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，允许人类和动物移动自己的环境，并且 在生活的各个方面都涉及这种行为。 伤害，包括脊髓损伤，中风和各种共济失调。 节奏和图案位于胸骨脊髓中，通常低于神经损伤水平。 这些电路可以通过各种中央和外围方法直接访问，但不包括 仅限于流行刺激。 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。 脊柱神经元电路产生协调的节奏输出的机制保持较差 理解并代表了我们对运动神经控制的理解 有节奏的运动行为基于三合会的相关性：（1）特定的“节律性”特性允许个人 神经元产生节奏振荡的神经元，（2）相互出现相互作用，将神经元活性同步到 有节奏的人口爆发，（3）网络抑制以协调活性不同的神经元 三合会组件高。 互连和每个组件的涉及条件依赖性。 高度集成的电生理学，药理，遗传和计算机 探索这些机制的具体贡献及其之间的相互作用，在一代和 运动节奏的模式。 因子Shox2作为一个 脊髓中的生成机制涉及在细胞的三合会和网络之间解释 对节律发生的贡献的特性是互置的，导致灵活性和适应性 作为在不同条件下的三合会的相对平衡的变化。 成人SHOX2神经元中的自发细胞振荡的基础。我们将评估兴奋性 节奏生成神经元之间的相互作用。 在调节运动频率方面的网络相互作用，并确定这些途径的操作 传入诱发的运动。 建立基于“真实”节奏产生细胞和的第一个Mamalian运动神经网络模型 网络属性，并确定我的影响力节奏的影响 和脊髓中产生的模式。 未来的设备和策略，旨在在受伤或运动障碍后进行运动的重新安排。