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：尽管自认识内在脊髓运动回路以来已有 100 多年的历史，但许多 这些回路的功能细节及其对脊髓损伤 (SCI) 后恢复的贡献 仍有待确定。最近开发的强大分子工具使得能够对 通过可逆地沉默神经传递和跨突触标记来调节神经回路。我们将结合这些 tools with sophisticated gait and kinematic analyses, that includes the full repertoire of speed dependent gaits, 提供构建和完善高级神经系统所需的功能和解剖信息 大鼠脊髓、身体和四肢的生物力学计算机模型。我们将重点关注两类脊柱 脊髓中间神经元，即长上升（LAPN）和下降（LDPN）本体脊髓神经元 将两个放大中的前肢和后肢电路以及中央模式发生器互连起来，并且 使用半切模型和挫伤模型研究它们在完整脊髓和 SCI 后的作用。我们的 初步数据表明，这些 LAPN/LDPN 是速度依赖步态的重要组成部分 表达。沉默这些神经元可以部分解耦每个腰带处的左右肢体。出奇， 在不完全挫伤后沉默这些神经元会导致更好的地面运动，结果 根据目前的知识和对未受伤动物的观察，很难调和这一点。使用基于病毒的 跨突触标记，我们将确定两个 LAPN 的感觉、下行和本体脊髓输入 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）来构建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 LAPN 和 LDPN 在运动行为中发挥作用，包括全方位的运动步态，并在恢复中发挥作用 半截断和不完全挫伤后的功能。我们建议更深入地了解长期 本体脊髓神经元代表了开发新治疗工具的重要一步 SCI后恢复。