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: 9810482
• 负责人: Travis Michael Rotterman
• 金额: $ 6.12万
• 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 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810482
• 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; Posture; 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 deficit; motor impairment; motor recovery; 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.

在周围神经损伤（PNI）后，感觉和运动神经元（MN）轴突都在损伤部位变性。 损伤，但两者都能再生到它们的肌肉目标。运动神经元重新获得产生肌肉力量的能力， 几乎一半的Ia组肌肉本体感受器重新神经支配肌梭，并响应于 肌肉长度然而，PNI后仍然存在的一个缺陷是Ia的中央投射分支 与MN形成单突触连接的传入神经回退并与运动池断开， 即使暂时成功的肌梭感受器神经再支配，也永远不会返回。该突触 当中枢运动网络失去反馈时， 调整姿势所需的机制。这种Ia型突触的丧失依赖于促炎性因子， 脊髓腹角的免疫反应然而，使用免疫抑制剂抑制免疫反应， 广谱抗生素米诺环素，完全防止Ia传入输入的结构损失， 轴突切断的MN。然而，主要的问题仍然存在，“这些保存的突触输入功能吗？”和 “保留Ia神经元能促进运动行为的恢复吗？”目的：探讨突触功能 和运动行为时，Ia传入神经和MN之间的连接被保留后PNI。 具体目的1，假设：挽救Ia - MN脊髓回路网络将促进肢体恢复 运动 具体目标2，假设：物理保存将挽救Ia产生的突触功能 运动神经元的传入神经 具体目标3，假设：Ia突触电流的放大足以恢复持续放电 运动神经元的损伤。 这些目的旨在系统地询问保存Ia传入突触的功能， 神经损伤所有这些实验都将在格鲁吉亚理工学院的赞助商，博士。 蒂姆科普，并从我们的合作者博士Young-Hui张额外的指导。两人都提供了他们的 他将在该项目的发展方面提供专业知识，并将监督所有三个目标的成功。