Plasticity of spinal neural networks directly impacts motor control following peripheral nerve injury

脊髓神经网络的可塑性直接影响周围神经损伤后的运动控制

• 批准号: 10588691
• 负责人: Travis Michael Rotterman
• 金额: $ 10.28万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588691
• 关键词: Acute; Anatomy; Anterior; Award; Axon; Axotomy; Cells; Central Nervous System; Crush Injury; Development; Disease model; Distal; Electric Stimulation; Environment; Excision; Fire - disasters; Gastrocnemius Muscle; Generations; Genes; Genetic; Glutamates; Goals; Hyperreflexia; Implant; Individual; Injury; Interneurons; Joints; Knowledge; Limb structure; Maps; Medial; Motion; Motor; Motor Neurons; Motor Pathways; Movement; Muscle; Muscle Spindles; Natural regeneration; Nerve; Nerve Crush; Nervous System; Neurons; Pathway interactions; Patients; Performance; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Phenotype; Physiological; Population; Process; Production; Proprioceptor; Recovery; Reflex action; Robotics; Sensory; Site; Source; Spinal; Spinal Cord; Stretching; Synapses; Synaptic Transmission; Testing; Transgenic Mice; Transgenic Model; Ventral Horn of the Spinal Cord; Vertebral column; Work; antagonist; arm; axonal degeneration; behavioral response; cell type; comparison control; density; designer receptors exclusively activated by designer drugs; dorsal horn; experience; experimental study; in vivo; motor control; motor deficit; mouse model; multi-electrode arrays; nerve injury; nerve transection; neural; neural network; neurobiotin; peripheral nerve damage; preservation; presynaptic; prevent; receptor; recruit; reinnervation; response; sensory feedback; skills; stem; stretch reflex; synaptic inhibition; synaptogenesis

Project Summary/Abstract Following peripheral nerve injury (PNI), sensory and motoneuron (MN) axons degenerate distal to the injury site but both maintain the ability to regenerate and reinnervate their muscle targets. Motoneurons regain the ability to produce muscle force and the majority of the muscle afferents (“propriosensors”) reinnervate the muscle spindles and fire in response to muscle stretch. However, regardless of successful peripheral regeneration, patients who experience PNI continue to suffer from life-long motor complications such as limb inter-joint discoordination and muscle co-contraction. The central hypothesis of this proposal is that plasticity in the connectivity of pre-motor spinal circuits following nerve injury results in permanent motor deficits. Specific Aim 1 (K99), hypothesis: hyper-excitatory drive to the spinal pre-motor interneurons following nerve transection promotes muscle co-contraction. Proprioceptor Ia afferent axons that synapse on spinal MNs are permanently degraded in lamina IX following nerve cut resulting in the loss of the stretch reflex. However, these same afferents double their synapses in the deep dorsal horn, where a heterogenous population of pre-motor interneurons reside. One specific subset of these neurons are those that express Isl1. This specific population of neurons are glutamatergic, project to divergent motor pools, and receive propriosensor input. An imbalance in synaptic drive to these cells could facilitate muscle co-contraction. This will be investigated using a combinatory approach with multi-electrode arrays (MEAs) and transgenic models to identify and manipulate the activity of the Isl1+ neurons using chemogenetics in an attempt to restore normal muscle activity following injury. Specific Aim 2 (R00), hypothesis: nerve crush abolishes presynaptic inhibition of Ia afferents and results in an exaggerated stretch reflex force. In difference to a nerve cut, following a crush injury the stretch reflex is not only restored it results in supra-normal levels of muscle force. One striking anatomical difference between these two injury types is that Ia afferent synapses are restored on MNs following crush regeneration but they lose a significant number of presynaptic inhibitory boutons (p-boutons) that gate Ia synaptic transmission. The hypothesize of this aim is that the loss in p-boutons is responsible for the exaggerated stretch reflex response after crush. In this aim will utilize chemogenetics to activate and/or suppress Gad2+ interneurons that provide presynaptic inhibition during the stretch reflex to investigate how modulating the activity of these cells impact the strength of the reflex. Then, Gad2 interneurons that provide the remaining p-boutons will be stimulated using chemogenetics to reduces hyperreflexia after crush. Finally, electrical stimulation will be provided to the nerve after crush to investigate if sustained activity of the afferents prevents the loss of p-boutons and restores normal muscle force generation in response to stretch.

项目摘要/摘要 遵循周围神经损伤（PNI），感觉神经元（MN）轴突脱离损伤部位的轴突 但是，两者都保持着再生和加剧其肌肉靶标的能力。运动神经元仍然能力 产生肌肉力量和大多数肌肉传入（“ propriosenors”）重新染色肌肉 响应肌肉伸展的纺锤和火。但是，无论成功的周围再生如何 经历PNI的患者继续遭受终身运动并发症（例如肢体之间的运动） 脱节和肌肉共同收缩。该提议的中心假设是 神经损伤后脊柱前回路的连通性导致永久运动缺陷。 特定的目标1（K99），假设：神经后脊柱前动物中间神经元的高兴奋性驱动器 交易促进肌肉共同收缩。脊柱MN突触的本体感受器IA传入轴突是 神经切割后，在椎板IX中永久退化，导致伸展反射的丧失。但是，这些 相同的传入将其突触加倍，在深层角中，其中异源性前运动群体 中间神经元居住。这些神经元的一个特定子集是表达ISL1的神经元。这个特定的人群 神经元是谷氨酸能的，投影了发散的运动池，并接收原则传感器输入。不平衡 在突触驱动到这些细胞中，可以促进肌肉的共同收缩。这将使用 与多电极阵列（MEA）和转基因模型的组合方法，以识别和操纵 ISL1+神经元使用化学遗传学的活性试图恢复受伤后正常的肌肉活动。 特定目标2（R00），假设：神经挤压废除了IA传入的突触前抑制，并导致 夸张的拉伸反射力。在神经切割的差异中，紧迫伤害后，伸展反射不仅是 恢复它会导致肌肉上的超正常水平。这两个罢工的解剖学差异 损伤类型是，粉碎再生后的MN恢复了IA传入突触，但它们失去了 大量的突触前抑制胸子（P-Boutons），该栅极IA突触传播。这 假设这个目的是p-bouton的损失是夸张的伸展反应响应的原因 迷恋后。在此目标中，将利用化学遗传学激活和/或抑制提供的GAD2+中间神经元 拉伸反射期间突触前抑制作用，以研究这些细胞活性如何影响 反射的强度。然后，使用提供剩余p-bouton的GAD2中间神经元将被刺激 化学遗传学以减少粉碎后的超反射症。最后，将向神经提供电刺激 粉碎后，调查传入的持续活动是否可以防止p-bouton的损失并恢复正常 响应拉伸的肌肉力产生。