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.

项目概要/摘要 周围神经损伤 (PNI) 后，感觉和运动神经元 (MN) 轴突在损伤部位远端退化 但两者都保持了再生和重新支配肌肉目标的能力。 产生肌肉力量，大部分肌肉传入神经（“本体传感器”）重新支配肌肉 然而，无论外周再生是否成功， 经历 PNI 的患者继续遭受终生运动并发症，例如肢体关节间 该提议的中心假设是可塑性。 神经损伤后运动前脊髓回路的连接导致永久性运动缺陷。 具体目标 1 (K99)，假设：神经后脊髓前运动中间神经元的过度兴奋驱动 横断促进肌肉共同收缩，本体感受器 Ia 传入轴突是脊髓 MN 上的突触。 神经切断后 IX 层永久降解，导致牵张反射丧失。 相同的传入神经在背角深部使它们的突触加倍，那里有异质的前运动群体 这些神经元的一个特定子集是表达 Isl1 的神经元。 神经元具有谷氨酸能，投射到不同的运动池，并接收本体传感器输入。 这些细胞的突触驱动可以促进肌肉共同收缩，这将使用以下方法进行研究。 多电极阵列（MEA）和转基因模型的组合方法来识别和操纵 使用化学遗传学研究 Isl1+ 神经元的活动，试图在受伤后恢复正常的肌肉活动。 具体目标 2 (R00)，假设：神经挤压消除了 Ia 传入神经的突触前抑制并导致 牵张反射力过大 与神经切断不同，挤压伤后牵张反射力不仅会增强。 恢复它会导致肌肉力量超正常水平，这两者之间有一个显着的解剖学差异。 损伤类型是 Ia 传入突触在挤压再生后在 MN 上恢复，但它们失去了 大量突触前抑制按钮（p-按钮）控制 Ia 突触传递。 这一目标的提升在于，p-boutons 的损失是造成夸张的牵张反射反应的原因 在此目标中，将利用化学遗传学来激活和/或抑制提供的 Gad2+ 中间神经元。 牵张反射期间的突触前抑制，以研究调节这些细胞的活性如何影响 然后，提供剩余 p-boutons 的 Gad2 中间神经元将被刺激。 最后，将通过化学遗传学来减少挤压后的反射亢进。 挤压后研究传入神经的持续活动是否可以防止 p-bouton 的丢失并恢复正常 响应拉伸而产生肌肉力量。