Propriopsinal neuron function in normal and post-SCI locomotion

正常和 SCI 后运动中的本体视神经元功能

• 批准号: 10563171
• 负责人: Simon Michael Danner
• 金额: $ 59.95万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563171
• 关键词: Adult; Anatomy; Animals; Axon; Behavior; Binding; Biomechanics; Cervical; Characteristics; Computer Models; Computer Simulation; Contusions; Data; Data Set; Development; Dissection; Experimental Models; Forelimb; Gait; Goals; Hindlimb; Injury; Interneurons; Ipsilateral; Knowledge; Label; Lateral; Left; Limb structure; Locomotion; Mediating; Modeling; Molecular; Movement; Musculoskeletal System; Neurons; Physiological; Play; Population; Publishing; Rattus; Recovery; Reverse engineering; Role; Running; Sensory; Source; Speed; Spinal; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Structure; Structure-Activity Relationship; Synapses; Techniques; Testing; Thoracic spinal cord structure; Validation; Vertebral column; Viral; Virus; Walking; animal data; biomechanical model; central pattern generator; design; experimental study; in silico; in vivo; kinematics; model development; neural circuit; neurotransmission; novel; novel therapeutics; predictive modeling; sensory input; tool

Abstract: Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits, many of the functional details of those circuits and their contributions to recovery following spinal cord injury (SCI) remain to be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling. We will combine these tools with sophisticated gait and kinematic analyses, that includes the full repertoire of speed dependent gaits, to provide the functional and anatomical information necessary for building and refining an advanced neuro- biomechanical computer model of the rat spinal cord, body and limbs. We will focus on two classes of spinal cord interneurons, the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons, that interconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements, and investigate their role in the intact spinal cord and after SCI using both hemisection and contusion models. Our preliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gait expression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisingly, silencing these neurons after an incomplete contusion injury results in better overground locomotion, a result that is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-based trans-synaptic labeling we will determine the sensory, descending and propriospinal inputs onto both LAPNs and LDPNs. We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as new anatomical data (Aim 2) to build and refine our computational model (Aim 3). Then, in vivo experiments and computer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissural LAPNs and LDPNs play in locomotor behavior, including the full range of locomotor gaits, and in recovered function after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of long propriospinal neurons represents an important step towards the development of new therapeutic tools for recovery after SCI.

翻译后摘要：尽管超过100年以来的认识，内在的脊髓运动回路，许多 这些回路的功能细节及其对脊髓损伤（SCI）后恢复的贡献 还有待确定。最近发展的强大的分子工具，使功能解剖的 通过可逆沉默神经传递和跨突触标记的神经回路。我们将联合收割机 具有复杂步态和运动学分析的工具，包括速度依赖步态的全部功能， 为建立和完善先进的神经系统提供必要的功能和解剖信息， 大鼠脊髓、身体和四肢的生物力学计算机模型。我们将重点介绍两类脊柱 脊髓中间神经元，长上升（LAPNs）和下降（LDPNs）propriospinal神经元， 在两个放大图中互连前肢和后肢回路以及中央模式发生器，以及 使用半切和挫伤模型研究它们在完整脊髓和SCI后的作用。我们 初步数据表明，这些LAPN/LDPN是参与速度依赖性步态的重要组成部分 表情沉默这些神经元部分地使左右肢在每个腰带处重叠。令人惊奇的是， 在不完全挫伤后沉默这些神经元会导致更好的地上运动， 根据目前的知识和对未受伤动物的观察，这很难调和。使用基于病毒的 跨突触标记，我们将确定两个LAPN的感觉，下行和脊髓本体输入 和LDPN。我们将利用现有的和新的生理和生物力学数据（目标1）以及新的 解剖数据（目标2），以建立和完善我们的计算模型（目标3）。然后，体内实验和 将并行进行计算机建模（目标4），以确定同侧和连合的作用， LAPNs和LDPNs在运动行为中起作用，包括运动步态的全方位，以及在恢复中起作用。 半切和不完全挫伤后的功能。我们建议，更深入地了解长期 脊髓本体神经元代表了朝着开发新的治疗工具的重要一步， SCI后的康复