Zona Incerta Contributions to Reward and Cocaine Addiction

不确定带(Zi)，或“不确定区”，是丘脑下部的一个特征不佳的结构。 ZI尾侧核和邻近的丘脑底核(STN)与冲动和动机有关 帕金森氏病(PD)患者中的一组疾病，最近的研究表明光遗传学 子的激活强烈地诱导了小鼠的暴饮式进食行为。因此，无论是人类研究还是动物研究 指出子在调节动机和行为障碍方面的作用没有得到重视。然而， 潜在的机制在很大程度上仍未得到探索。最近，基于狂犬病的全脑单突触 逆行标测显示，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。我们建议测试一下 假设ZI通过其向VTA的直接投射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- 测绘、光发生和化学发生刺激和抑制、电生理学和其他技术 全面研究Zi-VTA通路的潜在连通性和生理学。总的来说，我们的 目标包括：描述ZI和VTA之间特定细胞类型的连通性 使用现代解剖学工具和电生理学(目标I)；确定这些连接如何影响神经元 体内VTA主要细胞类型的活性和伏隔核多巴胺的释放(目标II)； 并确定这些途径的光遗传和化学发生调制如何驱动或破坏自然 奖赏和可卡因奖赏相关行为(目标三)。这些综合研究将提供机械性的 洞察一种鲜为人知的结构和途径。建议的研究将不会完成 只识别奖励和激励的新神经基础，但将填补一个知识空白，这最终可能 导致改善对激励性和成瘾障碍的治疗。

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.