Spinal circuits involved in skilled forelimb motor control

脊髓回路参与熟练的前肢运动控制

• 批准号: RGPIN-2022-03402
• 负责人: Fenrich, Keith
• 金额: $ 2.11万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764498
• 关键词: Spinal; circuits; involved; skilled; forelimb

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.

日常任务，如吃饭和使用移动的电话，需要复杂和精确控制的手臂，手和手指的运动。这些运动在一个称为精细运动控制的过程中协调，该过程涉及我们大脑，脑干和脊髓的各个部分。我们对精细运动控制中重要的各种大脑和脑干区域的一般理解已经研究了多年。然而，涉及精细运动控制的脊髓回路仍然知之甚少。这种知识的缺乏很大程度上是因为，直到最近，研究人员还缺乏实验记录和控制成年实验动物脊髓中特定神经元群体活动的工具。我的研究计划的长期目标是利用先进的遗传和外科技术梳理出精细运动控制的脊髓回路。 精细运动控制的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精确的动作。初级传入去极化（PAD）是脊髓重要的感觉通路之一。我们最近表明，PAD控制感觉信号是否可以到达脊髓（即，PAD是感觉信号的看门人）。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，当前提案的目的是研究PAD电路在精细运动控制中的作用。为了实现这一点，我们将使用在脊髓神经元中特异性表达光遗传和化学遗传蛋白的遗传修饰的成年小鼠（即，V3和GAD 2+神经元），我们已经证明是PAD电路的关键参与者。我将测试PAD神经元在SPRGR任务的特定阶段活跃的假设（即，在到达、抓握或取回阶段），并且阻断GAD 2+神经元的V3将减少精细运动控制，导致任务性能降低。为了做到这一点，我们将训练小鼠执行熟练的达到，抓取和检索，称为SPRGR任务。在V3和GAD 2+神经元中表达的光遗传报告蛋白允许我们在动物执行SPRGR任务时记录来自这些细胞的活性，以便我们可以了解这些细胞何时相对于任务的不同部分（例如，V3可能在到达期间打开，但在抓取期间关闭）。然后，我们将使用表达光遗传致动器或化学遗传蛋白的小鼠，这些蛋白将允许我们在动物执行SPRGR任务时使用光（光遗传学）或设计药物（化学遗传学）打开或关闭V3和GAD 2+神经元。任务表现的下降表明PAD神经元对精细运动控制很重要。这些研究的结果将为我们提供对精细运动控制脊髓神经回路的一些基本原理的新见解，并且非常适用于理解人类熟练的运动。