Alcohol-Induced Early-Stage Liver Injury Contributes to Increases in Voluntary Alcohol Intake and Cognitive Deficits in Mice.

BACKGROUND:Liver-brain communication is increasingly recognized as a potential contributor to vulnerability to alcohol use disorder (AUD). However, the behavioral consequences of early alcohol-associated liver disease (ALD) remain underexplored. This study aimed to determine whether alcohol-induced hepatic injury influences subsequent alcohol consumption and cognitive outcomes. METHODS:Female C57BL/6J mice were fed a Lieber-DeCarli (LDC) ethanol diet to induce early-stage ALD-like pathology, followed by a voluntary two-bottle choice (TBC) paradigm measuring alcohol consumption. Behavioral assessments included novel object recognition, T-maze with spontaneous alternation, and elevated plus maze. Hepatic steatosis was measured by histology and triglyceride quantification; inflammatory gene expression was evaluated by RT-qPCR, and hippocampal BDNF/TrkB signaling was investigated by western blot. RESULTS:LDC mice on an ethanol diet developed hepatic steatosis and hepatomegaly compared with controls. These mice also consumed significantly more alcohol during initial TBC testing, with intake positively correlated with the degree of steatosis. Hepatic steatosis was transient, recovering by the end of TBC period with accompanied upregulation of inflammatory markers and evidence suggestive of neutrophilic infiltration in ethanol-exposed mice. These mice also exhibited impaired spatial working memory without significant differences in long-term recognition or anxiety-like behavior in the elevated plus maze. In addition, ethanol exposure was associated with reduced hippocampal expression of BDNF and its receptor TrkB. CONCLUSION:These findings suggest that alcohol-induced early hepatic injury may contribute to increased alcohol consumption and impaired spatial working memory performance paralleling sustained hepatic inflammation and dysfunction in neurotrophic signaling. Further investigation is warranted to elucidate the mechanisms underlying liver-brain communication in the context of AUD and ALD progression.