Dissecting the role of thalamostriatal circuits in flexible versus automatized motor skill execution

项目总结/摘要 在我们的生活中，我们学会了各种各样的行为。从伸手去拿食物或反抗 敌人，许多行动需要精确的运动控制，以成功地导致一个理想的结果。学习 执行一个新的行动开始与行动是灵活的行为，并最终过渡到 自动执行。这些行为灵活和自动化的行动是如何产生的？神经 运动学习的机制尚未完全阐明，但已被假定为来自整合 关于运动指令、环境背景和纹状体结果的神经元信号。背 内侧纹状体（DMS）是重要的早期学习和目标导向的行动，而背外侧纹状体 (DLS)对自动化和习惯的形成更为重要。我假设丘脑对DMS的输入 调节运动技能的灵活表现，丘脑输入DLS维持自动执行 运动技能已经表明，纹状体的多巴胺能输入的可塑性对于运动神经元的运动功能是至关重要的。 学习以前对纹状体信息整合的研究主要集中在纹状体皮层 向背侧纹状体的投射。但人们在很大程度上忽略了背侧纹状体并不接受 脑电的输入不仅来自皮层，也来自丘脑。已经表明，特定的病变 投射到背侧纹状体的丘脑核团在目标导向学习和奖励方面产生缺陷 贬值。丘脑纹状体的两个致密投射来自束旁核（Pf）， 后内侧核（POm）。内侧Pf（mPF）广泛投射到DMS，而外侧Pf（lPf）和POM投射到DMS。 到DLS。这种分离的Pf和POm的投射回路以及DMS和DLS的既定作用， 运动学习的不同阶段，表明丘脑对DLS和DMS的投射可能具有不同的作用 在早期和晚期的运动学习中。目标1将专注于建立一个新的头部固定行为范式（ 操纵杆任务），其中小鼠学习执行前肢运动动作。目标2将描述 在灵活和自动执行目标1的操纵杆任务期间，丘脑输入DMS和DLS。 目标3将阐明Pf和POm是否是灵活和自动执行运动技能所必需的， 在执行来自Aim 1的操纵杆任务期间，光遗传学操纵丘脑核的活性。 这些实验将是第一个剖析丘脑纹状体投射在运动学习中的作用的实验。 行为的小鼠结合使用双光子钙成像的详细群体水平分析。探索 这些纹状体输入的作用将揭示丘脑的难以捉摸的本质，一个进化上古老的 结构及其在运动学习中的关键作用。

Project Summary / Abstract Over the course of our lives, we learn to perform a wide variety of actions. From reaching for food or fighting off an enemy, many actions require exact motor control to successfully lead to a desirable outcome. Learning to perform a novel action starts with the action being behaviorally flexible, and eventually transitions to automatized execution. How are these behaviorally flexible and automatized actions generated? The neural mechanism of motor learning has not been fully elucidated, but has been posited to arise from integrating neuronal signals about motor commands, environmental context, and outcome in the striatum. The dorsal medial striatum (DMS) is important for early learning and goal-directed action, while the dorsal lateral striatum (DLS) is more important for automatization and habit formation. I hypothesize that thalamic input into the DMS mediates flexible performance of motor skills and thalamic input into the DLS maintains automatic execution of motor skills. It has been shown that plasticity of glutamatergic inputs to the striatum are critical for motor learning. Previous investigations into striatal information integration have focused on the glutamatergic cortical projections to dorsal striatum. What has been largely ignored is that the dorsal striatum does not receive glutamatergic input only from the cortex, but also from the thalamus. It has been shown that lesions of specific thalamic nuclei that project to the dorsal striatum produce deficits in goal-directed learning and reward devaluation. The two densest thalamostriatal projections come from the parafasicular nucleus (Pf) and the posterimedial nucleus (POm). Medial-Pf (mPF) projects broadly to DMS, while lateral-Pf (lPf) and POm project to DLS. This segregated projection circuitry of Pf and POm and the established roles of DMS and DLS in distinct phases of motor learning, suggest that thalamic projections to DLS and DMS may have different roles in early and late motor learning. Aim 1 will focus on building a novel head-fixed behavioral paradigm (the joystick task) in which mice learn to perform forelimb motor actions. Aim 2 will characterize the activity of thalamic inputs to DMS and DLS during flexible and automatic performance of the joystick task from Aim 1. Aim 3 will elucidate if Pf and POm are necessary for flexible and automatic performance of motor skills by optogenetically manipulating the thalamic nuclei’s activity during performance of the joystick task from Aim 1. These experiments will be the first to dissect the role of thalamostriatal projections during motor learning in behaving mice coupled with detailed population level analysis using 2-photon calcium imaging. Exploring the role of these striatal inputs will shed light on the elusive nature of the thalamus, an evolutionarily ancient structure, and its critical role in motor learning.