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.

摘要 /摘要 背纹状体（DS）是正常感觉运动控制的重要大脑结构，包括 关于多大移动的决定。例如，多巴胺输入到DS的损失是造成的 帕金森氏病中的松霉素。然而，DS电路如何处理信息，以及如何处理此信息 加工是由多巴胺调节的，尚不清楚。 DS电路包括稀疏的中间神经元种群 - 最常见的是表达白蛋白 （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性 在人类图片中发现了刺刺投射神经元（SPN）和纹状体中间神经元的改变 肌张力障碍的综合征和啮齿动物模型。大脑切片的研究发现了多种方式 中间神经元可以通过直接连接和多巴胺释放来影响SPN和彼此。 但是，将这些各种结果连接到DS的连贯愿景是一项挑战 微电路函数。缺乏有关关节活动模式的关键数据阻碍了进步 DS中间神经元，SPN和局部多巴胺波动，在良好控制的行为中确切时刻 任务。 为了克服这一障碍，该提案使用了创新的，技术上的结合 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 自由移动的大鼠对线索的测量和操纵对线索有反应。 响应时间取决于大鼠对选定动作的奖励期望。利用 强化学习的计算框架，以得出内部决策的逐审估计 - 变量，我们将测试有关不同中间类型类型的活动的特定假设 最近的选择和奖励历史。 AIM 1将表征DS PV+，SST+和CHAT+中间神经元的活动，因为启动了动作。在 背外侧和背侧纹状体均可记录每个亚群中的大量钙信号，或 与多巴胺信号同时鉴定出的中间神经元的峰值。 AIM 2将检查如何以及何时， 中间神经元的瞬时抑制会影响运动开始和附近SPN集合的活性。 AIM 3将决定DS多巴胺的丧失如何共同影响中间神经元的活动和行为。 该研究计划的长期目标是确定基本的运营原则 纹状体电路。这些知识在设计改进的疗法方面具有巨大的价值 人类神经系统疾病的范围。