REORGANIZATION OF SPINAL INHIBITORY SYNAPTIC CIRCUITS AFTER NERVE INJURY

项目总结（见说明）：周围神经损伤后，轴突可以再生并重新建立周围的连接;然而，恢复的运动功能是不正常的。以前，我们已经表明，一些缺陷，如缺乏单突触反射，可以解释为永久回缩的LA本体感受突触从运动神经元。我们现在提出，电路重组是相对全球性的，也影响脊髓神经元间回路，不仅对受伤的运动神经元施加控制，但也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，但也明显是病态的。在拟议的工作中，我们将寻求确认脊髓神经元间回路的结构变化。这项工作将与项目1中提议的功能研究并行进行。我们将详细分析复发性和相互抑制的突触组织，这两个关键的抑制回路调节和模式运动神经元放电，因此肌肉收缩。复发性抑制通过一个名为Renshaw细胞的中间神经元对运动输出进行反馈控制，该中间神经元从运动轴突的脊髓内侧支接受直接兴奋。相互抑制由la抑制性中间神经元介导，所述la抑制性中间神经元接收与某些运动池（包括来自la传入的那些）共同的输入，并且用拮抗剂作用抑制运动神经元，从而允许例如在运动期间平滑的屈曲-伸展交替。我们假设，这两个中间神经元成为失神经分别从运动轴突和la传入神经损伤后。我们认为，这些改变导致脊髓回路的重大变化。在目标1中，我们将测试的假设，Renshaw细胞耦合到受损的运动轴突的神经支配导致突触重组的复发性抑制在整个脊髓节段。在目标2中，我们将检验以下假设：在相互通路中，抑制性和兴奋性中间神经元的差异性去传入导致有利于兴奋的平衡的转变。这些可以解释神经损伤后观察到的拮抗剂的过度共收缩。详细的连接分析将与技术的组合，包括新的逆行跨突触病毒示踪，允许揭示微电路连接。

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.