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

 描述(申请人提供)：尽管对脊髓固有运动回路的认识已有100多年的历史，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未确定。最近发展的强大的分子工具通过选择性和暂时地沉默神经传递来实现对神经回路的功能性解剖。我们将专注于两类脊髓中间神经元，它们已经在解剖学上被描述，但在功能上仍然是一个谜。这些神经元是长上升的固有脊髓神经元(LAPN)和长下降的固有脊髓神经元(LDPN)，它们共同组成了一个我们称之为“间膨大”的群体，因为它们在颈椎和腰椎膨大之间提供了直接和间接的联系。LAPN和LDPN被认为在四足动物的前肢-后肢协调以及协调人的手臂摆动和上半身-下半身运动中起着关键作用。我们推测，LAPN和LDPN为相应的放大提供了有关步态周期和肢体运动的详细时间信息，从而在正常成年大鼠的前肢-后肢协调和挫伤后的功能恢复中发挥了关键作用。这项提议将直接检验这些假设。强劲的初步数据毫不含糊地支持这一提议的理由。具体地说：目标1将确定LAPN/LDPN在运动中的作用，因为我们将独立地使双侧、同侧和连合的这些通路沉默。将使用复杂的步态和运动学分析以及末端组织学分析来量化功能缺陷。目的2确定LAPN/LDPN在脊髓损伤后功能恢复中的作用。在两种不同的损伤程度后，这些通路将在功能恢复达到平台期后被沉默。目的3将确定LAPN/LDPN在脊髓损伤后功能恢复过程中的作用。LAPN/LDPN网络将在脊髓损伤后3-10天和28-35天分别被沉默，这段时间是最初的负重和运动功能稳定的时间段。总的来说，拟议的实验将有望描绘出这些通路如何在治疗上针对脊髓损伤后的功能恢复。

 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.