Zona Incerta Contributions to Reward and Cocaine Addiction

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The zona incerta (ZI), or “zone of uncertainty”, is a poorly-characterized structure in the subthalamus. The caudal ZI and the adjacent subthalamic nucleus (STN) have been implicated in impulsive and motivational disorders in a subset of patients with Parkinson's disease (PD), and recent work has shown that optogenetic activation of the ZI robustly induces binge-like eating behavior in mice. Thus, both human and animal studies point to an unappreciated role for the ZI in regulating motivational and behavioral disorders. However, the underlying mechanisms remain largely unexplored. Recently, rabies-based, whole-brain monosynaptic retrograde mapping has revealed that the ZI sends projections to the ventral tegmental area (VTA). VTA dopamine and GABA neurons play a critical role in reward, motivation and addiction. We propose to test the hypothesis that the ZI regulates motivated and addictive behavior via its direct projection to the VTA. In this proposal, we will apply a variety of cutting-edge tools including viral-genetic anatomic and optogenetic circuit- mapping, optogenetic and chemogenetic stimulation and inhibition, electrophysiology, and other techniques to comprehensively study the underlying connectivity and physiology of the ZI-VTA pathway. Overall, our objectives include the following: characterize the cell type-specific connectivity between the ZI and the VTA using modern anatomic tools and electrophysiology (Aim I); determine how these connections affect neuronal activity in the major cell types of the VTA, and dopamine release in the nucleus accumbens, in vivo (Aim II); and determine how optogenetic and chemogenetic modulation of these pathways can drive or disrupt natural reward and cocaine reward-related behaviors (Aim III). These comprehensive studies will provide mechanistic insight into a structure and pathway of which very little is known. Completion of the proposed studies will not only identify novel neural substrates of reward and motivation, but will fill a knowledge gap that may ultimately lead to improved treatments for motivational and addictive disorders.