD significantly disrupted HCAR2 signaling, activated NF-κB/NLRP3 signaling pathway, promoted microglial M1 polarization and ensuing neuroinflammation, impaired synaptic plasticity in the hippocampus of mice, and thereby resulted in cognitive deficits. However, activating HCAR2 with niacin effectively reversed these changes and ultimately alleviated SD-induced cognitive impairment in mice. Our findings suggest that the impaired HCAR2 signaling may be one of the pathogenesis mechanisms of SD, and HCAR2 may represent a promising therapeutic target for sleep loss-related cognitive disorders.

Cognitive impairment; HCAR2; Microglia; Neuroinflammation; Sleep deprivation.