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

脊髓损伤后联合生物/仿生/康复治疗的关键脊髓回路变化可调节运动益处。

基本信息

批准号：
10447027
负责人：
Kimberly J Dougherty
金额：
$ 64.04万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

项目摘要

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.

抽象的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了解特定脊髓电路的可塑性以及硬膜外刺激对它们的影响。这项目建立在我们两个实验室开发的新观察和范式上。虽然我们越来越了解（a）在鉴定的分子遗传学水平上的（a）脊柱回路在脊髓损伤（SCI）的情况下，发育中间神经元类别和（b）脊柱可塑性，这两个信息类型仅在实验中很少集成，以充分利用其组合的能力。我们将使用一种新颖的范式，探索生物/病毒，仿生和康复的组合在大鼠和小鼠中完全SCI的疗法，以获得两种方法的能力 SCI后分析脊柱可塑性和病理。在此范式中的大鼠模型中，我们已经有了新数据表明完整的SCI后，康复和病毒衍生的BDNF治疗的结合导致由于这种组合处理，功能的显着增长。但是，在40％的治疗大鼠中最初的高收益达到了，观察到了高反射性的发展，导致大量崩溃功能。相反，观察到在接受硬膜外刺激（ES）的大鼠中治疗期间的脊髓（除了病毒驱动的BDNF和康复治疗）任何这样的过度反射症。该项目旨在利用这种范式来了解脊柱电路的可塑性支持功能，产生超反射和崩溃，并防止ES崩溃。我们还没有知道是否存在特定的时间窗口来防止ES功效。 ES以某种方式转向及时应用模型中的可塑性远离病理。我们的总体目标是表征ES的最佳时机，并详细了解导致的许多变化。我们寻求确定特定遗传鉴定的电路是否显示可塑性，并且是ES的靶标，以及这些电路如何贡献和改变以支持步行功能。我们还试图了解什么是出错的原因某些动物的功能崩溃未经ES治疗。我们计划的工作很重要且有影响力因为它将为SCI后的电路变化和功能提供新的启示。它将测试识别中间神经元如何脊髓中的种群和功能电路改变了。它将加深并扩大我们的理解硬膜外刺激在促进和塑造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，作用窗口以及相互作用。 ES是成为SCI条件的有前途且广泛适用的疗法，但我们对基本的理解作用机理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使用精确的生理和遗传学方法的差距。