Zona Incerta Contributions to Reward and Cocaine Addiction

不确定区对奖励和可卡因成瘾的贡献

• 批准号: 10439447
• 负责人: Qing-song Liu
• 金额: $ 36.58万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439447
• 关键词: Action Potentials; Addictive Behavior; Affect; Anatomy; Animals; Axon; Behavior; Behavior Disorders; Behavioral; Binge Eating; Brain; Brain region; Cells; Cocaine; Cocaine Dependence; Deep Brain Stimulation; Disease; Dopamine; Eating Behavior; Electrophysiology (science); FOS gene; Fatty acid glycerol esters; Feeding behaviors; Food; Glutamates; Goals; Gold; Human; Impulsivity; Knowledge; Lead; Maps; Modernization; Motivation; Mus; Nature; Neurons; Nucleus Accumbens; Output; Parkinson Disease; Pathological Gambling; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Physiological; Physiology; Pilot Projects; Play; Population; Prefrontal Cortex; Presynaptic Terminals; Psychological reinforcement; Rabies; Rewards; Role; Scanning; Self Administration; Site; Structure; Structure of subthalamic nucleus; Subthalamic structure; Synapses; Synaptic Potentials; Synaptic Transmission; Techniques; Testing; Thalamic structure; Time; Tracer; Tremor; Uncertainty; Ventral Tegmental Area; Work; addiction; base; cell type; cocaine self-administration; dopaminergic neuron; drug seeking behavior; experimental study; gamma-Aminobutyric Acid; improved; in vivo; insight; motivated behavior; motor disorder; novel; optogenetics; patient subsets; preference; relating to nervous system; screening; side effect; tool; virus genetics; zona incerta

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.

Zona Incerta（Zi）或“不确定性区域”是thalamus的一个特征较差的结构。 尾Zi和相邻的丘脑下核（STN）与冲动和动机有关 一部分帕金森氏病（PD）的疾病，最近的工作表明光遗传学 Zi的激活可牢固地诱导小鼠的暴饮暴食样行为。那是人类和动物研究 指出ZI在调节动机和行为障碍中的作用。但是， 潜在机制在很大程度上仍然是出乎意料的。最近，基于狂犬病的全脑单突触 逆行映射显示，ZI将项目发送到腹侧对接区域（VTA）。 VTA 多巴胺和GABA神经元在奖励，动机和成瘾中起着至关重要的作用。我们建议测试 假设ZI通过直接投射VTA来调节动机和加性行为。在这个 提案，我们将应用各种尖端工具，包括病毒遗传解剖和光遗传学回路 映射，光遗传学和化学遗传学模拟以及抑制作用，电生理学以及其他技术 总体而言，我们的 目标包括以下内容：表征ZI和VTA之间的小区类型特定连接性 使用现代的解剖工具和电生理学（AIM 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​​伏隔核中多巴胺释放，体内（AIM II）； 并确定这些途径的光遗传学和化学遗传调制如何驱动或破坏自然 奖励和可卡因奖励相关的行为（AIM III）。这些全面的研究将提供机理 深入了解其结构和途径很少知道。拟议研究的完成将不会 仅确定新颖的奖励和动力神经元基质，但会填补可能最终可能的知识差距 导致改进的动机和加性疾病的治疗方法。