RP4: Linking Spinal Circuits to Behavior

项目摘要：项目4-将脊髓回路与行为联系起来 尽管前肢运动在我们与世界的互动中扮演着重要的角色，但人们对它是如何做到的却知之甚少。 特定的神经回路控制这些行为的精确度、速度和保真度。虽然大多数关于前肢的研究 运动探索下行运动指令通路，颈髓的神经结构 脊椎上通路最终招募来执行灵巧的前肢运动仍然是个谜。至 为了应对这一挑战，我们将探讨两个核心问题：1)脊髓网络如何控制节律 模式生成过渡到协调非节奏性运动，这代表了前肢的大部分 运动行为？2)如何修改这些脊椎回路，以控制更复杂的关节运动，并实现 前肢灵巧？项目4将为运动的解剖学、生理学和分子描述架起桥梁。 颈髓中的回路(方案2和3)及其控制的前肢行为。这 功能信息将用于开发脊椎电路模型(项目1)并建立 颈髓多模式图谱(数据核心)。 虽然小鼠的遗传工具提供了一种定义神经回路的组织和功能的方法， 探索熟练的前肢控制的神经基础的主要障碍仍然是：a)标准化的分析方法 探测小鼠前肢行为的很少；以及b)缺乏对脊髓运动神经回路的电生理通路 在行为方面，动物排除了定义这些回路的活动如何与行为相对应的能力 输出。该项目提出了解决这些障碍的三个主要目标。目标1将开发和应用 灵敏的行为分析和前肢肌肉的肌电(EMG)记录提供更多 在定义的过程中，对前肢关节的运动控制进行全面和经验的实验访问 行为。目标2将应用现代分子遗传学微扰来研究细胞的功能组织 运动前神经元间网络，调节前肢运动神经元的活动并协调运动。 目标3将开发新的方法，从脊髓记录动物的前肢 运动，克服定义脊髓神经活动如何与运动相关的关键障碍，以及 这一活动如何受到有针对性的扰动的影响。通过同时检查每个主要步骤， 从脊髓神经回路活动到肌肉募集，再到肢体动力学和运动学，这项工作将 生成前肢电机电路的功能图，并对前肢控制的预测模型进行测试 也很精致。最终，这些进展将提供对运动的神经根的更广泛的洞察， 并有助于为更好地诊断和治疗因受伤或疾病引起的运动障碍奠定基础。

Project Summary: Project 4 – Linking Spinal Circuits to Behavior Despite the critical role forelimb movements play in our interaction with the world, little is known about how specific neural circuits control the precision, speed, and fidelity of these behaviors. While most studies of forelimb movement explore descending motor command pathways, the neural architecture of the cervical spinal cord that supraspinal pathways ultimately recruit to execute dexterous forelimb movement remains mysterious. To address this challenge, two central questions will be explored: 1) How do spinal networks that control rhythmic pattern generation transition to coordinate non-rhythmic movements, which represent the majority of forelimb motor behaviors? 2) How are these spinal circuits modified to control more complex joint movements and achieve forelimb dexterity? Project 4 will bridge the anatomical, physiological, and molecular delineation of motor circuits in the cervical spinal cord (Projects 2 and 3) with the forelimb behaviors they control. This functional information will be used to develop models of spinal circuitry (Project 1) and build a multimodal atlas of the cervical spinal cord (Data Core). While genetic tools in mice have provided a means to define the organization and function of neural circuits, major impediments to exploring the neural basis of skilled forelimb control remain: a) standardized assays for probing mouse forelimb behaviors are few; and b) the lack of electrophysiological access to spinal motor circuits in behaving animals precludes the ability to define how the activity of these circuits corresponds with behavioral output. This Project proposes three major Aims that will address these obstacles. Aim 1 will develop and apply sensitive behavioral assays and electromyography (EMG) recording from forelimb muscles to provide more comprehensive and empirical experimental access to motor control across forelimb joints during defined behaviors. Aim 2 will apply modern molecular-genetic perturbation to investigate the functional organization of pre-motor interneuron networks that modulate the activity of forelimb motor neurons and orchestrate movement. Aim 3 will develop novel approaches for recording from the spinal cord of animals performing forelimb movements, overcoming a critical barrier to defining how spinal neural activity correlates with movement, and how this activity is affected by targeted perturbation. By simultaneously examining each major step in the pathway, from spinal neural circuit activity, to muscle recruitment, to limb kinetics and kinematics, this work will generate a functional map of forelimb motor circuits and enable predictive models of forelimb control to be tested and refined. Ultimately, these advances will provide insight into the neural roots of movement more generally, and help to lay the foundation for better diagnosis and treatment of motor deficits caused by injury or disease.