Striatal Microcircuit Dynamics

摘要/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 关于如何积极行动的决定。作为一个例子，DS的多巴胺输入的丢失是 帕金森氏病的运动迟缓。然而DS电路是如何处理信息的，以及这些信息是如何 加工是由多巴胺调节的，目前还不是很清楚。 DS回路包括稀疏的中间神经元群体--最常见的是表达小白蛋白 (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动 抽动症患者纹状体中间神经元的变化及棘突投射神经元 肌张力障碍综合征和啮齿动物模型。对脑片的研究发现，纹状体在许多方面 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，要将这些不同的结果结合在一起形成一个连贯的DS愿景一直是一项挑战 微电路功能。由于缺乏关于#年联合活动模式的关键数据，进展受到阻碍。 在行为控制良好的精确时刻，DS中间神经元、SPN和局部多巴胺波动 任务。 为了克服这一障碍，该提案使用了创新的、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 当自由活动的大鼠对提示做出反应时，DS中间神经元和多巴胺的测量和操作。 反应时间取决于大鼠对所选动作的奖励期望。利用这一优势 强化学习的计算框架，以得出内部决策的逐次估计- 变量，我们将测试关于不同类型的中间神经元的活动是如何被塑造的具体假设 最近的选择和奖励历史。 目的1将表征DS PV+、SST+和ChAT+中间神经元在启动动作时的活动。在……里面 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 识别出的中间神经元的尖峰信号，与多巴胺信号同步。目标2将研究如何以及何时， 中间神经元的一过性抑制影响运动的启动和附近SPN的活动。 目标3将确定双链多巴胺的缺失如何共同影响神经元间的活动和行为。 这项研究计划的长期目标是确定基本的操作原则 纹状体环路。这一知识将在设计改进的治疗方法方面具有巨大的价值 人类神经疾病的范围。

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.