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: 10238885
• 负责人: Erik Zhi-Chong Li
• 金额: $ 4.21万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238885
• 关键词: Ablation; Affect; Alpha Rhythm; Ankle; Biological; Brain; Cervical spinal cord injury; Chest; Clinical; Computational Technique; Computer Models; 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; 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; 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; therapeutically effective; 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.

抽象的 有节奏的运动活动，包括步行、跑步和游泳，是由称为“脊髓回路”的脊髓回路控制的。 中央模式发生器（CPG）。这些电路整合了来自大脑的下行命令信号 指示肌肉长度和力量的上升反馈信号。生成行走的基本运动模式 由位于腰脊髓内的 CPG 驱动。尽管下行命令在脊柱中受到损害 脊髓损伤时，传入感觉信号保留 CPG 通路，并被认为可用于步态康复 疗法包括跑步机训练和硬膜外刺激。 CPG 元素更有效地参与 传入信号可以改善治疗结果。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立和摆动阶段时间的强大调节器。这些传入神经的激活 以可能或可能不会在后续周期中持续存在相位角偏移的方式扰动步态周期。这些 结果表明有一个两层 CPG 结构，其中节律生成 (RG) 层充当 节拍器并指导招募运动神经元的模式形成（PF）层。 RG 神经元的感觉输入 预计对运动功能具有最深远的影响。然而，感觉的组织 CPG 内的反馈知之甚少，部分原因是 CPG 的细胞身份和连接性 电路元件直到最近十年才开始被描述。最近，一群神经元 Shox2+/Chx10- (Shox2RG) 已被推定为 RG 层的一部分。拟议的目标 该项目旨在结合生物学和计算方法来探索感觉传入如何 输入在 CPG 的 RG 层内组织，并有助于站立/摆动阶段的持续时间和开始。 我们假设 Shox2RG 神经元的诱发多突触输入是步态传入调节的基础 定时。我们有初步数据表明，刺激特定的本体感觉传入会导致 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整合 Shox2RG 神经元通过分别刺激支配髋部和踝部屈肌和伸肌的神经 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。中间的 将测试这些多突触通路中的神经元，以确定传入输入的收敛是否受到介导 在 Shox2RG 神经元水平或之前。在静态准备中测量的输入模式将是 进行测试并与虚拟运动期间获得的结果进行比较。这些数据将被整合到计算中 CPG 模型，用于测试实验数据是否足以解释观察到的感觉调制 CPG 计时和激活。结果预计将为基本运作提供新的见解 影响 RG 回路的反馈系统可用于设计有效的治疗方法 损伤和疾病中运动 CPG 的募集。