Functional consequences of silencing propriospinal pathways after SCI in the adult rat

成年大鼠 SCI 后沉默本体脊髓通路的功能后果

• 批准号: 8996734
• 负责人: David SK Magnuson
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996734
• 关键词: Address; Adult; Animals; Behavior; Behavioral; Beryllium; Bilateral; Cells; Cervical; Contusions; Data; Development; Dissection; Doxycycline; Excision; Forelimb; Gait; Grant; Health; Hindlimb; Histology; Injury; Interneurons; Locomotion; Locomotor Recovery; Lumbar Regions; Molecular; Motor Activity; Movement; Neural Pathways; Neurons; Neurotransmitters; Outcome; Pathway interactions; Phenotype; Physiological; Play; Population; Presynaptic Terminals; Process; Rattus; Recovery; Recovery of Function; Role; Severities; Spinal; Spinal Cord; Spinal cord injury; Subfamily lentivirinae; Synaptic Transmission; System; Testing; Tetracycline Control; Time; Virus; Walking; Weight-Bearing state; Work; arm; central pattern generator; drinking water; insight; kinematics; limb movement; neural circuit; neurotransmission; neurotropic; novel; research study; tool; vector; white matter

 DESCRIPTION (provided by applicant): Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits, many of the physiological details of those circuits and their contributions to functional recovery following spinal cord injury (SCI) remain t be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry by selectively and temporarily silencing neurotransmission. We will focus on two classes of spinal cord interneurons that have been described anatomically but remain a mystery functionally. These are the long-ascending propriospinal neurons (LAPNs) and the long descending propriospinal neurons (LDPNs) that together comprise a population we have termed "inter-enlargement" because they provide direct and indirect connections between the cervical and lumbar enlargements. The LAPNs and LDPNs are assumed to play critical roles in forelimb-hindlimb coordination in quadrupeds and to coordinate arm-swing and upper body-lower body movements in people. We hypothesize that LAPNs and LDPNs provide detailed temporal information about the step cycle and limb movement to the corresponding enlargement and thus play critical roles in forelimb-hindlimb coordination in the normal adult rat and in functional recovery following a contusive SCI. This proposal will directly test these hypotheses. Strong preliminary data unequivocally support the rationale of this proposal. Specifically: Aim 1 will determine the role of LAPNs/LDPNs in locomotion as we will independently silence these pathways bilaterally, ipsilaterally, and commissurally. Sophisticated gait and kinematic analyses, as well as terminal histological analyses will be used to quantify functional deficits. Aim 2 will determine the role of LAPNs/LDPNs in recovered function after SCI. These pathways will be silenced after functional recovery has plateaued following two different injury severities. Aim 3 will determine the role of LAPNs/LDPNs in the process of functional recovery after SCI. LAPN/LDPN networks will be silenced 3-10 and 28-35 days post-SCI, time periods of initial weight bearing and stabilization of locomotor function, respectively. Collectively, the proposed experiments will hopefully delineate how these pathways may be therapeutically targeted for functional recovery after SCI.

 描述（由适用提供）：尽管识别固有的脊柱运动电路已有100多年的历史，但仍确定了这些电路的许多物理细节及其对功能恢复后的贡献（SCI）持续得以确定。强大的分子工具的最新开发可以通过选择性和暂时沉默神经传递来实现神经记录的功能解剖。我们将专注于两类的脊髓中间神经元，这些神经元在解剖学上被描述但在功能上仍然是神秘的。这些是长期存在的前脊髓神经元（LAPN）和较长的降落前脊髓神经元（LDPN），它们共同组成了我们称为“互相间”的种群，因为它们提供了宫颈和腰部扩大之间的直接和间接连接。假定LAPN和LDPN在四足动物的前肢协调中扮演着关键角色，并协调人的手臂旋转和上身较高的身体运动。我们假设LAPN和LDPN提供了有关相应增强的步骤周期和肢体运动的详细临时信息，因此在正常成年大鼠的前肢配位中起着关键作用，并在连续SCI后进行功能恢复。该建议将直接检验这些假设。强有力的初步数据明确支持该提案的基本原理。具体来说：AIM 1将确定LAPN/LDPN在运动中的作用，因为我们将双侧，同侧和连锁店独立地沉默这些途径。复杂的步态和运动学分析以及终末组织学分析将用于量化功能性缺陷。 AIM 2将确定LAPN/LDPN在SCI后恢复功能中的作用。在两种不同的伤害严重程度后，功能恢复后，这些途径将被沉默。 AIM 3将确定LAPN/LDPN在SCI后功能恢复过程中的作用。 SCI后3-10和28-35天，LAPN/LDPN网络将分别沉默3-10天和28-35天，初始负重轴承的时间段和运动功能的稳定时间。总体而言，拟议的实验将有望描绘出如何将这些途径用于SCI后的功能恢复。