Defining the role of cortical circuit dynamics in learning and addiction

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

Project Summary/Abstract The ability to update strategies as contingencies change, or cognitive flexibility, is a fundamental behavioral process that allows for maximizing positive, while minimizing aversive, outcomes. This process is critical for survival, and its dysregulation is a hallmark of a number neuropsychiatric disorders including addiction. For example, cocaine addicts have a slowed ability to learn new associations, and also make risky choices despite environmental cues indicating that more advantageous choices are available. In the K99 phase of this award, we defined the role of multiple projection-defined populations in the medial prefrontal cortex (mPFC) in mediating responses to natural stimuli with positive and negative value. By both observing and manipulating the activity of these neuronal populations we showed that these populations are integrally involved in producing adaptive behavioral responses. In the current R00 phase of this proposal, we aim to combine cutting-edge approaches to observing and manipulating neural activity with intravenous cocaine self-administration in rats to determine how fundamental behavioral processes are altered by excessive cocaine use. While hypotheses as to the circuit basis of cocaine-induced cognitive deficits have been generated from clinical studies, in many cases we lack direct, mechanistic preclinical data verifying these hypotheses. In our previous studies we have identified two projection- defined subpopulations in the mPFC, cells that project to the nucleus accumbens or those that project to the periaqueductal gray area, which divergently encode positive and negative stimuli. We hypothesize that these populations are involved in cognitive flexibility, and its dysregulation by cocaine. The experiments put forth in this proposal will systematically test this hypothesis by combining single-cell calcium imaging, to record endogenous activity, and optogenetics, to manipulate activity, with intravenous cocaine self-administration. We test the hypothesis that specific subpopulations in the mPFC are critically involved in fundamental behavioral control, cognitive flexibility, and cocaine-induced deficits in these processes. A successful outcome of this proposal will facilitate the development of my new independent research program, while advancing our understanding of the circuit basis of cocaine addiction.