Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking

University Of Texas Dallas, Richardson TX

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Abstract

The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol‐ associated cues. Repeated alcohol exposure induces neuroadaptations that persist beyond acute withdrawal, and which increase alcohol's incentive salience, leading to escalation of alcohol intake and aversion‐resistant alcohol seeking. Alcohol use also causes deficits in cognitive functions associated with the medial prefrontal cortex (mPFC), which further fuel compulsive drinking and relapse. In rodents, alcohol seeking activates specialized networks within the ventral (infralimbic, IL) and prelimbic (PL) regions of the mPFC, which play largely opposite roles in the control of relapse behavior. While activation of the PL drives reinstatement, neurons in the IL facilitate extinction learning and inhibit drug‐seeking through their projections to the Nucleus Accumbens shell, as well as the basolateral amygdala (BLA). However, there is a critical gap in the knowledge about the synaptic mechanisms that drive maladaptive plasticity in these circuits during the transition from controlled to compulsive alcohol‐seeking. Experiments in the parent grant application will provide a better understanding of network‐specific mechanisms through which chronic alcohol exposure and withdrawal affect executive cognitive functions of the mPFC and diminish inhibitory control over goal‐directed behavior. The objectives of this current proposal, which is submitted in response to opportunity “Research Supplement to Promote Diversity in Health‐Related Research (PA‐21‐071)”, are: First, to promote diversity in health‐related research by training Ms. Skylar Mendez, a PhD student from a background underrepresented in bio‐medical sciences, and second, to enhance a basic science aspect of the parent application by testing the central hypothesis that withdrawal‐activated neurons in the mPFC and the BLA are also responsible for negative affective states that emerge after prolonged alcohol exposure and withdrawal. Aim 1 will serve to train the candidate in behavioral measures of negative affect (specifically the Elevated Plus Maze, the Marble Burying Task, and the Novelty Suppressed Feeding Task) and to validate these measures in chronically EtOH‐exposed and withdrawn mice. In Aim 2 we will use Targeted Recombination in Active Populations (TRAP2) with Fos2AiCreER mice to express halorhodopsin selectively in withdrawal‐activated neurons in the IL and PL, respectively. Neurons TRAPed in this manner following either extended access to alcohol or under post‐dependent conditions will then be inhibited during tests of negative affect (as described in Aim 1) to determine the contribution of these neurons to withdrawal‐induced negative affective states. In Aim 3 we will similarly express halorhodopsin in TRAPed neurons in the BLA to test whether optogenetic silencing of withdrawal‐activated afferents from the BLA to the mPFC can reverse alcohol‐induced measures of negative affect. Taken together, these studies will provide important novel information about alcohol‐induced changes in networks of the mPFC and BLA that contribute to negative affect and cue‐induced reinstatement. This project will promote diversity in health‐related research, provide outstanding training opportunities in a multi‐level research training and career development program, and it will enhance the parent grant by determining whether specific withdrawal‐activated networks in the mPFC and BLA negative affect that contributes to relapse.