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

大脑将感官信息转化为决定，并将决定转化为行为，最终决定 健身行为可以被分解为一组离散的运动块，称为动作。基底 神经节（BG），特别是BG的输入核，纹状体，对于正确的测序和 行动的选择。在细胞水平上，纹状体由多刺投射神经元（SPNs）组成， 构成直接途径（dSPN）和间接途径（iSPN）。在中心-环绕的行动模式下 在选择中，dSPN被认为促进作用的表达，而iSPN被认为抑制作用的表达。 其他行为的表现。然而，目前尚不清楚每个途径如何有助于行动选择， 在获取行为的客观定量描述方法的限制。我们的实验室最近 开发了一个名为MoSeq的管道，它可以获取高分辨率的行为数据，并使用无监督的 算法来模拟定型的姿势动态（动作或“音节”）。在这里，我建议联合收割机这种状态- 最先进的行为采集和检测技术，具有细胞分辨率成像和光遗传学 扰动研究纹状体中的行为选择的种群动力学。我假设 SPN表现出音节特异性调谐，其中dSPN被紧密调谐以促进 相关音节，而iSPN更广泛地调节以抑制其他音节的同时表达。 音节.我将通过在特定的过程中记录和操作每个SPN类来剖析这两个过程。 音节表达式。在目标1中，我将使用细胞分辨率记录直接或间接途径， 遗传编码的钙指标和微型显微内窥镜在纹状体。我会检查 直接和间接途径在行为调节中的不同作用。我的初步数据 表明dSPN比iSPN更稀疏地调谐。在目标2中，我将在功能上测试中央环绕 通过直接和间接途径抑制模型。我将使用抑制阴离子传导的视紫红质，ACR 2。使用 一个能够实时检测音节表达的系统，我会扰乱每一个被触发的通路， 特定音节的表达，以在许多试验中比较相同的选择上下文。总而言之， 这里提出的实验将有助于对BG如何执行动作的机械理解 在每时每刻的时间尺度上进行选择。这一提议首次检验了该中心做出的预测-- 环绕模型，并将推进我们对BG如何编码动作的理解。

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.