Cortical Control of Motor Learning

 描述（由申请人提供）：运动学习是一种基本的学习形式，对包括人类在内的许多动物物种的健康至关重要。在运动障碍如多发性硬化症和ALS中，学习运动程序的重要性得到了强调。运动学习的神经回路机制已经被广泛研究，然而，运动学习背后的不同神经元类型的精确可塑性机制还没有得到很好的理解。我们在运动皮层中解决这个问题，运动皮层是负责运动学习的关键大脑区域。这个提议的中心假设是，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， 运动学习为了在运动学习过程中直接可视化运动皮层内的这些可塑性事件，我们将在清醒小鼠中长期应用体内双光子成像，在数周内执行运动学习任务，重点关注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，在运动皮层兴奋性神经元合奏。这种活动变化与树突棘的更替相一致，树突棘是突触后的主要部位。 兴奋性神经元上的兴奋性突触（Peters等人，Nature 2014）。在此基础上，本研究拟揭示抑制性回路在调节兴奋性回路可塑性中的作用。在目标1&2中，我们将描述学习过程中PV-和SOM-IN的活性和突触数量。我们假设，运动学习瞬时增加PV抑制和减少SOM抑制。我们将通过使用GCaMP 6 f及其轴突突触前末梢对PV-和SOM-IN的活动进行长期成像来验证这一假设。在目标3中，我们将测试这一假设，即SOM抑制的减少对兴奋性突触可塑性和学习很重要。我们将通过使用光遗传学操纵SOM-IN活性来测试这一点，并检查对学习和树突棘周转的影响。最后，在目标4中，我们将为头部固定的小鼠开发额外的运动学习范例，将来将与上述实验相结合，以测试我们对可塑性机制的发现对各种任务的可推广性。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回路可塑性，并建立可应用于未来其他形式的学习和行为的范式。

 DESCRIPTION (provided by applicant): 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 he 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 paradigm that can be applied to other forms of learning and behaviors in the future.