The role of the red nucleus in motor control of skilled and unskilled movements

有人争辩说，我们的大脑存在是为了产生定义我们行为的运动。我们对大脑特定区域在产生不同动作中的作用的了解仍处于初级阶段。指导我们的研究通常依赖于损伤或电激活大脑的区域。虽然有用，但这些方法不会选择性地激活神经元，而且损伤往往会阻断通路的纤维。在这项建议中，我们着重于激活红核(RN)投射到脊髓，已知有助于控制运动和熟练的伸展。我们在使用光遗传技术，选择性地激活和失活特定的神经回路方面获得了广泛的经验。我们已经集成了光度学方法来记录RN神经元的特定下降到脊髓。我们现在打算使用这些方法来深入了解当动物执行熟练和非熟练动作时，已识别的RN下行投射对脑干和脊髓的贡献。目前的提议将提供关于全脑连接、运动功能以及技能获得过程中神经元群体活动变化的关键新信息。它建立在我们之前由NSERC资助的关于运动下行控制的研究计划的基础上。目标1.识别RN马达电路连接体。使用横断面病毒方法，我们将检查从RN到颈髓和延髓腹侧网状结构(MDV)的投射。病毒方法将使我们不仅可以检测到直接的解剖学投射，还可以检测到RN神经元到大脑其他区域的侧支分支，这在文献中是一个重要的空白。2.检查熟练和非熟练运动任务执行过程中RN神经元的活动。我们将使用钙指示剂(GCaMP6)记录RN-脊髓投射神经元的活动。我们将RN内的活动与EMG活动相关联，以确定在不同任务期间RN活动相对于EMG活动的潜伏期。然后，我们将检查随着熟练训练的进行，RN下行神经元的激活随时间的变化。3.激活和失活通向颈髓的RN专用通路。在这里，我们将测试RN对脊柱通路的必要性和充分性，以控制不熟练的行走(在平地上)，熟练的前肢运动中的使用，以及熟练的抓握。我们将使用一种组合病毒策略来靶向向延髓腹侧网状结构或颈髓的下行RN投射的激活和失活。意义这项工作将通过使用全脑成像和光遗传学方法研究RN的功能连接组，为RN在熟练和非熟练运动的运动控制中的作用提供独特的见解。

It has been argued that our brain exists to produce movements which define our behavior. Our understanding of the role of specific areas of the brain in producing different movements is still in its infancy. Research guiding us often relies on lesioning or electrically activating areas of the brain. While useful, these approaches do not selectively activate neurons, and lesioning often interrupts fibres of passage. In this proposal, we focus on activating red nucleus (RN) projections to the spinal cord, known to contribute to the control of locomotion and in skilled reaching. We have gained extensive experience in the use of optogenetic techniques, to selectively activate and inactivate specific neural circuits. We have integrated photometry approaches to record from RN neurons that specifically descend to the spinal cord. We now intend to use these approaches to gain insight into the contribution of identified descending RN projections to the brainstem and spinal cord when animals are performing skilled and unskilled movements. The current proposal will provide critical new information on whole-brain connectomics, motor function, and on changes in population activity of neurons during skill acquisition. It builds on our previously NSERC-funded research program on descending control of movement.  Aims 1. Identify the RN motor circuit connectome. Using intersectional viral approaches, we will examine the projections from the RN to the cervical spinal cord and the ventral medullary reticular formation (MdV). The viral approach will allow us to detect not only direct anatomical projections but also collateral branching of the RN neurons to other areas of the brain, which is an important gap in the literature. 2. Examine the activity of RN neurons during performance of skilled and unskilled motor tasks. We will record activity from RN-spinal cord projecting neurons using calcium indicators (GCaMP6). We will correlate activity within the RN with EMG activity to determine the latency of RN activity with respect to the EMG activity during the different tasks. We will then examine changes in activation of descending RN neurons over time as skilled training progresses. 3. Activate and inactivate dedicated RN pathways to the cervical spinal cord. Here we will test the necessity and sufficiency of RN to spinal pathways in the control of unskilled walking (over flat ground), skilled forelimb use during locomotion, and skilled grasping. We will use a combinatorial viral strategy to target the activation and inactivation of descending RN projections to either the ventral medullary reticular formation or cervical spinal cord. Significance This work will provide unique insight into the role of the RN in motor control of skilled and unskilled movements by examining the RN functional connectome using whole-brain imaging, and optogenetic approaches.