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

基本信息

批准号：
10005503
负责人：
Erik Zhi-Chong Li
金额：
$ 5.05万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
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/10005503
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 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

项目摘要

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，跑步和游泳中央模式发生器（CPG）。这些电路整合了大脑的下降命令信号上升反馈信号，表明肌肉长度和力。产生了步行的基本运动模式通过位于腰椎脊髓内的CPG。虽然在脊柱中降低命令被妥协绳索损伤，传入的感觉信号保留CPG访问，被认为是在步态康复中招募的包括跑步机训练和硬膜外刺激在内的疗法。通过CPG元素更有效地参与传入信号传导可以改善治疗结果。猫和大鼠的大量数据已经鉴定出髋关节伸展和踝关节载荷作为姿势和挥杆相时的强调调节器。这些传入的激活在随后的周期中可能会或可能不会将步态循环驱逐出来，也可能不会持续或可能不会持续为相角移动。这些结果提出了两层CPG结构，其中节奏生成（RG）层充当节拍器并指导募集运动神经元的图案形成（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。但是，感官的组织 CpG内的反馈知之甚少，部分原因是CPG的细胞身份和连通性在过去的十年中，电路元素才开始描述。最近，一群神经元 SHOX2+/CHX10-（SHOX2RG）已被推定为RG层的一部分。提议的目标项目是利用生物学和计算方法的组合来探索感官的传播输入是在CPG的RG层中组织的，并有助于姿势/摆动相位持续时间和发作。我们假设诱发了SHOX2RG神经元的多突触输入是步态传入调制的基础定时。我们有初步数据表明，刺激特定的本体感受传入导致许多SHOX2神经元中的突触后反应。我们将测试来自特定传入的信息集成通过分别刺激神经支配屈肌和伸缩肌肉的神经来刺激神经元的SHOX2RG神经元在孤立的脊髓制剂中的Shox2RG神经元的视觉引导贴片夹中。中间的这些多突触途径中的神经元将被测试，以查看传入输入的收敛性是否介导在Shox2RG神经元或之前的水平。在静止准备中测得的输入模式将是测试并与虚拟运动期间获得的测试并进行了比较。这些数据将集成到计算中 CPG的模型测试实验数据的充分性，以说明观察到的感觉调制 CpG的时序和激活。预计结果将为基本操作提供新的见解影响RG电路的反馈系统，可用于设计有效治疗剂招募伤害和疾病中的运动CPG。