# Zona Incerta Contributions to Reward and Cocaine Addiction

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $365,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10439447
- **Project number:** 5R01DA047269-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Qing-song Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $365,750
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439447

## Citation

> US National Institutes of Health, RePORTER application 10439447, Zona Incerta Contributions to Reward and Cocaine Addiction (5R01DA047269-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10439447. Licensed CC0.

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