Mediodorsal thalamus of alcohol-dependent mice shows genetic and physiological adaptations and alcohol-biased calcium signaling.

Alcohol Use Disorder (AUD) is a significant health concern characterized by cognitive dysfunction and an inability to control alcohol intake, leading to severe social and health consequences. It is crucial to uncover neuroadaptations and cellular mechanisms responsible for poor decisions surrounding alcohol drinking. Although the mediodorsal thalamus (MD) is an essential brain region for cognitive function and reward-guided choices, the effects of alcohol dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol over natural rewards (i.e., sucrose) are not well understood. Genetic and physiological adaptations in the MD were assessed in mice treated with the chronic intermittent ethanol (CIE) exposure model of dependence, which increased alcohol intake and preference during choice sessions for water or sucrose in males and females. Results indicated that CIE exposure induced time-dependent changes in c-Fos and transcript expression and increased excitability of MD neurons during withdrawal. Enrichment analysis of alcohol-sensitive genes revealed dysregulation of genes that control glial function and axonal myelination. Fiber photometry recordings demonstrated that MD activity was elevated at the start of and after licking bouts for alcohol, water, or sucrose, and the signal for alcohol was significantly higher than the signal for other solutions in control and alcohol dependent mice. These findings demonstrate that CIE exposure causes alcohol-biased choice behaviors and genetic and physiological neuroadaptations in the MD, with MD neurons showing a unique response to alcohol over other solutions.