The Role of the Nucleus Accumbens Core in Scaling Fear to Degree of Threat

Abstract

Identifying the neural circuits underlying adaptive fear is fundamental to understanding and developing more effective treatments for anxiety disorders. Adaptive behavior requires fear to scale to the level of threat and dysfunction in this capacity is a hallmark of fear-related anxiety disorders. Identifying the neural circuits underlying adaptive fear is fundamental to understanding anxiety disorders and propelling more effective treatments for patients. Fear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty, and safety cues, our laboratory has found rapid fear scaling (within 2 s of cue presentation). However, the neural underpinnings of this behavior are unknown. The overarching goal of this dissertation is to examine a role for the nucleus accumbens core (NAcc) in scaling fear to degree of threat. In three experiments I used neurotoxic lesions, optogenetic inhibition, and in vivo electrophysiology combined with an intricate fear learning procedure to elucidate a role for the NAcc in both general and rapid scaling of fear. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. Further, I demonstrated that NAcc activity is threat responsive and exhibits heterogeneity in the timing and specific nature of threat firing. The results reveal that the NAcc is essential to scale fear to degree of threat and responds to threat cues across both rapid and general timescales. Taken together, the results reveal a novel role for the NAcc in scaling fear and identify it as a plausible source of dysfunction in stress and anxiety disorders. Identifying the brain regions underlying adaptive fear is fundamental to understanding and developing more effective treatments for anxiety disorders.