Mechanisms of locomotor rhythm generation in rodent spinal cord

啮齿动物脊髓运动节律的产生机制

• 批准号: 10605444
• 负责人: Kimberly J Dougherty
• 金额: $ 52.31万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605444
• 关键词: Adult; Affect; Animals; Ataxia; Behavior; Clinical; Computer Models; Contralateral; Coupling; Data; Development; Devices; Disease; Disinhibition; Electrophysiology (science); Elements; Environment; Equilibrium; Excision; Extensor; Flexor; Food; Frequencies; Future; Gap Junctions; Generations; Genetic; Genetic study; Human; Individual; Injury; Interneurons; Ipsilateral; Left; Life; Locomotion; Methods; Motor; Motor Activity; Movement; Neonatal; Neural Network Simulation; Neuraxis; Neurons; Output; Pathway interactions; Pattern; Periodicity; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Physiological; Population; Preparation; Property; Recovery; Regulation; Research Personnel; Rodent; Role; Shapes; Slice; Spinal; Spinal Cord; Spinal cord injury; Stroke; Synapses; Testing; Transgenic Mice; Triad Acrylic Resin; base; flexibility; insight; locomotor control; motor behavior; motor disorder; multidisciplinary; neuromechanism; neuronal circuitry; neuroregulation; operation; relating to nervous system; restoration; synaptic inhibition; tool; transcription factor; voltage

ABSTRACT Locomotion is a fundamental behavior that allows humans and animals to move through their environments and is critically involved in all aspects of life. This behavior is impeded in a number of diseases, disorders, and injuries, including spinal cord injury, stroke, and various ataxias. All of the essential circuity to generate locomotor rhythm and pattern is located in the thoracolumbar spinal cord, most often below the level of neural damage. These circuits can be accessed directly via various central and peripheral stimulation methods, including but not limited to epidural stimulation. Rhythm generating circuits are the entry point for initiation and control of locomotion, affect all downstream neurons related to locomotion, and, therefore, are the first step in establishing spinal control of locomotion. Successful activation of the rhythm generator clinically has been hampered because the mechanisms by which spinal neuronal circuits generate coordinated rhythmic output remain poorly understood and represents a major gap in our understanding of neural control of movement. The generation of rhythmic motor behaviors is based on a triad involving: (1) specific “rhythmogenic” properties allowing individual neurons to generate rhythmic oscillations, (2) mutual excitatory interactions to synchronize neuronal activity into rhythmic populational bursting, and (3) network inhibition to coordinate activity between different neuronal populations, which can both shape locomotor pattern and control frequency. Triad components are highly interconnected and the involvement of each component is condition-dependent. The proposed study will use highly integrated electrophysiological, pharmacological, genetic, and computational approaches to systematically explore the specific contributions of these mechanisms and the interactions between them, in the generation and patterning of the locomotor rhythm. Utilizing spinal neurons identified in transgenic mice by the transcription factor Shox2 as a representative rhythm generating population, we will test the overarching hypothesis that rhythm generating mechanisms in the spinal cord involve interplay between the triad of cellular, population, and network properties, whose contribution to rhythmogenesis is interdependent, leading to flexibility and adaptability seen as alterations in the relative balance of the triad in different conditions. We will first determine the voltage-gated currents underlying spontaneous cellular oscillations in adult Shox2 neurons. We will then assess excitatory interactions between rhythm generating neurons. Lastly, we will establish the role of ipsilateral and contralateral network interactions in regulating locomotor frequency, and determine the operation of these pathways during afferent-evoked locomotion. Together, our multidisciplinary study will reveal mechanisms of rhythm generation, establish the first mammalian locomotor neural network model based on “real” rhythm generating cellular and network properties, and determine the ways by which afferent stimulation may influence the locomotor rhythm and pattern generated in the spinal cord. The results of these studies will identify specific neural targets for the future devices and strategies aimed at restoration of locomotion following injury or motor disorders.

抽象的 运动是一种基本行为，允许人类和动物在其环境中移动 与生活的各个方面有批判性参与。这种行为在多种疾病，疾病和 损伤，包括脊髓损伤，中风和各种共济失调。产生运动的所有基本电路 节奏和图案位于胸骨脊髓中，通常低于神经元损伤水平。 这些电路可以通过各种中央和外围刺激方法直接访问，包括但不能 仅限于硬膜外刺激。节奏产生电路是启动和控制的切入点 运动，影响与运动有关的所有下游神经元，因此是建立的第一步 运动的脊柱控制。在临床上成功激活节奏发电机已受到阻碍 脊柱神经元电路产生协调的节奏输出的机制保持较差 理解并代表我们对运动神经控制的理解。一代 有节奏的运动行为基于涉及的三合会：（1）特定的“节律性”特性允许个人 神经元产生节奏振荡，（2）相互兴奋的相互作用，将神经元活性同步到 有节奏的种群破裂，（3）网络抑制以协调不同神经元之间的活性 种群，既可以塑造运动模式和控制频率。三合会组件高度高 互连和每个组件的参与是条件依赖性的。拟议的研究将使用 高度整合的电生理，药物，遗传和计算方法 探索这些机制的具体贡献及其之间的相互作用，在一代和 运动节奏的图案。利用转录在转基因小鼠中鉴定的脊柱神经元 因子SHOX2作为代表性的节奏产生人群，我们将检验以下的总体假设 脊髓中的生成机制涉及细胞，种群和网络三合会之间的相互作用 对节律发生的贡献的特性是相互依存的，导致了灵活性和适应性 随着在不同条件下三合会的相对平衡的改变。我们将首先确定电压门控 目前，成人SHOX2神经元中的基本赞助细胞振荡。然后，我们将评估兴奋性 节奏产生神经元之间的相互作用。最后，我们将确定同侧和对侧的作用 确定运动频率的网络相互作用，并确定这些途径的操作 传入诱发的运动。我们的多学科研究一起将揭示节奏产生的机制， 建立基于“真实”节奏产生细胞和的第一个哺乳动物运动神经网络模型 网络属性，并确定传入刺激可能影响运动节奏的方式 和脊髓中产生的图案。这些研究的结果将确定特定的神经目标 未来的设备和策略旨在恢复受伤或运动障碍后的运动。