Cortical Control of Motor Learning

项目摘要 运动学习是学习的一种基本形式，对许多动物的健康很重要 包括人类在内的物种。习得的运动项目的重要性在它们被强调的时候被强调。 运动障碍，如多发性硬化症和肌萎缩侧索硬化症。神经回路机制 运动学习已经得到了广泛的研究，然而，不同的精确的可塑性机制 运动学习背后的神经元类型还没有被很好地理解。我们在发动机中解决了这个问题 大脑皮层是负责运动学习的大脑关键区域。这项提议的中心假设是 抑制神经元的亚型特异性变化调节兴奋回路的可塑性 对于运动学习来说是必要的。将运动皮质内的这些可塑性事件直接可视化 在运动学习期间，我们将在清醒的小鼠身上长期应用体内双光子成像 为期数周的运动学习任务，重点是运动皮质中的三种主要神经元类型(主要 兴奋性神经元、小白蛋白表达抑制神经元(PV-INS)和生长抑素表达 抑制神经元(SOM-INS))。 我们最近开发了一个杠杆按压任务，作为头部固定小鼠的运动学习范式。我们 研究发现，在超过两周的时间里，学习这项任务会诱导出一种新的、可重复的活动模式 运动皮质兴奋性神经元集合。这种活性变化与树枝晶的周转相吻合。 刺突，兴奋性突触的主要突触后部位，位于兴奋性神经元上(彼得斯等人)。 《自然》2014)。在这些初步发现的基础上，本提案旨在揭示抑制的作用 调节兴奋回路可塑性的回路。在目标1和目标2中，我们将描述活动的特征和 学习过程中PV-in和SOM-in的突触数目。我们假设运动技能的学习是短暂的 增加PV抑制和降低SOM抑制。我们将通过长期的实验来检验这个假设 用GCaMP6f及其轴突突触前终末对PV和SOM-ins的活动进行成像。在AIM 3，我们将检验这样一个假设，即SOM抑制的减少对兴奋性突触重要 可塑性和学习。我们将通过使用光遗传学操纵SOM-IN活动来测试这一点 检查对学习和树突脊椎周转的影响。最后，在目标4中，我们将开发其他 头部固定小鼠的运动学习范例，将与上述实验相结合 未来要测试我们关于塑性机制的发现对各种任务的普适性有多大。这些 实验结合了尖端技术，包括慢性高分辨率双光子成像， 固定头部的小鼠的行为任务，标记特定神经元类型的小鼠遗传学和光遗传学。 这些实验将揭示运动学习背后的精细电路可塑性，并建立 未来可以应用于其他形式的学习和行为的范例。

Project Summary Motor learning is a fundamental form of learning important for the well-being of many animal species including humans. The importance of learned motor programs is underscored when they are compromised in motor disorders such as multiple sclerosis and ALS. Neural circuit mechanisms of motor learning have been extensively studied, however, precise plasticity mechanisms of distinct neuron types underlying motor learning are not well understood. We address this issue in the motor cortex, a critical brain region responsible for motor learning. The central hypothesis in this proposal is that subtype-specific changes of inhibitory neurons regulate the plasticity of excitatory circuits necessary for motor learning. To directly visualize these plasticity events within the motor cortex during motor learning, we will apply in vivo two-photon imaging chronically in awake mice performing a motor learning task over weeks, focusing on three major neuron types in the motor cortex (principal excitatory neurons, parvalbumin-expressing inhibitory neurons (PV-INs), and somatostatin-expressing inhibitory neurons (SOM-INs)). We recently developed a lever-press task as a motor learning paradigm for head-fixed mice. We found that learning of this task over two weeks induces a novel and reproducible activity pattern in motor cortex excitatory neuron ensembles. This activity change coincided with a turnover of dendritic spines, the major postsynaptic sites of excitatory synapses, on the excitatory neurons (Peters et al. Nature 2014). Following up on these initial findings, this proposal aims to reveal the role of inhibitory circuits in regulating the plasticity of excitatory circuits. In Aims 1&2, we will characterize the activity and synapse number of PV- and SOM-INs during learning. We hypothesize that motor learning transiently increases PV inhibition and decreases SOM inhibition. We will test this hypothesis by chronically imaging the activity of PV- and SOM-INs using GCaMP6f and their axonal presynaptic terminals. In Aim 3, we will test the hypothesis that the decrease in SOM inhibition is important for excitatory synaptic plasticity and learning. We will test this by manipulating SOM-IN activity using optogenetics and examine the effect on learning and dendritic spine turnover. Finally in Aim 4, we will develop additional motor learning paradigms for head-fixed mice, which will be combined with above experiments in the future to test how generalizable our findings on plasticity mechanisms are to various tasks. These experiments combine cutting-edge technologies including chronic high-resolution two-photon imaging, behavioral tasks by head-fixed mice, mouse genetics to label specific neuron types and optogenetics. These experiments will reveal fine-scale circuit plasticity underlying motor learning and also establish a paradigm that can be applied to other forms of learning and behaviors in the future.