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.
This grant examines the role of the long ascending and descending propriospinal neurons (LAPNs, LDPNs) in the inter-enlargement control of forelimb hindlimb coordination. Using a novel two virus vector system, we can transiently silence these neural pathways and examine the effects on both normal walking behavior and their contribution to functional recovery after spinal cord injury (SCI). Successful completion of the experiments outlined in this proposal would provide important insight in the potential for harnessing these pathways to enhance functional recovery after SCI.
|Pocratsky, Amanda M; Burke, Darlene A; Morehouse, Johnny R et al. (2017) Reversible silencing of lumbar spinal interneurons unmasks a task-specific network for securing hindlimb alternation. Nat Commun 8:1963|
|Nielson, Jessica L; Guandique, Cristian F; Liu, Aiwen W et al. (2014) Development of a database for translational spinal cord injury research. J Neurotrauma 31:1789-99|