Afferent modulation of rhythm-generating neurons in the spinal locomotor central pattern generator

脊髓运动中枢模式发生器中节律生成神经元的传入调制

• 批准号: 9814601
• 负责人: Erik Zhi-Chong Li
• 金额: $ 4.51万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2022-06-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814601
• 关键词: Ablation; Affect; Alpha Rhythm; Ankle; Biological; Brain; Cervical spinal cord injury; Chest; Clinical; Computational Technique; Computer Simulation; Cutaneous; Data; Deafferentation procedure; Disease; Electrophysiology (science); Elements; Experimental Models; Extensor; Feedback; Felis catus; Flexor; Frequencies; Gait; Generations; Genetic; Goals; Hindlimb; Hip Joint; Hip region structure; Impairment; Injury; Interneurons; Label; Length; Liquid substance; Locomotion; Lumbar spinal cord structure; Maintenance; Mammals; Measures; Mediating; Motor; Motor Activity; Motor Neurons; Movement; Muscle; Nerve; Neurons; Pathway interactions; Pattern; Periodicity; Phase; Population; Preparation; Proprioceptor; Rattus; Recovery; Rehabilitation therapy; Rodent Model; Role; Running; Sensory; Signal Pathway; Signal Transduction; Specific qualifier value; Speed; Spinal; Spinal Cord; Spinal cord injury; Stroke; Structure; Swimming; Synapses; System; Testing; Therapeutic; Transgenic Mice; Treatment Efficacy; Walking; ankle joint; base; central pattern generator; computational network modeling; design; experimental study; fictional works; gait rehabilitation; improved; insight; neural circuit; operation; patch clamp; postsynaptic; recruit; response; sensory feedback; sensory gating; sensory input; therapy outcome; transcription factor; treadmill; treadmill training

ABSTRACT Rhythmic motor activities including walking, running and swimming are controlled by spinal circuits known as central pattern generators (CPGs). These circuits integrate descending command signals from the brain and ascending feedback signals indicating muscle length and force. The basic motor pattern for walking is generated by a CPG located within the lumbar spinal cord. Although the descending commands are compromised in spinal cord injury, afferent sensory signals retain CPG access and are thought to be recruited in gait rehabilitation therapies including treadmill training and epidural stimulation. More effective engagement of CPG elements via afferent signaling may improve therapeutic outcomes. Extensive data from the cat and the rat have identified hip extension and ankle load as strong modulators of stance and swing phase timing. Activation of these afferents perturb the gait cycle in ways that may or may not persist as a phase angle shift in subsequent cycles. These results have suggested a two-layer CPG structure in which a rhythm-generating (RG) layer acts as the metronome and directs a pattern-forming (PF) layer that recruits motoneurons. Sensory inputs to the RG neurons are expected to have the most profound effects on locomotor function. However, the organization of sensory feedback within the CPG is poorly understood, in part because the cellular identity and connectivity of CPG circuit elements have only begun to be described within the last decade. Recently, a population of neurons that are Shox2+/Chx10- (Shox2RG) has been putatively identified as part of the RG layer. The goal of the proposed project is to use a combination of biological and computational approaches to explore how sensory afferent inputs are organized within the RG layer of the CPG and contribute to stance/swing phase duration and onset. We hypothesize that evoked polysynaptic inputs to Shox2RG neurons underlie the afferent modulation of gait timing. We have preliminary data showing that stimulation of specific proprioceptive afferents results in postsynaptic responses in many Shox2 neurons. We will test integration of information from specific afferents in Shox2RG neurons by separately stimulating nerves innervating flexor and extensor muscles at the hip and ankle during visually-guided patch clamp of Shox2RG neurons in isolated spinal cord preparations. Intermediate neurons in these polysynaptic pathways will be tested to see whether convergence of afferent input is mediated at the level of Shox2RG neurons or before. The pattern of input measured in the quiescent preparation will be tested and compared to that obtained during fictive locomotion. These data will be integrated into a computational model of the CPG to test for the sufficiency of the experimental data to account for observed sensory modulation of CPG timing and activation. Results are expected to provide new insights into the fundamental operation of feedback systems affecting RG circuits which could be used in the design of effective therapeutics for the recruitment of locomotor CPGs in injury and disease.

摘要 包括行走、跑步和游泳在内的有节奏的运动活动由被称为 中央图案生成器(CPG)。这些电路整合来自大脑的下行命令信号，并 指示肌肉长度和力量的上行反馈信号。生成用于行走的基本运动模式 由位于腰椎脊髓内的CPG完成。尽管下行指令在脊椎上受到了威胁 脊髓损伤，传入感觉信号保留CPG通路，并被认为在步态康复中被招募 治疗包括跑步机训练和硬膜外刺激。通过以下方式更有效地接触中央人民政府成员 传入信号可能会改善治疗结果。来自猫和老鼠的大量数据已经确定了髋关节 伸展和脚踝负荷作为站姿和摆动阶段计时的强大调节器。这些传入神经的激活 扰乱步态周期的方式，可能会或可能不会持续作为相角移动在随后的周期。这些 结果表明，CPG是一种两层结构，其中节律生成(RG)层充当 节拍器，并指导一个模式形成(PF)层，招募运动神经元。视网膜节神经元的感觉输入 预计对运动功能有最深远的影响。然而，感官的组织 CPG内部的反馈知之甚少，部分原因是CPG的细胞身份和连接性 电路元件在过去十年里才开始被描述。最近，一群神经元 Are Shox2+/Chx10-(Shox2RG)已被推测为RG层的一部分。建议的目标是 项目是使用生物学和计算方法的组合来探索感觉传入是如何 输入是在CPG的RG层内组织的，并有助于站立/摆动阶段的持续时间和开始。 我们假设，对Shox2RG神经元的多突触输入是步态传入调制的基础 时机到了。我们有初步数据显示，刺激特定的本体感受性传入导致 许多Shox2神经元的突触后反应。我们将测试来自特定传入的信息的集成 分别刺激支配髋部和踝部屈伸肌神经的2RG神经元 在视觉引导下对分离的脊髓标本中的Shox2RG神经元进行膜片钳。中级 将对这些多突触通路中的神经元进行测试，以确定传入信息的汇聚是否参与了 在Shox2RG神经元或更早的水平上。在静态准备中测量的输入模式将为 测试并与在虚拟运动中获得的结果进行比较。这些数据将被集成到一个计算 用于检验实验数据是否足以解释观察到的感觉调节的CPG模型 CPG的时间选择和激活。预计结果将为以下基本操作提供新的见解 影响RG回路的反馈系统，可用于设计有效的治疗方法 运动CPG在损伤和疾病中的招募。