The Neurophysiology Project will test the hypothesis that dysfunction of the infralimbic (IL) subdivision of the mPFC contributes to the negative affect that drives withdrawal-induced drinking. We predict that IL pyramidal neurons that project to CeA (IL->CeA) may normally inhibit ethanol seeking and drinking under stress, a function that is compromised (decreased) in AUD, rendering subjects vulnerable to stress-induced negative urgency for ethanol. Mechanistically, we anticipate that ethanol dependence and abstinence produce an imbalance between brain stress (e.g., CRF) and anti-stress [e.g., nociceptin/orphanin FQ (N/OFQ)] systems within the IL->CeA circuitry.

Our preliminary data support that the IL->CeA neurons represent a subset of neurons with unique electrophysiological properties and responsiveness to chronic ethanol. Thus, we will investigate 1) the mechanisms mediating N/OFQ and CRF modulation of IL function and 2) the unique electrophysiological properties of the IL->CeA neurons and their role in the behavioral symptomatology of ethanol withdrawal.

We will use ex vivo electrophysiology and proteomics of circuit-defined IL->CeA neurons, in situ hybridization, protein assays, neuronal tracing, chemogenetics, and behavioral testing.