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: 10369724
• 负责人: Simon Michael Danner
• 金额: $ 59.9万
• 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/10369724
• 关键词: Adult; Anatomy; Animals; Axon; Behavior; Biomechanics; Cervical; Characteristics; Computer Models; Computer Simulation; Contusions; Data; Data Set; Development; Dissection; 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; Viral; Virus; Walking; animal data; base; 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.

摘要：尽管自认可固有的脊柱运动电路以来有100多年 这些电路的功能细节及其对脊髓损伤后恢复的贡献（SCI） 仍有待确定。强大的分子工具的最新开发可以使功能解剖 神经电路通过可逆地沉默神经传递和反式突触标记。我们将结合这些 具有复杂步态和运动学分析的工具，其中包括依赖速度步态的完整曲目， 提供构建和完善高级神经 - 的功能和解剖学信息 大鼠脊髓，身体和四肢的生物力学计算机模型。我们将专注于两类脊柱 绳索中间神经元，长升（LAPN）和下降（LDPN），脊髓神经元， 在两个扩大中的前肢和后肢电路和中央模式发生器互连， 使用半分裂和挫伤模型研究它们在完整的脊髓和SCI之后的作用。我们的 初步数据表明，这些LAPN/LDPN是与速度依赖步态有关的重要组成部分 表达。沉默这些神经元在每个腰带处部分地将左右四肢脱离。出奇， 在不完全挫伤损伤后沉默这些神经元会导致更好的地球运动，结果 这很难根据当前的知识和未受伤的动物的观察结果进行调和。使用基于病毒的 跨突触标签我们将确定两个LAPN的感觉，降和前脊髓输入 和LDPN。我们将同时利用现有的和新的生理和生物力学数据（AIM 1）以及新的 解剖数​​据（AIM 2）以构建和完善我们的计算模型（AIM 3）。然后，体内实验和 计算机建模将并行执行（AIM 4），以确定同侧和合并的角色 LAPN和LDPN在运动行为中发挥作用，包括全范围的运动步态，并在恢复 半剖分后的功能和不完全的挫伤损伤。我们建议对长期有更深入的了解 天脊髓神经元代表着开发新的治疗工具的重要一步 科学后的恢复。