Neural and computational mechanisms underlying the assembly of motor skills

从打字到开车，运动技能对我们的日常生活至关重要。技能是由一组较小的自然运动元素模块组成的，例如单个的击键或手臂运动，但人们对支持将运动元素模块化组成为习得技能的神经机制知之甚少。本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层和多巴胺能输入之间的相互作用来实现的。我们将通过一项新技术的开发获得对这一过程的新见解，CAPTURE，它使我们能够以最高的时空分辨率连续跟踪老鼠的头部，躯干和四肢的位置。通过将熟练的运动任务和自然行为中的运动元素对齐，CAPTURE使我们能够精确地描述运动技能是如何从动物自然行为中预先存在的运动元素中组装起来的（目的1）。我们将CAPTURE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，这种组合使我们能够精确地表征神经表征如何在技能学习中重塑（目标2）。利用这种对技能学习过程的高度精确描述，我们可以进行脑损伤和光遗传刺激，以精确识别运动皮层和阶段性多巴胺瞬态在技能学习中的作用（目的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新的定量实验平台。它还应该为寻找帕金森病和强迫症等人类运动和行为疾病的电路基础提供新的方向。为了指导我的研究和职业发展，我将听取一组经验丰富的导师和专家在基底神经节、多巴胺和计算分析方面的建议。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，并辅以哈佛大学强大的科学环境，这里有众多的核心设施、科学家和正式的课程来支持我的工作。我将有能力通过本科指导成长为一名导师，并获得广泛的专业发展课程。我将通过在本地和国际科学会议上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。我的总体职业目标是在一个重要的学术中心建立一个研究实验室，这个指导的研究项目将建立一个新的、独特的实验平台，以区分我的研究计划，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.