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。

• 批准号: 10213148
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213148
• 关键词: Address; Afferent Pathways; Aftercare; Animals; Biological; Bionics; Brain-Derived Neurotrophic Factor; Caliber; Chronic; Collaborations; Combined Modality Therapy; Data; Development; Electrophysiology (science); Future; Genetic; Genetic Techniques; Goals; H-Reflex; Hyperreflexia; Hyporeflexia; In Vitro; Interneurons; Knowledge; Laboratories; Light; Locomotion; Locomotor Recovery; Mediating; Methods; Modeling; Molecular; Molecular Genetics; Motor; Mus; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathology; Pattern; Pharmacology; Physiological; Population; Preparation; Prevention; Process; Rattus; Recovery; Recovery of Function; Reflex action; Rehabilitation therapy; Research Personnel; Robot; Rodent; Sensory; Shapes; Signal Transduction; Spatial Distribution; Specificity; Spinal; Spinal Cord; Spinal cord injury; System; Tactile; Testing; Therapeutic; Time; Training; Transgenic Mice; Variant; Ventral Roots; Viral; Walking; Work; experimental study; functional improvement; improved; improved outcome; in vivo; loss of function; motor recovery; mouse model; neural stimulation; novel; novel therapeutic intervention; optogenetics; presynaptic; prevent; rehabilitation paradigm; relating to nervous system; sensory gating; side effect; skills; spinal nerve posterior root; spinal reflex; synergism; therapeutic target; treadmill

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.

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， 目的是了解特定脊髓回路的可塑性以及硬膜外刺激对这些回路的影响。的 该项目是建立在我们两个实验室开发的新的观察和范式。虽然我们 越来越多地了解两个（a）在分子遗传学水平上确定的脊髓回路 （B）脊髓损伤（SCI）背景下的脊髓可塑性，这两个 各种类型的信息很少通过实验进行整合，以充分利用其组合的力量。 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 在大鼠和小鼠中进行完全SCI的治疗，以获得两种方法的功效， 分析脊髓损伤后的脊髓可塑性和病理学。在这种模式的大鼠模型中，我们已经有了新的数据 表明完全SCI后康复和病毒衍生的BDNF治疗的组合导致 这种联合治疗的结果是功能显着改善。然而，在40%的治疗大鼠中， 在达到最初的高增益后，观察到反射亢进发展，导致 功能与此相反，在同样接受腰骶部硬膜外刺激（ES）的大鼠中观察到， 在治疗期间（除了病毒驱动的BDNF和康复治疗之外），没有大鼠显示 任何反射亢进。该项目旨在使用这种范式来理解脊髓回路的可塑性， 支持功能，产生反射亢进和塌陷，并通过ES防止这种塌陷。我们还不 知道是否存在ES在防止崩溃方面的有效性的特定时间窗口。ES在某种程度上 及时应用可使模型的可塑性过程远离病理。我们的总体目标是 描述ES的最佳时机，并详细了解导致的许多变化。我们寻求 确定特定的遗传识别电路是否显示出可塑性，并且是ES的目标，以及这些电路如何 有助于和改变以支持行走功能。我们还试图了解是什么出了差错， 在没有ES治疗的一些动物中的功能崩溃。我们计划的工作是重要和有影响力的 因为它将揭示脊髓损伤后电路的变化和功能。它将测试如何识别中间神经元 脊髓中的种群和功能回路发生改变。它将加深和拓宽我们的理解 硬膜外刺激在促进和塑造脊柱可塑性支持行走中的作用，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是 成为一个有前途的和广泛适用的治疗SCI条件，但我们的理解基本 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 利用精确的生理学和遗传学的方法。