Dissecting basal ganglia circuits underlying motivated behaviors

剖析动机行为背后的基底神经节回路

基本信息

批准号：
10391761
负责人：
Bo LI
金额：
$ 72.36万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
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/10391761
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 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 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 mu opioid receptors multiplexed imaging nervous system disorder neurochemistry novel optogenetics prodynorphin programs resilience social defeat striosome synaptic function tool two-photon

项目摘要

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.

解剖动机行为的基础低音神经节电路项目摘要基底神经节，尤其是背纹状体，在运动控制中起着重要作用，动机调节和增强学习。另一方面，纹状体功能障碍已在许多中暗示神经和精神疾病，包括帕金森氏病，亨廷顿氏病，痴迷强迫症，自闭症，抑郁和药物成瘾。背纹状体的一个显着特征是分为两个神经化学上不同的隔室，骨骼组（或“斑块”）室，周围的矩阵隔室。据认为，矩阵中的神经元和那些曲折的神经元具有独特的功能，前者对运动功能至关重要，而后者对于评估功能很重要学习和监管动机。此外，尤其暗示了骨骼组的隔室在神经系统疾病的非运动方面，例如学习缺陷，情绪和动机畸变。但是，进行密集研究，迄今为止，神经元在静止在很大程度上没有特色。因此，神经元如何有助于增强学习和动机的调节尚不清楚。这些神经元中功能障碍是否以及如何发生并有助于疾病也未知。研究曲折的一个主要挑战在于它的形状是迷宫，尚无清晰解剖界限，因此很难精确地靶向体内记录或操纵。解决这个问题问题，我们最近探索了用于靶向Striosome中神经元的小鼠遗传学。这个策略提出了选择性监测和操纵不同人群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发现来研究健康和疾病中的独特人群，并发现基础电路和细胞机制。我们的中心假设是，功能上不同的静态人群对控制的控制有所不同通过不同的电路机制寻求和惩罚避免奖励。我们进一步假设在重大压力性生活事件后，这些曲折的神经元变得功能失调，从而导致不良适应性行为。我们将在以下目的中检验我们的假设：目的1。确定不同类别神经元的行为作用。目的2。确定曲线膜组函数的电路和细胞机制。目的3。阐明压力引起的不良适应行为的基础功能障碍。