Striatal Microcircuit Dynamics

纹状体微电路动力学

• 批准号: 10281166
• 负责人: JOSHUA D BERKE
• 金额: $ 45.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281166
• 关键词: Acetylcholine; Affect; Amphetamines; Behavior; Behavior Control; Behavioral; Bilateral; Bradykinesia; Brain; Brain Diseases; Calcium; Calcium Signaling; Cells; Cognitive; Corpus striatum structure; Cues; Data; Decision Making; Dopamine; Dopaminergic Agents; Dorsal; Dystonia; Electrophysiology (science); Event; Fiber Optics; Functional disorder; Gilles de la Tourette syndrome; Goals; Human; Individual; Infusion procedures; Interneurons; Investigation; Joints; Knowledge; Laboratories; Learning; Methods; Modeling; Monitor; Motor; Movement; Neurons; Optics; Oxidopamine; Parkinson Disease; Parvalbumins; Pathway interactions; Pattern; Photometry; Play; Population; Process; Psychological reinforcement; Rattus; Reaction Time; Recording of previous events; Research; Rewards; Rodent Model; Role; Sensory; Shapes; Side; Signal Transduction; Slice; Somatostatin; Structure; Testing; Training; Variant; Vision; computer framework; design; expectation; experimental study; improved; information processing; innovation; innovative technologies; insight; nervous system disorder; operation; optogenetics; programs; reward anticipation; sensor; temporal measurement; tool

Summary / Abstract The dorsal striatum (DS) is an important brain structure for normal sensorimotor control, including decisions about how vigorously to move. As one example, loss of the dopamine input to DS is responsible for bradykinesia in Parkinson's Disease. Yet how DS circuits processes information, and how this information processing is modulated by dopamine, are not well understood. DS circuits include sparse populations of interneurons - most commonly expressing either parvalbumin (PV+), somatostatin (SST+) or acetylcholine (ChAT+). Interneurons appear to coordinate the activity of striatal spiny projection neurons (SPNs), and alterations in striatal interneurons are found in human Tourette Syndrome and rodent models of dystonia. Studies in brain slices have found many ways in which striatal interneurons can affect SPNs and each other, via direct connections and by modulation of dopamine release. However it has been challenging to connect these various results together into a coherent vision of DS microcircuit function. Progress has been hampered by the lack of critical data about the joint activity patterns of DS interneurons, SPNs, and local dopamine fluctuations, at precise moments during well-controlled behavioral tasks. To overcome this obstacle, this proposal uses an innovative, technically-advanced combination of behavioral electrophysiology, optogenetics and optical dopamine sensors. We will perform real-time measurements and manipulations of DS interneurons and dopamine, as freely-moving rats respond to cues. The response times depend on rats' reward expectation for the selected action. Taking advantage of the computational framework of reinforcement learning to derive trial-by-trial estimates of internal decision- variables, we will test specific hypotheses about how the activity of distinct interneuron types is shaped by recent choice and reward history. Aim 1 will characterize the activity of DS PV+, SST+ and ChAT+ interneurons as actions are initiated. In both dorsolateral and dorsomedial striatum we will record bulk calcium signals from each subpopulation, or the spiking of identified interneurons, simultaneously with dopamine signals. Aim 2 will examine how, and when, transient suppression of interneurons affects movement initiation and the activity of nearby SPN ensembles. Aim 3 will determine how loss of DS dopamine jointly affects interneuron activity and behavior. The long-term goals of this research program are to determine the fundamental operational principles of striatal circuits. This knowledge would be of immense value in designing improved therapies for a wide range of human neurological disorders.

总结/摘要 背侧纹状体（DS）是正常感觉运动控制的重要脑结构，包括 决定如何大力行动。作为一个例子，多巴胺输入到DS的损失是负责 帕金森氏病中的运动迟缓然而，DS电路如何处理信息，以及这些信息如何 大脑的加工过程是由多巴胺调节的，这些都还没有被很好地理解。 DS回路包括稀疏的中间神经元群体-最常见的表达小白蛋白或 (PV+）、生长抑素（SST+）或乙酰胆碱（ChAT+）。中间神经元似乎协调纹状体的活动， 多刺投射神经元（SPN）和纹状体中间神经元的改变被发现在人类妥瑞症 肌张力障碍的综合征和啮齿动物模型。对大脑切片的研究发现， 中间神经元可以通过直接连接和调节多巴胺释放来影响SPN和彼此。 然而，将这些不同的结果连接到一个连贯的DS愿景中一直是一个挑战 微电路功能由于缺乏关于联合国系统各机构联合活动模式的关键数据， DS中间神经元，SPNs和局部多巴胺波动，在良好控制的行为过程中的精确时刻， 任务 为了克服这一障碍，该提案采用了创新的、技术先进的组合， 行为电生理学、光遗传学和光学多巴胺传感器。我们将实时执行 测量和操纵DS中间神经元和多巴胺，因为自由移动的大鼠对线索作出反应。 反应时间取决于大鼠对所选动作的奖励期望。利用了 强化学习的计算框架，以获得内部决策的逐个试验估计， 变量，我们将测试有关不同中间神经元类型的活动如何受到以下因素影响的具体假设 最近的选择和奖励历史。 目的1将表征动作启动时DS PV+、SST+和ChAT+中间神经元的活性。在 背外侧和背内侧纹状体，我们将记录来自每个亚群的大量钙信号，或者 识别出的中间神经元的尖峰，同时多巴胺信号。目标2将研究如何以及何时， 中间神经元的瞬时抑制影响运动起始和附近SPN系综的活性。 目标3将确定DS多巴胺的损失如何共同影响中间神经元的活动和行为。 这项研究计划的长期目标是确定基本的操作原则 纹状体回路的结构这一知识将在为广泛的疾病设计改进的治疗方法方面具有巨大的价值。 一系列人类神经系统疾病