Crucial spinal circuit changes that mediate locomotion benefits of combined biological/bionic/rehabilitation therapies after spinal cord injury.

摘要 我们的项目代表了两个具有不同但互补技能的实验室的新合作， 目的了解特定脊髓环路的可塑性以及硬膜外刺激对其的影响。这个 该项目建立在我们两个实验室开发的新观察和新范例的基础上。虽然我们 在分子遗传学水平上对两个(A)脊髓环路有越来越多的了解 发育中间神经元分类和(B)脊髓损伤(SCI)背景下的脊髓可塑性，这两个 只有少数几种类型的信息被试验性地集成起来，以充分利用它们组合的力量。 我们将使用一种新的范式，探索生物/病毒、仿生和康复的结合 治疗完全性脊髓损伤的大鼠和小鼠，以获得这两种方法的力量 脊髓损伤后脊髓可塑性和病理学分析。在这个范例中的老鼠模型中，我们已经有了新的数据 显示完全性脊髓损伤后康复和病毒来源的BDNF治疗相结合导致 这种联合治疗的结果是显著提高了功能。然而，在40%的治疗大鼠中，在 最初获得的高收益，观察到反射亢进的发展，导致了大的崩溃 功能。相反，观察到在同样接受硬膜外刺激(ES)的大鼠中， 脊髓治疗期间(除了病毒驱动的脑源性神经营养因子和康复治疗外)没有大鼠表现出 任何这样的反射亢进。这个项目试图使用这个范例来理解脊髓回路的可塑性 支持功能，造成反射亢进和崩溃，并防止这种崩溃与ES。我们现在还不知道 了解ES在防止坍塌方面的有效性是否存在特定的时间窗口。在某种程度上，ES掌舵着 在模型中及时应用可塑性远离病理的过程。我们的总体目标是 确定ES的最佳时机，并详细了解由此产生的许多变化。我们寻求 确定特定的遗传识别电路是否表现出可塑性，是否是ES的目标，以及这些电路如何 贡献和改变以支持行走功能。我们还试图了解是什么出了差错 一些动物在没有ES治疗的情况下功能崩溃。我们计划的工作很重要，也很有影响力 因为它将为脊髓损伤后的电路变化和功能提供新的线索。它将测试如何识别出中间神经元 脊髓中的种群和功能回路会发生变化。它将加深和拓宽我们的理解 硬膜外刺激在促进和塑造支持行走的脊柱可塑性方面的作用，并确定 硬膜外刺激与其他疗法的治疗靶点、作用窗口和相互作用。ES IS 成为治疗脊髓损伤的一种有前途和广泛适用的疗法，但我们对基础知识的理解 作用机制和与其他疗法的相互作用仍然有限。这个项目开始解决这个问题 GAP使用精确的生理和遗传方法。

Abstract Our project represents a new collaboration of two laboratories with differing but complementary skills, with the goal of understanding plasticity of specific spinal circuits and the effects of epidural stimulation on these. The project is built on new observations and paradigms developed by both our laboratories. Although we understand increasingly more about both (a) spinal circuits at the level of molecular genetics identified developmental interneuron classes and (b) spinal plasticity in the context of spinal cord injury (SCI), these two types of information are only rarely integrated experimentally to fully leverage the power of their combination. We will use a novel paradigm which explores the combination of biological/viral, bionic and rehabilitation therapies in complete SCI in both the rat and the mouse in order to obtain the power of both approaches in analyzing spinal plasticity and pathology after SCI. In the rat model in this paradigm we already have new data showing that the combination of rehabilitation and virally derived BDNF treatment after complete SCI leads to significant gains in function as a result of this combination treatment. However, in 40% of the treated rats, after the initial high gains achieved, it was observed that a hyperreflexia developed, causing a large collapse in function. In contrast, it was observed that in rats which also receive epidural stimulation (ES) of lumbosacral spinal cord during treatment (in addition to the viral driven BDNF and rehabilitative treatments) no rats showed any such hyperreflexia. This project seeks to use this paradigm to understand plasticity of spinal circuits that support function, create hyperreflexia and collapse, and that prevent such collapse with ES. We do not yet know if there exist specific time windows for the ES efficacy in preventing collapse. The ES in some way steers the course of plasticity away from pathology in the model when applied in a timely way. Our overall Aims are to characterize the best timing of ES and to understand in detail many of the changes that result. We seek to determine if specific genetically identified circuits show plasticity, and are targets of ES, and how these circuits contribute and alter in order to support walking functions. We also seek to understand what goes awry to cause collapse of function in some animals without ES treatment. Our planned work is important and impactful because it will shed new light on circuit changes and function after SCI. It will test how identified interneuron populations and functional circuits in the spinal cord are altered. It will deepen and broaden our understanding of the actions of epidural stimulation in promoting and shaping spinal plasticity supporting walking, and identify the therapeutic targets, windows of action, and interactions of epidural stimulation with other therapies. ES is becoming a promising and broadly applicable therapy for SCI conditions, but our understanding of fundamental mechanisms of action and interaction with other therapies remains limited. This project begins to address this gap using precise physiological and genetic methods.