REORGANIZATION OF SPINAL INHIBITORY SYNAPTIC CIRCUITS AFTER NERVE INJURY

神经损伤后脊髓抑制突触回路的重组

• 批准号: 8562551
• 负责人: FRANCISCO J ALVAREZ
• 金额: $ 25.68万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8562551
• 关键词: Affect; Agonist; Animals; Axon; Complication; Coupled; Deafferentation procedure; Denervation; Equilibrium; Feedback; Fiber; Future; Global Change; Horns; Inhibitory Synapse; Injury; Instruction; Interneurons; Knowledge; Limb structure; Locomotion; Mediating; Modification; Motor; Motor Neurons; Motor output; Movement; Muscle; Muscle Contraction; Names; Natural regeneration; Nature; Nerve; Nerve Regeneration; Neurons; Operative Surgical Procedures; Output; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nerves; Peripheral nerve injury; Recovery; Recurrence; Reflex action; Renshaw Cell; Sensory; Spinal; Spinal Cord; Synapses; Techniques; Testing; Viral; Work; base; coping; dorsal horn; improved; injured; injury and repair; limb movement; monosynaptic reflex; motor deficit; nerve injury; neural circuit; neuropathology; novel; operation; stretch reflex; synaptic function

PROJECT SUMMARY (See Instructions): After peripheral nerve injuries axons can regenerate and reestablish connectivity in the periphery; however restored motor function is not normal. Previously we have shown that some deficits, like lack of monosynaptic reflexes, can be explained by the permanent retraction of la proprioceptive synapses from motoneurons. We now propose that circuit reorganizations are relatively global and affect also spinal intermeuronal circuits that exert control over not only injured motoneurons, but also other motor pools controlling the same limb. As a result, a novel limb control pattern emerges that allows some function, but is also clearly pathological. In the proposed work we will seek confirmation for structural changes in spinal interneuronal circuits. The work will parallel functional studies proposed in project 1. We will analyze in detail the synaptic organization of recurrent and reciprocal inhibition, two key inhibitory circuits that modulate and pattern motoneuron firing and therefore muscle contractions. Recurrent inhibition exerts feedback control of motor output through an interposed interneuron named the Renshaw cell that receives direct excitation from intraspinal collaterals of motor axons. Reciprocal inhibition is mediated by la inhibitory interneurons which receive common inputs with certain motor pools, including those from la afferents, and inhibit motoneurons with antagonist action allowing for example smooth flexion-extension alternation during movement. We hypothesize that both interneurons become denervated from respectively, motor axons and la afferents after nerve injury. We propose that these alterations cause major changes in spinal circuitry. In aim 1 we will test the hypothesis that denervation of Renshaw cells coupled to injured motor axons causes synaptic reorganizations of recurrent inhibition in the whole spinal segment. In aim 2 we will test the hypothesis that differential la de-afferentation of inhibitory and excitatory interneurons in reciprocal pathways causes a shift in balance favoring excitation. These could explain the excessive co-contraction of antagonists observed after nerve injuries. Detail analyses of connectivity will be performed with a combination of techniques, including novel retrograde transynaptic viral tracing that allows revealing microcircuit connectivity.

项目总结(见说明书)：周围神经损伤后，轴突可以再生并重新建立周围的连接；但恢复的运动功能不正常。以前我们已经证明，一些缺陷，如缺乏单突触反射，可以用运动神经元上本体感觉突触的永久回缩来解释。我们现在提出，回路重组是相对全局性的，也会影响脊髓间神经元回路，这些回路不仅对受损的运动神经元施加控制，而且还控制同一肢体的其他运动池。结果，一种新的肢体控制模式出现了，它允许一些功能，但也明显是病理性的。在拟议的工作中，我们将寻求证实脊髓神经元间回路的结构变化。这项工作将与项目1中提出的功能研究平行进行。我们将详细分析反复和相互抑制的突触组织，这是两个关键的抑制回路，调节和模式运动神经元放电，从而肌肉收缩。反复抑制通过一个名为Renshaw细胞的中间神经元对运动输出进行反馈控制，该神经元从运动轴突脊内侧支接受直接兴奋。相互抑制是由LA抑制中间神经元介导的，这些神经元接受与某些运动池的共同输入，包括来自LA传入的输入，并通过拮抗作用抑制运动神经元，例如在运动过程中平滑的屈伸交替。我们假设，在神经损伤后，两个中间神经元分别从运动轴突和LA传入中失神经。我们认为这些改变会导致脊髓回路的重大变化。在目标1中，我们将检验这样一个假设，即Renshaw细胞与受损运动轴突失神经耦合导致整个脊髓节段反复抑制的突触重组。在目标2中，我们将检验这样一种假设，即相互通路中抑制性和兴奋性中间神经元的不同LA去传入会导致有利于兴奋的平衡转移。这些可以解释神经损伤后观察到的拮抗剂过度共收缩的现象。将结合多种技术对连接性进行详细分析，包括允许揭示微电路连接性的新型逆行跨突触病毒跟踪。