tACS and nervonic acid inhibit microglial overactivation via the Rap1 signaling pathway and ameliorate sleep deprivation-induced cognitive impairment

Sleep deprivation (SD) has become a critical global health concern, with consequences including cognitive decline. Transcranial alternating current stimulation (tACS) holds significant potential for improving cognitive impairment. This study aimed to evaluate the effects of tACS on SD-associated cognitive deficits. Male C57BL/6 mice were subjected to SD using the horizontal platform method. Cognitive function was assessed via multiple behavioral tests, and local field potential (LFP) signals were recorded. Untargeted metabolomics was employed to identify key metabolites and regulatory pathways in mouse brain tissue. Mouse models and co-culture systems were combined to investigate the regulatory relationships among microglia, synapses, and neurons. tACS significantly improved memory and cognitive function in SD-induced model mice, accompanied by inhibited microglial phagocytosis, increased synaptic density, and reduced neuronal apoptosis. Untargeted metabolomics revealed that tACS may regulate nervonic acid (NA) abundance and the Rap1 signaling pathway during SD. Further studies demonstrated that NA suppresses lipopolysaccharide (LPS)-induced microglial overactivation and synaptic loss via the Rap1 signaling pathway, thereby blocking neuronal apoptosis. Additionally, similar to the therapeutic effects of tACS, NA administration markedly alleviated cognitive impairment and neural damage in SD mice. These data support the regulatory roles of tACS and NA in neuronal activity and synaptic plasticity and propose novel therapeutic targets for SD-related cognitive deficits.