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 项目摘要 基底神经节，特别是背侧纹状体，在运动控制、动机调节、 和强化学习另一方面，纹状体功能障碍与许多 神经和精神障碍，包括帕金森氏病、亨廷顿氏病、强迫症、 强迫症、自闭症、抑郁症和毒瘾。背侧纹状体的一个显著特征是它的 分离成两个神经化学上不同的隔室，纹状体（或“补丁”）隔室和 周围基质隔室。据认为，基质中的神经元和纹状体中的神经元具有不同的神经元结构。 功能，前者对运动功能至关重要，而后者对评估功能很重要， 学习和动机的调节。此外，纹状体区室尤其与 在神经系统疾病的非运动方面，如学习缺陷，情绪和动机 失常。然而，尽管深入研究，迄今为止，纹状体中神经元的功能仍然存在， 基本上没有特征。因此，纹状体神经元如何有助于强化学习， 动机的调节不明确。这些神经元的功能障碍是否以及如何发生，并有助于 疾病也是未知的。 研究纹状体的一个主要挑战在于，它的形状是圆形的， 解剖学边界，使得难以精确定位用于体内记录或操纵。为了解决这个 我们最近利用小鼠遗传学来靶向纹状体中的神经元。这一战略奠定了 选择性地监测和操纵不同群体的纹状体神经元的活动的基础。 在拟议的研究中，我们将利用我们的方法和研究结果来调查 不同的健康和疾病中的纹状体群体，并揭示潜在的电路和细胞 机制等我们的中心假设是功能不同的纹状体群体差异控制 奖励寻求和惩罚回避通过不同的电路机制。我们进一步假设， 这些纹状体神经元在重大压力性生活事件后变得功能失调，从而导致适应不良， 行为。我们将在以下目标中检验我们的假设： 目标1。以确定不同类别的纹状体神经元的行为作用。 目标二。以确定电路和细胞机制下的纹状体功能。 目标3。阐明应激诱导的适应不良行为背后的纹状体功能障碍。