Dissecting the Role of Infralimbic Circuitry in Dysfunctional Alcohol Seeking

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Recovering from alcohol use disorders is made exceedingly difficult by both an initial inability to quit drinking and a chronic susceptibility to relapse. Improving behavioral and pharmacological treatments for alcoholism will require a better understanding of the neural circuitry that mediates these behaviors. Recent studies highlight the importance of the ventral portion of medial prefrontal cortex, the infralimbic cortex (ilPFC), in regulating alcohol seeking. However, the role of ilPFC projections to specific subcortical targets in these behaviors is still largely unknown. Our preliminary data suggest that ilPFC may bi-directionally regulate alcohol-related behaviors via its connectivity with nucleus accumbens shell (NAcS) and basolateral amygdala (BLA). Specifically, we have seen that functionally disconnecting ilPFC from NAcS increases self- administration and cue-induced reinstatement of alcohol seeking, while disconnecting ilPFC from BLA decreases cue-induced reinstatement. It is unclear whether these effects result from a disruption of infralimbic afferent or efferents, and whether the circuits are specifically necessary for reinstatement or play a more general role in alcohol seeking overall. Here we propose to use a novel combination of viral and behavioral techniques to selectively manipulate ilPFC projections to both NAc and BLA to determine their precise roles in these behaviors. Aim 1 will test the hypothesis that the ilPFC ? NAcS projection inhibits alcohol seeking during extinction and reinstatement. Experiment 1a will utilize a novel, target-specific ablation strategy to test the effects of loss of function in this projection during extinction and reinstatement. Experiment 1b will use excitatory DREADDs to test the effects of activating the projection during these same behaviors. Aim 2 will test the hypothesis that the ilPFC à? BLA projection drives alcohol seeking during extinction and reinstatement. Using the same strategies as in Aim 1, we will decrease (Experiment 2a) and increase (Experiment 2b) the activity of this pathway to test its role in alcohol extinction and reinstatement. While ilPFC projections to NAcS and BLA are known to regulate other behaviors (e.g., fear conditioning and cocaine seeking), their role in alcohol-related behaviors is unclear. The proposed research will therefore provide novel insight into the circuit-level regulation of alcohol seeking, and highlight how circuit dysregulation may underlie an inability to quit drinking We believe that the knowledge gained from these experiments will ultimately be translated into improved therapeutic strategies for alcohol use disorders in humans.