Project Summary / Abstract Alcoholism is a chronic relapsing disorder characterized by alcohol preoccupation, loss of control over intake and a negative emotional state. Alcoholics have reduced prefrontal cortex volumes and significant deficits in ventromedial prefrontal cortex (vmPFC)-related tasks, such as dysfunctional emotional processing and loss of inhibitory control. The rodent medial prefrontal cortex (mPFC) is functionally analogous to the vmPFC as both regions direct the flexible regulation of behavior by regulating subcortical regions in a “top-down” manner. Within the mPFC, the prelimbic (PrL) and infralimbic (IfL) cortices have opposing addiction-related functions, with the PrL driving drug-seeking and the IfL involved with extinction. The IfL is implicated in anxiety-like and excessive drinking behaviors, suggesting that alcohol dependence-induced dysregulation of specific IfL- subcortical projections may contribute to the negative affective state that emerges during alcohol addiction. Thus, the challenge of current and future studies is to identify the neuroadaptations within specific IfL- subcortical circuits that drive different aspects of these alcohol dependence-induced behaviors. CeA recruitment is a hallmark of alcohol dependence and leads to the emotional dysregulation that governs withdrawal-induced anxiety and drinking. The IfL directly projects to the CeA, and we propose that neuroadaptation of this pathway may activate the CeA after chronic ethanol exposure. Clinically, the noradrenergic system has been implicated in the alcohol consumption of alcohol-dependent patients, and tightly regulates IfL function. Therefore, here we will examine how alcohol dependence induces noradrenergic neuroadaptation within the IfL to dysregulate its output to the CeA, and whether this system mediates alcohol withdrawal-induced drinking and anxiety-like behaviors. We have intentionally designed this project to maximize its interdisciplinary nature by ensuring that the information obtained via the different experimental modalities can be compared. We will employ retrograde tracers to label IfL-CeA projection neurons, allowing for the electrophysiological and immunohistochemical characterization of alcohol dependence-induced noradrenergic influence over this pathway after chronic ethanol exposure. To extend these cellular and molecular results to the network level, during my K99 phase I will train in in vivo microdialysis to measure changes in IfL norepinephrine in awake, behaving mice exposed to chronic ethanol. I will also train in behavioral pharmacology techniques to assess the voluntary drinking of ethanol-dependent mice prior to their anxiety-like behavioral testing. Collectively, this work will provide insight into the influence of noradrenergic signaling on the IfL-CeA pathway, and its neuroadaptation with alcohol dependence.

PROJECT NARRATIVE: The infralimbic cortex (IfL) directly projects to the central amygdala (CeA), and both these region drive anxiety-like behavior and excessive alcohol consumption. Clinically, the noradrenergic system has been implicated in the alcohol consumption of alcohol-dependent patients, and tightly regulates IfL function. Therefore, here we will examine how alcohol dependence induces noradrenergic neuroadaptation within the IfL to dysregulate its output to the CeA, and whether this system mediates alcohol withdrawal-induced behaviors.