Degenerative cervical myelopathy (DCM) is the most common cause of non-traumatic spinal cord injury (SCI),
characterized by pain, sensory deficits, fine motor dysfunction, and impaired gait and balance. Individuals with
DCM report upper limb functional deficits as particularly disabling due to decreased independence and quality
of life. Although surgical spinal cord decompression is the primary treatment of DCM and leads to functional
improvements for most patients, over 30%, do not achieve meaningful clinical recovery of motor function, and
over 40% report substantial residual impairment. Currently, no subsequent strategies are available to improve
neurological recovery following surgical intervention; as such, patients may continue to live with a disability.
Changes in neural circuits governing forelimb function in DCM are unknown. This knowledge gap impedes the
development of treatments to improve upper limb function after decompression surgery. Targeted
neuromodulation of spinal interneurons (INs) is a potential therapeutic strategy for DCM that is expected to
enhance forelimb function. V2a and dI3, genetically-defined spinal interneuron populations, have been shown to
play critical roles in integrating supraspinal, proprioceptive, and cutaneous sensory inputs in forelimb reaching
and grasping tasks.
Further, recent data demonstrate that spinal dI3 INs are crucial during neonatal development of motor circuits
and following SCI. As such, we hypothesize that following surgical decompression, activation of dI3 INs is
necessary for the recovery of forelimb function, and stimulation of these INs will enhance forelimb recovery. Aim
1 will determine the changes in descending cortical and peripheral sensory input onto cervical dI3 INs associated
with forelimb deficits in a mouse model of DCM. In Aim 2, we determine if dI3 INs underpin plasticity in forelimb
function that occurs after DCM and after surgical decompression. Finally, Aim 3 will examine the efficacy of
stimulating cervical dI3 INs in enhancing forepaw motor recovery following decompressive surgery.
The current proposal will be the first to determine how the neuronal integration of dI3 INs is altered in DCM such
that dI3 INs become a necessary component of the grasping function in DCM. The successful completion of this
project will guide future research by (1) determining the plasticity of dI3 INs within the forelimb neural network in
DCM, (2) uncovering the sensorimotor mechanism associated with dI3 neuronal plasticity in DCM, and (3)
demonstrating the efficacy of targeted neuromodulation as a promising treatment strategy for DCM. We expect
our results to facilitate the development of neuromodulation treatments to augment recovery of upper limb
function after surgery for DCM.
