Dissecting basal ganglia circuits underlying motivated behaviors

剖析动机行为背后的基底神经节回路

• 批准号: 10577766
• 负责人: Jessica Tollkuhn
• 金额: $ 70.08万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-28 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577766
• 关键词: Address; Affect; Anatomy; Anxiety Disorders; Basal Ganglia; Behavior; Behavioral; Brain; Calcium; Clinical; Code; Corpus striatum structure; Cyclic AMP-Dependent Protein Kinases; Disease; Dorsal; Drug Addiction; Electrophysiology (science); Evaluation; Family; Foundations; Functional disorder; Ganglia; Genetic; Globus Pallidus; Goals; Habenula; Health; Huntington Disease; Knock-in Mouse; Label; Learned Helplessness; Learning; Life Stress; Maps; Mediating; Mental Depression; Mental disorders; Midbrain structure; Monitor; Mood Disorders; Moods; Motivation; Motor; Movement; Mus; Negative Reinforcements; Negative Valence; Neurons; Obsessive-Compulsive Disorder; Opioid Receptor; Parkinson Disease; Pathway interactions; Play; Population; Population Control; Positive Reinforcements; Positive Valence; Predisposition; Procedures; Property; Psychological reinforcement; Publishing; Punishment; Regulation; Research; Rewards; Role; Shapes; Signal Transduction; Stimulus; Stress; Stressful Event; Techniques; Testing; Zinc Fingers; autism spectrum disorder; avoidance behavior; dopaminergic neuron; fluorescence lifetime imaging; in vivo; in vivo imaging; maladaptive behavior; motivated behavior; motor control; mouse genetics; multiplexed imaging; nervous system disorder; neurochemistry; novel; optogenetics; prodynorphin; programs; resilience; social defeat; striosome; synaptic function; tool; two-photon

Dissecting basal ganglia circuits underlying motivated behaviors Project Summary The basal ganglia, in particular the dorsal striatum, play essential roles in motor control, motivational regulation and reinforcement learning. On the other hand, striatal dysfunctions have been implicated in a number of neurological and psychiatric disorders, including Parkinson's disease, Huntington’s disease, obsessive compulsive disorder, autism, depression and drug addiction. A notable feature of the dorsal striatum is its separation into two neurochemically distinct compartments, the striosome (or “patch”) compartment and the surrounding matrix compartment. It is thought that neurons in the matrix and those in the striosome have distinct functions, with the former critical for motor functions, whereas the latter important for evaluation functions during learning and for regulation of motivation. In addition, the striosome compartment has been especially implicated in the non-motor aspects of the neurological disorders, such as learning deficits, and mood and motivational aberrations. However, despite intensive study, to date the functionality of neurons in the striosome remains largely uncharacterized. Consequently, how striosome neurons contribute to reinforcement learning and regulation of motivation is unclear. Whether and how dysfunctions in these neurons occur and contribute to the diseases are also unknown. A major challenge to studying the striosome lies in the fact that it is labyrinthine in shape and has no clear anatomical boundaries, making it difficult to precisely target for in vivo recording or manipulation. To address this issue, we recently exploited mouse genetics for targeting neurons in the striosome. This strategy laid the foundation for selectively monitoring and manipulating the activities of different populations of striosome neurons. In the proposed study, we will capitalize on our approach and findings to investigate the behavioral roles of distinct striosome populations in health and disease, and to uncover the underlying circuit and cellular mechanisms. Our central hypothesis is that functionally distinct striosome populations differentially control reward seeking and punishment avoidance through different circuit mechanisms. We further hypothesize that these striosome neurons become dysfunctional after major stressful life events, thereby causing maladaptive behaviors. We will test our hypotheses in the following Aims: Aim 1. To determine the behavioral roles of distinct classes of striosome neurons. Aim 2. To determine the circuit and cellular mechanisms underlying striosome functions. Aim 3. To elucidate the striosome dysfunctions underlying stress-induced maladaptive behaviors.

剖析动机行为背后的基底神经节回路 项目概要 基底神经节，特别是背侧纹状体，在运动控制、动机调节中发挥重要作用 另一方面，纹状体功能障碍与许多问题有关。 神经和精神疾病，包括帕金森病、亨廷顿病、强迫症 强迫症、自闭症、抑郁症和毒瘾是背侧纹状体的一个显着特征。 分成两个神经化学上不同的区室，即纹状体（或“贴片”）区室和 据认为，基质中的神经元和纹状体中的神经元具有不同的特征。 功能，前者对于运动功能至关重要，而后者对于评估功能很重要 此外，纹状体区室也特别重要。 神经系统疾病的非运动方面，例如学习缺陷、情绪和动机 然而，尽管进行了深入的研究，迄今为止，纹状体中神经元的功能仍然存在。 纹状体神经元如何促进强化学习，在很大程度上尚未得到表征。 这些神经元的功能障碍是否以及如何发生以及如何导致动机调节尚不清楚。 疾病也是未知的。 研究纹状体的一个主要挑战在于它的形状是迷宫式的，并且没有明确的结构。 解剖学边界，使得很难精确定位体内记录或操作来解决这个问题。 为了解决这个问题，我们最近利用小鼠遗传学来靶向纹状体中的神经元。 为选择性监测和操纵不同纹状体神经元群的活动奠定了基础。 在拟议的研究中，我们将利用我们的方法和发现来调查 健康和疾病中不同的纹状体群体，并揭示潜在的电路和细胞 我们的中心假设是功能不同的纹状体群体差异控制。 通过不同的电路机制寻求奖励和避免惩罚。 这些纹状体神经元在重大压力生活事件后变得功能障碍，从而导致适应不良 我们将在以下目标中测试我们的假设： 目标 1. 确定不同类别纹状体神经元的行为作用。 目标 2. 确定纹状体功能背后的电路和细胞机制。 目标 3. 阐明压力诱导的适应不良行为背后的纹状体功能障碍。