Alcohol exposure significantly influences gene expression in the hypothalamus, highlighting complex links with gonadotropin-releasing hormone signaling and thyroid hormone production in adolescent mice.

Objective: Hypothalamic dysfunction occurs in alcohol use disorder (AUD). Here, we investigated the effects of alcohol exposure on hypothalamic gene expression in mice, and examined the role of the hypothalamus in AUD pathogenesis.

Methods: An alcohol exposure model was constructed in male C57BL/6 mice using the two-bottle drinking method. Transcriptome sequencing was used to analyze differential gene expression in the hypothalamus of alcohol exposure model and control mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the differentially expressed genes were performed. In addition, real-time quantitative PCR was used to verify the differential expression of genes.

Results: We identified 225 differentially expressed genes by transcriptome sequencing, of which 64 showed increased expression and 161 decreased expression. GO enrichment analysis showed highest enrichment for developmental process terms. KEGG enrichment analysis showed highest enrichment for the gonadotropin-releasing hormone (GnRH) signaling pathway. PCR validation showed reduced expression of Prkcd, Ptk2b, and Adcy1 in the alcohol group compared with the control group, consistent with the sequencing results. The thyroid hormone synthesis pathway was significantly enriched, and PCR results showed that expression of Adcy1, Gpx2, and Ttr were decreased in the alcohol group compared with the control group, which was consistent with the sequencing results.

Conclusion: Alcohol exposure in mice modulates the expression of genes associated with hypothalamic GnRH signaling pathway and thyroid hormone synthesis pathway. Expression of GnRH signaling pathway genes, Prkcd and Ptk2b, and of thyroid hormone synthesis pathway genes, Gpx2, Ttr, and Adcy1, was decreased. Our findings indicate that alcohol exposure is associated with altered expression of these genes, which may be relevant to the pathophysiology of AUD.