Cortical Control of Motor Learning

项目摘要 运动学习是一种基本的学习形式，对许多动物的健康很重要 包括人类在内的物种。学习运动程序的重要性是强调，当他们 在运动障碍如多发性硬化症和肌萎缩侧索硬化症中受损。神经回路机制 运动学习已经得到了广泛的研究，然而，精确的可塑性机制的不同 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这个问题 大脑皮层是负责运动学习的关键区域。这一提议的核心假设是 抑制性神经元的亚型特异性变化调节兴奋性回路的可塑性 运动学习所必需的。为了直接可视化运动皮层中的这些可塑性事件， 在运动学习过程中，我们将在清醒的小鼠中长期应用体内双光子成像， 运动学习任务，重点是运动皮层中的三种主要神经元类型（主要 兴奋性神经元、表达小清蛋白的抑制性神经元（PV-IN）和表达生长抑素的 抑制性神经元（SOM-IN））。 我们最近开发了一个快速按压任务作为头部固定小鼠的运动学习范例。我们 发现，学习这项任务超过两周诱导一种新的和可重复的活动模式， 运动皮层兴奋性神经元集合。这种活性变化与树突状细胞的更替相一致。 棘，兴奋性突触的主要突触后位点，在兴奋性神经元上（Peters et al. Nature 2014）。在这些初步研究结果的基础上，本研究旨在揭示抑制性的作用。 调节兴奋性回路可塑性的回路。在目标1&2中，我们将描述活动的特点， 在学习过程中PV-和SOM-IN的突触数量。我们假设运动学习的短暂性 增加PV抑制和降低SOM抑制。我们将通过长期的 使用GCaMP 6 f和它们的轴突突触前末梢对PV-和SOM-IN的活性进行成像。在Aim中 3、我们将检验SOM抑制的减少对兴奋性突触的重要性这一假设。 可塑性和学习。我们将通过使用光遗传学操纵SOM-IN活性来测试这一点， 检查对学习和树突棘转换的影响。最后，在目标4中，我们将开发更多的 头部固定小鼠的运动学习范例，其将与上述实验相结合， 未来，我们将测试我们对可塑性机制的研究结果如何推广到各种任务。这些 实验结合了联合收割机尖端技术，包括慢性高分辨率双光子成像， 头部固定小鼠的行为任务，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，并建立一个 这种模式可以在未来应用于其他形式的学习和行为。

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.