Spinal circuits involved in skilled forelimb motor control

日常工作，如吃饭和使用手机，需要复杂和精确地控制手臂、手和手指的动作。这些运动是在一个称为精细运动控制的过程中协调的，这个过程涉及我们大脑、脑干和脊髓的不同部分。我们对各种大脑和脑干区域在精细运动控制中的重要作用的一般理解已经研究了很多年。然而，参与精细运动控制的脊髓回路仍然知之甚少。这种知识的缺乏在很大程度上是因为，直到最近，研究人员还缺乏工具来实验记录和控制成年实验动物脊髓中特定神经元群体的活动。我的研究计划的长期目标是使用先进的遗传和外科技术来梳理出精细运动控制的脊椎回路。精细运动控制的一个要求是从皮肤和肌肉到脊髓的感觉反馈。我们之所以知道这一点，是因为缺乏感官反馈的动物和人类无法做出流畅而准确的动作。初级传入去极化(PAD)是脊髓重要的感觉通路之一。我们最近发现，PAD控制着感觉信号是否能到达脊髓(即PAD是感觉信号的守门人)。鉴于精细运动控制需要感觉信号，而PAD控制脊髓中的感觉信号，本提案的目的是研究PAD电路在精细运动控制中的作用。为了实现这一点，我们将使用转基因成年小鼠，这些小鼠专门在脊髓神经元(即V3和GAD2+神经元)中表达光遗传和化学生成蛋白，我们已经证明它们是PAD环路中的关键角色。我将测试这样的假设，即PAD神经元在SPRGR任务的特定阶段(即，在到达、抓住或提取阶段)是活跃的，并且阻断GAD2+神经元的V3会减少精细运动控制，从而降低任务中的绩效。为了做到这一点，我们将训练小鼠执行一项称为SPRGR任务的熟练的伸展、抓取和提取任务。在V3和GAD2+神经元中表达的光遗传报告蛋白使我们能够记录动物执行SPRGR任务时这些细胞的活动，以便我们能够了解这些细胞何时相对于任务的不同部分处于活动状态(例如，V3可能在伸手时打开，但在抓取时关闭)。然后，我们将使用表达光遗传致动器或化学发生蛋白的小鼠，当动物执行SPRGR任务时，这些蛋白将允许我们使用光(光遗传学)或设计药物(化学遗传学)打开或关闭V3和GAD2+神经元。这项任务中表现的下降将表明PAD神经元对精细运动控制很重要。这些研究的结果将使我们对精细运动控制的脊髓神经回路的一些基本原理有新的见解，并将非常适用于理解人类熟练的运动。

Everyday tasks such as eating and using a mobile phone require complex and precisely controlled arm, hand and finger movements. These movements are coordinated in a process called fine motor control, which involves various parts of our brain, brainstem, and spinal cord. Our general understanding of the various brain and brainstem regions important in fine motor control have been studied for many years. However, the spinal circuitry involved in fine motor control remains poorly understood. This lack of knowledge is largely because, until recently, researchers lacked the tools to experimentally record and control the activity of specific neuronal populations in the spinal cords of adult experimental animals. The long-term goal of my research program is to use advanced genetic and surgical techniques to tease out the spinal circuitry of fine motor control. A requirement of fine motor control is sensory feedback from skin and muscles to the spinal cord. We know this because animals and humans lacking sensory feedback are unable to make smooth and precise movements. Primary afferent depolarization (PAD) is one of the key sensory pathways of the spinal cord. We recently showed that PAD controls whether sensory signals can get to the spinal cord or not (i.e., PAD is the gatekeeper of sensory signaling). Given that fine motor control requires sensory signals, and PAD controls sensory signaling in the spinal cord, the aim of the current proposal is to study the roles of PAD circuitry in fine motor control. To accomplish this, we will use genetically modified adult mice that express optogenetic and chemogenetic proteins specifically in spinal cord neurons (i.e., V3 and GAD2+ neurons) we have shown to be key players in PAD circuity. I will test the hypothesis that PAD neurons are active at specific phases of the SPRGR task (i.e., during reaching, grasping, or retrieval phases) and that blocking V3 of GAD2+ neurons will reduce fine motor control leading to reduced performance in the task. To do this, we will train mice to perform a skilled reaching, grasping, and retrieval called the SPRGR task. Optogenetic reporter proteins expressed in V3 and GAD2+ neurons allow us to record the activity from these cells as animals perform the SPRGR task so that we can understand when these cells are active relative to different parts of the task (e.g., V3s might be ON during reaching, but OFF during grasping). We will then use mice expressing optogenetic actuator or chemogenetic proteins that will allow us to turn ON or OFF V3 and GAD2+ neurons using light (optogenetics) or designer drugs (chemogenetics) as the animals perform the SPRGR task. A drop in performance in the task will indicate that PAD neurons are important for fine motor control. The results from these studies will give us new insights to some of the fundamental principles of the spinal cord neural circuitry of fine motor control and will be highly applicable to understanding human skilled movement.