Zona Incerta Contributions to Reward and Cocaine Addiction

不确定区（ZI）或“不确定区”是下丘脑中的一个特征不明显的结构。 尾侧ZI和邻近的丘脑底核（subthalamic nucleus，简称ZI）与冲动和动机有关。 帕金森病（PD）患者的一个子集的疾病，最近的工作表明，光遗传学 ZI的激活强烈诱导小鼠的暴食样进食行为。因此，人类和动物研究 指出了ZI在调节动机和行为障碍方面未被重视的作用。但 基本的机制仍然没有被探索。最近，基于狂犬病的全脑单突触 逆行标测揭示了ZI向腹侧被盖区（VTA）发送投射。VTA 多巴胺和GABA神经元在奖赏、动机和成瘾中起着关键作用。我们建议测试 假设ZI通过其直接投射到VTA来调节动机和成瘾行为。在这 建议，我们将应用各种尖端工具，包括病毒遗传解剖和光遗传电路- 映射、光遗传学和化学遗传学刺激和抑制、电生理学和其他技术， 全面研究ZI-VTA通路的潜在连接性和生理学。总体而言，我们 其目标包括：表征ZI和VTA之间的特定于小区类型的连通性 使用现代解剖工具和电生理学（目的I）;确定这些连接如何影响神经元 VTA的主要细胞类型中的活性，以及延髓核中的多巴胺释放，体内（Aim II）; 并确定这些途径的光遗传学和化学遗传学调节如何驱动或破坏自然 奖励和可卡因奖励相关行为（目标III）。这些全面的研究将提供机制 我们对它的结构和途径知之甚少。完成拟议的研究将不会 这只是发现了奖励和动机的新神经基质，但将填补一个知识空白， 从而改善对动机和成瘾性障碍的治疗。

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.