Investigating the role of the medial orbitofrontal cortex (mOFC) in negative reinforcement learning

PROJECT SUMMARY/ABSTRACT
Obsessive compulsive disorder (OCD) is a debilitating psychiatric illness with a complex etiology. The negative
reinforcement-based model of OCD asserts that anxiety is a key driver of compulsions: compulsive behaviors
are performed to avoid obsession-evoked anxiety, reinforcing these behaviors when anxiety is temporarily
relieved. This theory forms the basis of exposure with response prevention (ERP), the primary therapy
recommended for OCD. However, only 40% of patients achieve maximal symptom reduction with ERP, and
successful treatment response is limited by excessive baseline levels of avoidance. The medial orbitofrontal
cortex (mOFC) is a key driver of avoidance in OCD and a promising therapeutic target as transcranial magnetic
stimulation of the mOFC reduces avoidance behavior and the urge to complete compulsions. Despite the clinical
relevance and potential to guide future treatments, there is a dearth of evidence exploring how avoidance is
learned and maintained under normal conditions. This F30 project aims to investigate the cellular- and circuit-
level mechanisms of negative reinforcement learning by monitoring and manipulating the activity of mOFC
neurons while mice learn a novel negative reinforcement task. Preliminary data show that mice successfully
learn to avoid predicted punishment and that mOFC neurons develop diverse responses to task elements over
learning. In Aim 1, I will use single-color in vivo microendoscopy to assess mOFC correlates of negative
reinforcement learning, investigating how neural responses evolve over learning at the single-cell (Aim 1a) and
population level (Aim 1b). In Aim 2, I will determine if unique information is communicated from mOFC to distinct
downstream targets [basolateral amygdala (BLA) and nucleus accumbens (NAc)] using dual-color in vivo
microendoscopy to simultaneously measure activity in both projections over the course of learning. Finally, in
Aim 3 I will determine the necessity of mOFC→BLA and mOFC→NAc for negative reinforcement learning using
projection-specific optogenetics. The results of these studies will offer insight into the role of mOFC in negative
reinforcement learning in healthy conditions, providing a framework for how aberrant mOFC activity may
contribute to the development of compulsive behaviors in OCD. To achieve the aims included in this proposal, I
have formed a mentorship committee comprised of Dr. Susanne Ahmari (primary mentor), an expert in the neural
circuits of OCD, optogenetics, and in vivo microendoscopy, and Dr. Vijay
Namboodiri
(consultant), an expert in
computational analyses of neural activity. Additionally, I will supplement these technical skills with tailored didactic
and professional training experiences at the University of Pittsburgh. By the end of the fellowship, I will be well-
positioned for a successful future career as a physician-scientist.

Grant Number: 5F30MH134471-02
NIH Institute/Center: NIH
Principal Investigator: Brittany Chamberlain