Dissecting the role of the direct and indirect pathways in moment-to-moment action selection.

剖析直接和间接途径在即时行动选择中的作用。

• 批准号: 10026026
• 负责人: Winthrop Gillis
• 金额: $ 3.34万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026026
• 关键词: Address; Algorithms; Animals; Anions; Basal Ganglia; Behavior; Behavioral; Brain; Cell Nucleus; Corpus striatum structure; Data; Detection; Endoscopes; Environment; Exhibits; Goals; Human; Image; Individual; Methodology; Modeling; Motion; Movement; Neurons; Organism; Output; Pathway interactions; Pattern; Play; Population; Population Dynamics; Postural adjustments; Process; Property; Resolution; Rhodopsin; Rodent; Role; Sensory; Series; Stereotyping; Substantia nigra structure; System; Technology; Testing; Time; Work; calcium indicator; complement pathway; experimental study; fitness; indexing; microendoscopy; miniaturize; optogenetics; tool; unsupervised learning

Brains transform sensory information into decisions and decisions into behaviors, which ultimately determine fitness. Behavior can be broken down into a set of discrete chunks of movement, called actions. The basal ganglia (BG) and in particular the input nucleus of the BG, the striatum, is critical for the proper sequencing and selection of actions. At a cellular level, the striatum is comprised of spiny projection neurons (SPNs) that constitute the direct pathway (dSPNs) and indirect pathway (iSPNs). Under the center-surround model of action selection, dSPNs are thought to facilitate the expression of an action while iSPNs are thought to inhibit the expression of other actions. However, it is not clear how each pathway contributes to action selection due to methodological constraints in acquiring an objectively quantitative description of behavior. Our lab has recently developed a pipeline, known as MoSeq, that acquires high-resolution behavioral data and uses an unsupervised algorithm to model stereotyped pose dynamics (actions or “syllables”). Here I propose to combine this state-of- the-art behavioral acquisition and detection technology with both cellular-resolution imaging and optogenetic perturbation to study the population dynamics underlying action selection in the striatum. I hypothesize that SPNs exhibit syllable-specific tuning, where dSPNs are tightly tuned to facilitate the expression of related syllables, while iSPNs are more broadly tuned to suppress the simultaneous expression of other syllables. I will dissect these two processes by recording and manipulating each SPN class during specific syllable expression. In aim 1, I will perform cellular-resolution recordings of the direct or indirect pathway using genetically encoded calcium indicators and miniaturized microendoscopy in the striatum. I will examine the differential roles of the direct and indirect pathways in the context of behavioral tuning. My preliminary data suggest that dSPNs are more sparsely tuned than iSPNs. In aim 2, I will functionally test the center-surround model via direct and indirect pathway inhibition. I will use the inhibitory anion-conducting rhodopsin, ACR2. Using a system capable of detecting syllable expression in real-time, I will perturb each pathway triggered upon the expression of specific syllables to compare the same selection context across many trials. In summary, the experiments proposed here will contribute to a mechanistic understanding of how the BG performs action selection on a moment-to-moment timescale. This proposal is the first to test the predictions made by the center- surround model and will advance our understanding of how the BG encodes actions.

大脑将感觉信息转化为决策，将决策转化为行为，这最终决定了 健身。行为可以分解为一组离散的运动块，称为动作。最基本的 神经节(BG)，特别是BG的输入核，纹状体，对于正确的测序和 动作选择。在细胞水平上，纹状体由多刺投射神经元(SPN)组成 构成直接途径(DSPN)和间接途径(ISPN)。在中心-环绕行动模式下 选择，dSPN被认为促进了一种行为的表达，而iSPN被认为抑制了 其他行为的表达。然而，由于以下原因，尚不清楚每条途径如何对动作选择做出贡献 获得行为的客观定量描述的方法论限制。我们的实验室最近 开发了一种称为MoSeq的管道，它可以获取高分辨率的行为数据，并使用无人监督的 模型化固定姿势动态(动作或“音节”)的算法。在这里，我建议将这一状态- 同时具有细胞分辨率成像和光遗传学的最先进的行为采集和检测技术 扰动以研究纹状体中潜在的行为选择的种群动力学。我假设 SPN表现出特定于音节的调谐，其中dSPN被紧密地调谐以便于表达 相关音节，而iSPN被更广泛地调整以抑制其他 音节。我将通过记录和操作每个SPN类来剖析这两个过程 音节表达。在目标1中，我将执行直接或间接路径的细胞分辨率记录，使用 基因编码的钙指示剂和纹状体的微型显微内窥镜检查。我会研究一下 直接通路和间接通路在行为调节中的不同作用。我的初步数据 建议dSPN比iSPN进行更稀疏的调整。在目标2中，我将对中心环绕进行功能测试 模型通过直接和间接途径抑制。我将使用抑制阴离子传导的视紫红质，ACR2。vbl.使用 一个能够实时检测音节表达的系统，我将扰乱在 表达特定的音节，以比较多个试验中相同的选择上下文。总而言之， 这里提出的实验将有助于从机械上理解BG是如何执行动作的 按时刻到时刻时间刻度进行选择。这项提议是第一次检验该中心的预测-- 环绕模型，并将促进我们对BG如何编码动作的理解。