CAREER: High-level control of low-level circuits in the mammalian motor system

所有的行为--动物做的每一件事--都是由它们的动作决定的。因此，控制灵活、灵巧、目标导向的运动是神经系统最重要的功能之一。脊椎动物大脑中的运动回路是分层排列的。脑干和脊髓中的低水平电路--例如控制呼吸和运动的中央模式发生器--可以自主地产生基本的运动模式。高级运动回路使动物能够学习和适应动作，检测和纠正错误，预测动作的成本和收益，并将动作组装成复杂的序列，以在长时间尺度上实现行为目标。高级电路通常不直接控制运动，而是接合和修改由低级电路产生的基本电机程序。低电平电路又集成了来自许多高电平区域的一组输入，以合成驱动运动神经元和肌肉的运动指令。尽管这一过程是所有灵活行为的中心，但目前人们对众多高级运动中心如何以协调的方式共同控制低级电路知之甚少。该项目的总体目标是确定鼠标电机系统的高级区域如何开启、关闭和修改由低级电路产生的电机模式。关键是，解决这个问题将区分两种相互竞争的分级控制模式，这两种模式可能用于哺乳动物的大脑。在合作模型中，高级运动中枢与负责不同计算过程的不同电路之间存在“分工”--其中任何一个或全部可以根据行为需求同时调用。或者，平行模型预测，许多高水平的大脑区域同样有能力指挥整体的运动，不同的区域将控制归入它们专门处理的行为背景中。该项目利用一种尖端的小鼠实验工具包来操纵神经活动，并以细胞类型特异性跟踪它们之间交流的信号。该项目专注于控制一个定义明确的中央模式生成器，负责控制小鼠的舌头运动，以利用一种新的范例，在与不同高级控制过程相关的上下文中，小鼠执行相同的舌头运动。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

All behavior – everything that an animal does – is defined by their movements. As a result, the control of flexible, dexterous, goal-directed movements is one of the most important functions of the nervous system. Motor circuits in the vertebrate brain are arranged hierarchically. Low-level circuits in the brainstem and spinal cord – such as the central pattern generators that control breathing and locomotion – can autonomously produce basic motor patterns. High-level motor circuits allow animals to learn and adapt movements, detect and correct errors, predict the cost and benefits of actions, and assemble movements into complex sequences to attain behavioral goals over long time scales. High-level circuits do not generally control movements directly, but, instead, engage and modify the basic motor programs produced by low-level circuits. Low-level circuits in turn integrate an array of inputs from many high-level areas to synthesize the motor commands that drive motor neurons and muscles. Little is currently known about how a multitude of high-level motor centers together control low-level circuits in a coordinated fashion, despite the centrality of this process to all flexible behavior. The overarching goal of this project is to identify how high-level regions of the mouse motor system turn on, turn off, and modify the motor patterns produced by low-level circuits. Critically, tackling this problem will differentiate between two competing models of hierarchical control that may be utilized in the mammalian brain. In the Cooperative model, there exists a ‘division of labor’ between high-level motor centers with different circuits responsible for different computational processes – any or all of which may be invoked simultaneously according to behavioral demands. Alternatively, the Parallel model predicts that many high-level brain regions are equally capable of commanding movements in their entirety, with different regions subsuming control in the behavioral context for which they are specialized. This project leverages a cutting-edge experimental toolkit in mice for manipulating neural activity and tracking the signals communicated between them with cell-type specificity. This project focuses on control of a well-defined central pattern generator responsible for controlling tongue movements in mice to leverage a novel paradigm in which mice perform the same tongue movements in contexts associated with different high-level control processes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.