Altered molecular signaling pathways in the hippocampus of rhesus monkeys following chronic alcohol use
Context-induced relapse is a significant factor limiting recovery from alcohol use disorder (AUD).  However, the molecular processes in the hippocampus, a critical region for contextual memory, impacted by chronic alcohol use remain poorly understood. We used a non-human primate model to test the hypothesis that chronic alcohol use impacts hippocampal molecular pathways that may serve as therapeutic targets for context-induced relapse and memory processing issues associated with chronic alcohol use. We conducted RNAseq profiling on hippocampal samples from adult male rhesus monkeys with chronic alcohol use (n=7) and controls (n=5) from the Monkey Alcohol Tissue Research Resource (MATRR).  We identified 2,291 differentially expressed genes (DEGs) in subjects with chronic alcohol use, including genes implicated in genome-wide association studies (GWAS), such as GLP2R and GABBR2. Downregulated pathways included chemical synaptic transmission, trans-synaptic signaling, and neuron development, and upregulated pathways involved mitochondrial function. Targeted pathway analysis highlighted significant downregulation of synaptic signaling pathways (e.g., axonal fasciculation) and upregulation of mitochondrial processes (e.g., electron transport).  Leading-edge analysis revealed several downregulated genes involved in synaptic signaling including GRIN2B, CACNA1C, and NLGN1 and upregulated genes such as NDUFS3 and MT-ND1  involved in mitochondrial processes.  Drug repurposing analysis identified several targets including epidermal growth factor receptor (EGFR) inhibitors, and L-type calcium channel blockers as potential therapeutic targets.  Our results provide critical insights into molecular pathways underlying hippocampal pathology in chronic alcohol use, emphasizing the roles of mitochondrial function, synaptic regulation and calcium channels in the hippocampus, and offering potential novel therapeutic targets. Overall design: RNAseq profiling of hippocampal tissue samples from adult male rhesus monkeys with chronic alcohol use and controls