Genetic and functional adaptations and alcohol-biased signaling in the mediodorsal thalamus of alcohol dependent mice

Alcohol Use Disorder (AUD) is a significant health concern characterized by an individual’s inability to control alcohol intake. With alcohol misuse increasing and abstinence rates declining, leading to severe social and health consequences, it is crucial to uncover effective treatment strategies for AUD by focusing on understanding neuroadaptations and cellular mechanisms. The mediodorsal thalamus (MD) is a brain region essential for cognitive functioning and reward-guided choices. However, the effects of alcohol (ethanol) dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol and a natural reward (sucrose) are not well understood. Adult C57BL/6J mice treated with chronic intermittent ethanol (CIE) exposure were used to assess genetic and functional adaptations in the MD. Fiber photometry-based recordings of GCaMP6f expressed in the MD of C57BL/6J mice were acquired to investigate in vivo neural adaptations during choice drinking sessions for alcohol (15%) and either water or sucrose (3%). There were time-dependent changes in cFos and transcript expression during acute withdrawal and early abstinence. Differentially expressed genes were identified in control mice across different circadian time points and when comparing control and alcohol dependent mice. Gene Ontology enrichment analysis of the alcohol-sensitive genes revealed disruption of genes that control glial function, axonal myelination, and protein binding. CIE exposure also increased evoked firing in MD cells at 72 hours of withdrawal. In alcohol-dependent male and female mice that show increased alcohol drinking and preference for alcohol over water, we observed an increase in alcohol intake and preference for alcohol when mice were given a choice between alcohol and sucrose. Fiber photometry recordings demonstrated that MD activity is elevated during and after licking bouts for alcohol, water, and sucrose, and the signal for alcohol is significantly higher than that for water or sucrose during drinking. The elevated signal during alcohol bouts persisted in alcohol dependent mice. These findings demonstrate that CIE causes genetic and functional neuroadaptations in the MD and that alcohol dependence enhances alcohol-biased behaviors, with the MD uniquely responsive to alcohol, even in dependent mice.