PROJECT SUMMARY/ABSTRACT Poor decision-making is both a cause and a consequence of addiction. Though dysfunction of the orbitofrontal cortex (OFC) is thought to underlie decision-making deficits in addicts, a circuit-based mechanism has not been identified due to overwhelming functional heterogeneity. Preliminary retrograde labelling experiments suggest that individual OFC projection neurons selectively target subcortical structures, but it is unknown if this anatomical separation mirrors a functional division-of-labor and a fundamental subcortical sorting principle. Integrating state-of-the-art techniques from functional genetics and electrophysiology, the objective of this proposal is to directly map a decision-making variable to a distinct cell-type in the OFC. The proposed aims will test the central hypothesis that that there is a division-of-labor between different OFC output neurons and more specifically, that OFC-to-VTA projection neurons represent a distinct output tract that selectively routes choice value. In Aim 1, I will determine the target selectivity of OFC-to-VTA projection neurons at a single neuron resolution. In Aim 2, I will determine if OFC-VTA projection neurons represent a genetically-distinct cell-type. In Aim 3, I will provide cell-type specific recordings in rats performing a rich, perceptual decision-making task and determine the role of OFC-VTA projection neurons in supporting choice behavior. These studies contribute to a mechanistic understanding of how decisions are computed and potentially, reveal an overarching, fundamental principle that governs cortical-subcortical information distribution in the OFC. The proposed studies lay the foundation for the identification of cell-type specific dysfunction in addiction and in future, the development of more effective, circuit-based therapies. Ultimately, this proposal serves to prepare me for a career as an independent physician-scientist. I will obtain a unique and multi-disciplinary skill-set that, in the future, will enable me to better bridge the gap between experimental neuroscience and clinical practice.

PROJECT NARRATIVE Long-lasting decision-making deficits in addicts represent a serious barrier to treatment adherence and long- term sobriety. A fundamental organizational principle that might sift through the overwhelming cellular heterogeneity and identify specific cell-types that might be therapeutically targeted is currently lacking. This proposal aims to delineate the circuit-level architecture of the orbitofrontal cortex (OFC) and define its distinct subcortically targeting output neurons as distinct streams of information, elucidating a fundamental principle of information routing.