Research Component 5: Mulholland & Rinker

Alcohol Dependence and Loss of Reward-Based Flexible Behavior: Role of Mediodorsal Thalamus to PFC Circuit

Principal Investigator: Patrick J. Mulholland, Ph.D.
Co-Investigator: Jennifer A. Rinker, Ph.D.

This research project examines chronic alcohol-induced functional changes in the mediodorsal thalamus (MDT) that contribute to inflexible, excessive alcohol drinking associated with dependence. The MDT serves as a hub for integration of cortical (OFC, PFC) and subcortical (striatal, limbic) information involved in executive cognitive function. Studies will use unique transgenic (FosTRAP2) mice to first identify populations of neurons in the MDT that are activated by alcohol drinking and then examine how chronic alcohol exposure alters functional activity in these neural ensembles in the MDT that project to the mPFC (IfL cortex). Studies also will probe how functional adaptations in these cortical-projecting MDT neurons contribute to dependence-related inflexible alcohol drinking. Animals will receive chronic alcohol (CIE) treatment in the ARC Animal Core, followed by slice electrophysiology, fiber photometry, and chemogenetic manipulations to test the overarching hypothesis that chronic alcohol-induced alterations in cortical-projecting MDT neurons drive excessive, compulsive-like drinking and alcohol-biased choice behaviors that reflect loss of reward-based flexible behaviors.

Specific Aims of the project include:

• Identify neural ensembles and characterize functional adaptations (slice electrophysiology) of cortically projecting neurons in the mediodorsal thalamus (MDT) that are activated by alcohol drinking and dependence.
• Test the hypothesis that functional activity of MDT→IfL neurons (fiber photometry) will be modulated by alcohol drinking (licking behavior) and this pattern of activity will be altered in alcohol-dependent mice.
• Test the hypothesis that cortical projecting MDT neurons drive excessive drinking and alcohol-biased choice behaviors in dependent male and female C57BL/6J mice.