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

项目摘要/摘要 在我们的一生中，我们学会了执行各种各样的动作。从伸手去拿食物或打架 作为敌人，许多行动都需要精确的运动控制才能成功地达到理想的结果。学习如何 执行新奇的动作开始于行为灵活，最终过渡到 自动执行死刑。这些行为灵活和自动化的动作是如何产生的？神经学 运动学习的机制尚未完全阐明，但被认为是由整合产生的。 纹状体中有关运动指令、环境背景和结果的神经元信号。背部 内侧纹状体(DMS)对早期学习和目标定向动作很重要，而背外侧纹状体(DMS)对早期学习和目标定向动作很重要 (DLS)对于自动化和习惯养成更为重要。我假设丘脑输入到DMS 调节运动技能的灵活表现和丘脑对DLS的输入维持自动执行 运动技能。已有研究表明，纹状体谷氨酸能输入的可塑性对运动至关重要。 学习。以往对纹状体信息整合的研究主要集中在谷氨酸能皮层 向背侧纹状体投射。在很大程度上被忽视的是，背侧纹状体没有接收到 谷氨酸能输入不仅来自皮质，也来自丘脑。已有研究表明，特殊的皮损 投射到背侧纹状体的丘脑核团在目标定向学习和奖赏方面产生缺陷 货币贬值。最密集的两个丘脑纹状体投射来自鞍旁核(Pf)和 后内侧核(POM)。中间-PF(MPF)广泛投射到DMS，而外侧-PF(LPF)和POM项目 致DLS。Pf和POM的这种分离的投影电路以及DMS和DLS在 运动学习的不同阶段，表明丘脑对DLS和DMS的投射可能有不同的作用 在运动学习的早期和晚期。目标1将专注于构建一种新的头部固定行为范式(the 操纵杆任务)，即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，丘脑输入到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 在执行目标1中的操纵杆任务时，通过光遗传学操作丘脑核团的活动。 这些实验将首次剖析丘脑纹状体投射在运动学习中的作用。 行为小鼠结合使用双光子钙成像进行详细的种群水平分析。探索 这些纹状体输入的作用将有助于揭示丘脑的难以捉摸的性质，丘脑是一种进化上古老的 结构，以及它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.