NIH/NINDS R01 NS112304; 03/15/2021 - 01/31/2026
PIs: Danner SM, Magnuson DS, Whittemore SR

Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits, many of the functional details of those circuits and their contributions to recovery following spinal cord injury (SCI) remain to be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling.

We will combine these tools with sophisticated gait and kinematic analyses, that includes the full repertoire of speed dependent gaits, to provide the functional and anatomical information necessary for building and refining an advanced neurobiomechanical computer model of the rat spinal cord, body and limbs. We will focus on two classes of spinal cord interneurons, the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons, that interconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements, and investigate their role in the intact spinal cord and after SCI using both hemisection and contusion models.

Our preliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gait expression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisingly, silencing these neurons after an incomplete contusion injury results in better overground locomotion, a result that is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-based trans-synaptic labeling we will determine the sensory, descending and propriospinal inputs onto both LAPNs and LDPNs.

We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as new anatomical data (Aim 2) to build and refine our computational model (Aim 3). Then, in vivo experiments and computer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissural LAPNs and LDPNs play in locomotor behavior, including the full range of locomotor gaits, and in recovered function after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of long propriospinal neurons represents an important step towards the development of new therapeutic tools for recovery after SCI.