Investigating the interplay between ventral tegmental area dopamine, medial orbitofrontal cortex, and ventromedial striatum in compulsive-like behavior

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ABSTRACT Obsessive-compulsive disorder (OCD) is a top ten cause of disability worldwide. Existing treatments for OCD are incomplete, which underscores the need for a more thorough understanding of the neuronal basis of OCD pathology. An extensive literature suggests the medial orbitofrontal cortex (mOFC) and ventromedial striatum (VMS) are hyperactive in OCD patients, and that OCD is associated with increased dopamine in VMS. Little is known, however, about how neurons in these networks communicate or interact to produce OCD symptoms. The overarching goal of this proposal is to elucidate how mOFC and VTA dopamine projections to VMS contribute to development of compulsive-like behaviors. The central hypotheses are 1) VTA dopamine regulation of corticostriatal circuitry and 2) excessive synchrony and coherence in corticostriatal networks contribute to induction of this phenotype. Compulsive-like behaviors will be modeled via repeated optogenetic stimulation of mOFC terminals in VMS of EMX-cre mice, which causes a progressive, neuroplastic induction of repetitive grooming. Electrophysiological activity will be recorded simultaneously in mOFC and VMS during induction of the compulsive-like phenotype to determine how these networks communicate as this pathological behavior is established (Aim 1). Changes in VTA firing patterns will be assessed by recording electrophysiological activity during induction of the phenotype, and optogenetic phototagging will be used to identify dopaminergic neurons (Aim 2). Finally, inhibitory designer receptors exclusively activated by designer drugs (DREADDs) will be used to determine if VTA dopamine is necessary for induction of compulsive-like grooming (Aim 3). These experiments will provide novel information on the interregional network interactions underlying OCD-related behavioral phenotypes. Uncovering the dynamics of these interactions, and their evolution as compulsive behaviors develop, will reveal valuable information on neuropathology related to OCD that will strongly inform network based theories of compulsive-like behaviors and OCD pathologies. This proposal provides extensive training opportunities through the inclusion of numerous methodologies that are novel to the applicant, including optogenetics, chemogenetics, analysis of naturalistic behaviors, transgenic mouse models of disease, and multi-region neuronal manipulations. Thus, this integrated research and training plan will provide skills that are critical for a future career development (K) award and an eventual independent investigator position.