Cortical Control of Motor Learning

运动学习的皮质控制

基本信息

批准号：
9767357
负责人：
Takaki Komiyama
金额：
$ 4.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767357
关键词：
Address Affect Aging Alzheimer&apos s Disease Animals Area Axon Behavior Behavioral Brain Brain region Chronic Dementia Dendrites Dendritic Spines Disease Distal Event Excitatory Synapse Food Forelimb Future Genetic Head Human Huntington Disease Image Inhibitory Synapse Label Learning Memory Disorders Microscope Monitor Motor Motor Cortex Motor Skills Movement Movement Disorders Multiple Sclerosis Mus Nature Neurons Oral cavity Parkinson Disease Parvalbumins Pattern Personal Satisfaction Play Population Presynaptic Terminals Publications Reproducibility Research Resolution Role Site Somatostatin Stroke Structure Synapses Synaptic plasticity Techniques Technology Testing Training Walking awake base excitatory neuron experience experimental study frontier imaging approach in vivo two-photon imaging inhibitory neuron innovation insight learned behavior motor control motor disorder motor learning neural circuit neuromechanism novel optical imaging optogenetics postsynaptic presynaptic programs relating to nervous system sample fixation skills two-photon

项目摘要

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.

项目概要运动学习是学习的基本形式，对许多动物的福祉很重要包括人类在内的物种。当学习到的运动程序被多发性硬化症和 ALS 等运动障碍受到损害。神经回路机制运动学习已被广泛研究，然而，不同的运动学习的精确可塑性机制运动学习背后的神经元类型尚不清楚。我们在电机中解决这个问题皮质，负责运动学习的关键大脑区域。该提案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所必需的。直接可视化运动皮层内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身上长期应用体内双光子成像，执行为期数周的运动学习任务，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) 和表达生长抑素的神经元抑制性神经元（SOM-IN））。我们最近开发了一种杠杆按压任务作为头部固定小鼠的运动学习范例。我们发现在两周内学习这项任务会引发一种新颖且可重复的活动模式运动皮层兴奋性神经元群。这种活性变化与树突的周转同时发生棘是兴奋性突触的主要突触后位点，位于兴奋性神经元上（Peters 等，2016）。自然 2014）。根据这些初步发现，该提案旨在揭示抑制的作用调节兴奋性电路可塑性的电路。在目标 1 和 2 中，我们将描述活动的特征并学习期间 PV-IN 和 SOM-IN 的突触数量。我们假设运动学习是短暂的增加 PV 抑制并减少 SOM 抑制。我们将通过长期测试这个假设使用 GCaMP6f 及其轴突突触前末梢对 PV-和 SOM-IN 的活动进行成像。瞄准 3，我们将检验以下假设：SOM 抑制的减少对于兴奋性突触很重要可塑性和学习性。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周转的影响。最后，在目标 4 中，我们将开发更多头部固定小鼠的运动学习范例，将与上述实验相结合未来将测试我们关于可塑性机制的发现如何推广到各种任务。这些实验结合了尖端技术，包括长期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，并建立一个未来可以应用于其他形式的学习和行为的范式。