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

 描述（由申请人提供）：尽管自认识到内在脊髓运动回路以来已有100多年，但这些回路的许多生理细节及其对脊髓损伤（SCI）后功能恢复的贡献仍有待确定。最近发展的强大的分子工具，使功能解剖的神经回路选择性和暂时沉默神经传递。我们将集中在两类脊髓中间神经元，已被描述解剖，但仍然是一个谜的功能。这些是长上行固有脊髓神经元（LAPN）和长下行固有脊髓神经元（LDPN），它们共同组成了我们称为“内扩大”的群体，因为它们在颈椎和腰椎扩大之间提供了直接和间接的联系。LAPNs和LDPNs被认为在四足动物的前肢-后肢协调中起着关键作用，并在人类中协调手臂摆动和上半身-下半身运动。我们假设，LAPN和LDPN提供详细的时间信息的步骤周期和肢体运动，以相应的扩大，从而发挥关键作用，在正常成年大鼠的前肢-后肢协调和功能恢复后，挫伤性SCI。本提案将直接检验这些假设。强有力的初步数据明确支持这一提议的理由。具体而言：目的1将确定LAPNs/LDPNs在运动中的作用，因为我们将独立地使这些通路双侧、同侧和连合沉默。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缺陷。目的2将确定LAPNs/LDPNs在SCI后功能恢复中的作用。在两种不同的损伤严重程度后，这些通路将在功能恢复达到平台后沉默。目的3将确定LAPNs/LDPNs在SCI后功能恢复过程中的作用。LAPN/LDPN网络将在SCI后3-10天和28-35天（分别为初始负重和运动功能稳定的时间段）沉默。总的来说，拟议的实验将有望描绘这些途径如何可能是治疗SCI后功能恢复的目标。

 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.