Hou_2025_Life.Sci_377_123795

AIMS: Heavy alcohol use during adolescence significantly impacts cognitive function in adulthood. However, the neural mechanisms underlying adolescent alcohol exposure-induced adult cognitive deficits remain unclear. This study aimed to elucidate the effects of adolescent intermittent ethanol (AIE) exposure on cholinergic neurons in the medial septum (MS) and the resultant cognitive deficits in adult mice. MATERIALS AND METHODS: From postnatal day (PND) 28 to PND 41, mice received ethanol through intragastric gavage on alternate days to establish the model of AIE. To assess the electrophysiological and morphological alterations in cholinergic neurons located in the medial septum (MS), patch-clamp recordings and biocytin injections were conducted. Additionally, chemogenetic techniques were employed to stimulate the cholinergic neurons within the MS. Furthermore, The acetylcholinesterase inhibitor donepezil was administered to the mice via intraperitoneal injection to increase acetylcholine levels in the brain. KEY FINDINGS: Our findings showed that AIE-exposed mice exhibited marked cognitive deficits in adulthood. AIE exposure also led to reduced synaptic transmission and decreased intrinsic excitability of cholinergic neurons in the MS. Additionally, we observed diminished dendritic branching and spine density of MS cholinergic neurons, indicating structural impairments. Notably, chemogenetic activation of septo-hippocampal cholinergic circuits improved cognitive performance in AIE-exposed mice. Furthermore, pharmacological intervention with donepezil ameliorated these cognitive deficits. SIGNIFICANCE: Our results provide direct evidence that disruption of septo-hippocampal cholinergic circuits contributes to AIE-induced cognitive deficits in adulthood and suggest that these deficits may be modulated through the cholinergic system.