The role of cortico-striatal circuitry in model-based decision-making

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

ABSTRACT The ability to adapt behavior to changing conditions is crucial to survival, and deficits in behavioral flexibility contribute to a number of psychiatric symptoms. Both humans and rodents have evolved a decision-making system known as model-based control (MBC) to effectively adjust behavior in novel and uncertain situations. MBC relies on using a cognitive map of how actions, sensory cues, and outcomes relate to one another to plan the best decision. Impairments in MBC are a hallmark of compulsive disorders such as obsessive-compulsive disorder, addiction, and eating disorders. Although compulsive behaviors are associated with disrupted activity in the same cortico-striatal circuits that are hypothesized to be important for MBC, the specific roles of cortico- striatal circuits in MBC are unknown due to a paucity of in vivo studies of neural activity. This K08 project aims to determine how MBC is represented in distinct cell types in the prelimbic cortex (PL) and dorsomedial striatum (DMS) – two areas implicated in both MBC and compulsive behaviors – by monitoring and manipulating neural activity using in vivo electrophysiology and optogenetics, respectively. To do this, I have developed one of the first mouse versions of the two-step task, an established assay of human MBC. A key strength of the two-step task is that behavior can be quantified using reinforcement learning models so that specific decision-making processes can be effectively mapped onto neural activity. In Aim 1, I will determine whether intratelencephalic and pyramidal tract neurons, the two main subtypes of cortical projection neurons in the PL, carry segregated information critical for MBC. In Aim 2, I will determine if direct and indirect pathway spiny projection neurons, the two main cell types in the DMS, compete to reinforce actions during MBC. In Aim 3, I will determine whether synchronization of activity between the PL and DMS facilitates MBC. In addition to the proposed studies, I have put together a comprehensive training plan and formed an interdisciplinary mentorship team to develop the technical, computational, and professional skills necessary to become a successful independent investigator. This plan is mentored by Dr. Susanne Ahmari, a translational psychiatrist with expertise in dissecting the neural circuitry of compulsive disorders. Additionally, I will work with co-mentor Dr. Eric Yttri, an expert in striatal function and in vivo electrophysiology and co-mentor Dr. Alex Dombrovski, an expert in human decision-making and reinforcement learning. By the end of the K08 award period, I will be positioned to launch a career as an independent investigator with a research program that dissects the neural circuits of psychiatrically relevant decision-making tasks in mice, with the ultimate goal of developing novel, circuit-based treatments in humans.