Neural and computational mechanisms underlying the assembly of motor skills

从在键盘上打字到开车，运动技能对我们的日常生活都是必不可少的。技能是由一组较小的自然运动要素组成的，例如个人击键或手臂动作，但人们对支持将运动要素组合成习得技能的神经机制知之甚少。这个建议的目的是了解这种模块化是如何通过背外侧纹状体与其运动皮质和多巴胺能输入之间的相互作用来实现的。我们将通过开发一种名为Capture的新技术来获得对这一过程的新见解，该技术允许我们以最高的时空分辨率连续跟踪大鼠头、躯干和四肢的位置。通过在熟练的运动任务和自然行为中排列运动元素，Capture使我们能够准确地描述运动技能是如何从动物自然行为体系中预先存在的运动元素组装而成的(目标1)。我们将捕获与我们实验室最近开发的一种方法配对，该方法允许连续的多单元神经记录，这一组合使我们能够准确地描述神经表征如何在学习技能的过程中重塑(目标2)。使用这种对技能学习过程的高精度描述，我们可以进行大脑损伤和光遗传刺激，以准确地识别运动皮质和相多巴胺瞬间在技能学习中的作用(目标3)。我们的目标的完成将为运动和技能学习的神经基础的新计算模型提供动力，并为未来的研究建立一个新的量化实验平台。它还应该为寻找人类运动和行为疾病(如帕金森氏病和强迫症)的电路基础提供新的方向。为了指导我的研究和职业发展，我将得到一个在基底节、多巴胺和计算分析方面经验丰富的导师和专家团队的建议。这个团队将通过频繁的会议为我的研究项目和职业发展提供建议，并得到哈佛大学巨大的科学环境的补充，哈佛大学拥有众多核心设施、科学家和正规课程来支持我的工作。我将有能力通过本科生的建议和获得广泛的专业发展课程来成长为一名导师。我将通过在当地和国际科学会议上发表演讲和撰写科学文章来发展我的专业网络、演讲和写作技能。我的整个职业目标是在一个主要的学术中心建立一个研究实验室，这个有指导的研究项目将建立新的、独特的实验平台，使我的研究计划与众不同，并发展几个独特的研究方向。

From typing on a keyboard to driving a car, motor skills are essential for our daily lives. Skills are modularly composed from a smaller set of natural motor elements – for instance individual keystrokes or arm movements – but little is known about the neural mechanisms that support this modular composition of motor elements into learned skills. The aim of this proposal is to understand how this modularity is achieved by interactions between the dorsolateral striatum and its motor cortical and dopaminergic inputs. We will gain new insights into this process through the development of a new technique, CAPTURE, which allows us to continuously track the position of a rat’s head, trunk, and limbs with superlative spatiotemporal resolution. By aligning motor elements across a skilled motor task and natural behaviors, CAPTURE allows us to precisely describe how a motor skill is assembled from pre-existing motor elements in an animal’s natural behavioral repertoire (Aim 1). We pair CAPTURE with a method recently developed in our laboratory that allows for continuous multi-unit neural recordings, a combination that allows us to precisely characterize how neural representations are reshaped across learning of a skill (Aim 2). Using this highly precise description of the skill learning process, we can then perform brain lesions and optogenetic stimulation to precisely identify the role of the motor cortex and phasic dopamine transients in skill learning (Aim 3). Completion of our aims should power new computational models of the neural basis of movement and skill learning and establish a new quantitative experimental platform for future studies. It should also provide new directions in the search for the circuit basis of human diseases of movement and behavior such as Parkinson’s disease and Obsessive Compulsive disorder. To guide my research and career development, I will by advised by a team of experienced mentors and experts in the basal ganglia, dopamine, and computational analysis. This team will advise my research project and career development through frequent meetings and be complemented by the tremendous scientific environment at Harvard University, which has numerous core facilities, scientists, and formal coursework to support my work. I will have the ability to grow as a mentor through undergraduate advising, and access to a broad curriculum in professional development. I will develop my professional network, presentation, and writing skills by presenting at local and international scientific meetings and writing scientific articles. My overall career goals are to establish a research laboratory at a major academic center and this mentored research project will establish new, unique experimental platform to differentiate my research program and develop several unique directions for research.