Preservation of sensory la afferent boutons on motoneurons after peripheral nerve injury restores synaptic transmissions and rescues whole limb kinematics

周围神经损伤后运动神经元上感觉传入神经元的保留可恢复突触传递并挽救整个肢体运动学

• 批准号: 10462090
• 负责人: Travis Michael Rotterman
• 金额: $ 3.32万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462090
• 关键词: 3-Dimensional; Adult; Animal Behavior; Antibiotics; Award; Axon; Back; Behavior; Closure by clamp; Data; Dendrites; Development; Disease; Electrophysiology (science); Ensure; Feedback; Fire - disasters; Goals; Image; Immune response; Inflammatory; Injury; Joints; Knowledge; Length; Light; Limb structure; Locomotion; Measures; Mediating; Microscopy; Minocycline; Motor; Motor Activity; Motor Neurons; Muscle; Muscle Spindles; Natural regeneration; Nerve; Nerve Regeneration; Nervous System Trauma; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Pharmacology; Postural adjustments; Presynaptic Terminals; Proprioceptor; Rattus; Recovery; Recovery of Function; Roentgen Rays; Sensory; Site; Spinal; Spinal Cord; Spinal cord injury; Stretching; Structure; Synapses; Synaptic Potentials; Synaptic Transmission; Synaptic plasticity; Technical Expertise; Techniques; Testing; Therapeutic; Time; Tissues; Training; Trauma; Ventral Horn of the Spinal Cord; Work; assault; base; behavioral study; design; experimental study; functional restoration; improved; in vivo; insight; kinematics; limb movement; motor behavior; motor deficit; motor impairment; motor recovery; muscle reinnervation; nerve injury; peripheral nerve regeneration; preservation; prevent; receptor; reinnervation; response; stretch reflex; success; synaptic function; synaptogenesis; voltage clamp

Following peripheral nerve injury (PNI), both sensory and motoneuron (MN) axons degenerate at the site of injury, but both regenerate to their muscle targets. Motoneurons regain the ability to produce muscle force and almost half of group Ia muscle proprioceptors reinnervate muscle spindles and fire in response to changes in muscle length. However, one deficit that remains after PNI is that the central projecting branch of the Ia afferents that forms monosynaptic connections with the MNs dies back and disconnects from the motor pool, never to return even with provisionally successful reinnervation of muscle spindle receptors. This synaptic retraction has a major impact on common motor activities as the central motor network losses the feedback mechanism necessary for postural adjustments. This Ia synaptic loss is dependent on a pro-inflammatory immune response in the ventral horn of the spinal cord. However, suppressing the immune response using the broad-spectrum antibiotic minocycline, completely prevents the structural loss of Ia afferent inputs on axotomized MNs. However, the major questions remain, “are these preserved synaptic inputs functional?” and “does preservation of Ia’s improve recovery of motor behavior?” Objective: Investigate synaptic function and motor behavior when the connections between Ia afferents and MNs are preserved following PNI. Specific Aim 1, Hypothesis: Rescuing Ia - MN spinal circuit network will promote recovery of limb movement. Specific Aim 2, Hypothesis: Physical preservation will rescue function at synapses made by Ia afferents on motoneurons. Specific Aim 3, Hypothesis: Amplification of Ia synaptic current is sufficient to restore sustained firing in motoneurons after injury. These aims are designed to systematically interrogate the function of preserved Ia afferent synapses after nerve injury. All of these experiments will take place at Georgia Tech under the direction of the sponsor, Dr. Tim Cope, and additional guidance from our collaborator Dr. Young-Hui Chang. Both have provided their expertise in the development of this project and will oversee the success of all three aims.

周围神经损伤 (PNI) 后，感觉轴突和运动神经元 (MN) 轴突在损伤部位退化 受伤，但它们的肌肉目标都恢复了产生肌肉力量和能力的能力。 几乎一半的 Ia 组肌肉本体感受器重新支配肌梭并响应肌梭的变化 然而，PNI 后仍然存在的一个缺陷是 Ia 的中央突出分支。 与 MN 形成单突触连接的传入神经消失并与运动池断开， 即使肌梭受体暂时成功重新神经支配，这种突触也永远不会返回。 由于中央运动网络失去反馈，收缩对常见运动活动有重大影响 这种 Ia 突触损失依赖于促炎性机制。 然而，利用脊髓腹角的免疫反应来抑制免疫反应。 广谱抗生素米诺环素，完全防止 Ia 传入输入的结构损失 然而，主要问题仍然存在，“这些保留的突触输入是否有功能？” “保留 Ia 是否可以改善运动行为的恢复？” 目的：研究突触功能 当 Ia 传入神经和 MN 之间的连接在 PNI 后被保留时，以及运动行为。 具体目标1、假设：抢救Ia-MN脊髓回路网络将促进肢体康复 移动。 具体目标 2，假设：物理保存将挽救 Ia 产生的突触功能 运动神经元的传入。 具体目标 3，假设：Ia 突触电流的放大足以恢复持续放电 损伤后的运动神经元。 这些目的旨在系统地询问传入突触的保存功能 所有这些实验都将在佐治亚理工学院的赞助商 Dr. 的指导下进行。 Tim Cope 和我们的合作者 Young-Hui Chang 博士都提供了他们的指导。 该项目开发方面的专业知识，并将监督所有三个目标的成功。