Diversity Supplement to 2R01NS064004

Hyperreflexia is a devastating consequence of a lesion that damages the corticospinal tract (CST), in isolation, or at its origins in the cortex, or after a spinal cord injury (SCI). Multiple possible mechanisms underlie hyperreflexia.

One mechanism reflects aberrant sprouting of proprioceptive afferent (PA) fibers caudal to the injury after CST loss; with more PA fibers synapsing on motoneurons, the strength of PA reflexes may be augmented. PA terminals are normally under GABAergic presynaptic inhibitory regulation.

We hypothesize that PA sprouting after an injury occurs without associated GABAergic presynaptic regulation and that this can enhance reflex actions, leading to the clinical consequences of hyperreflexia, which is spasticity and spasms.

An overall focus of the parent R01 is to determine which motor impairments after a contusion SCI may be attributable to the loss of the CST, and then to initiate CST repair to target the particular impairment.

The proposed studies in this Diversity Supplement will examine the GABAergic dysregulation hypothesis in a unilateral pyramidal tract lesion (PTX), a model injury that severs all CST axons from one hemisphere without producing injury to the spinal cord, or a cervical spinal cord contusion, a preclinical injury model that lesions the CST as well as other pathways and components of the spinal cord.

We will use high-resolution morphologic analyses of PA synapse changes in the spinal gray matter (Aim 1) together with a novel multi-channel spinal cord electrophysiological recording approach (Aim 2) to address hyperreflexia. The focus for most of year 1 of the project will be on hyperreflexia after selective CST lesion (PTX).

Using this CST lesion model for Thelma's supplement project complements the parent R01 SCI focus by providing additional novel mechanistic underpinnings of the problem of hyperreflexia and how neuromodulation can ameliorate it. Near the completion of year 1 of the project, the candidate plans to submit an NRSA F31 application.

Successful completion of proposed year 1 studies will position the candidate to prepare a competitive NRSA F31 application based on a strong premise of impactful findings. It is expected that the SCI injury model will be examined after application submission, during year 2. Successful completion of the project will inform the mechanisms of hyperreflexia.

In addition to conducting the research, the candidate will learn new cutting-edge techniques that provide a novel and unique perspective on the problem of hyperreflexia and this will bolster her training related to physiological processes underlying changes in neuronal excitability after trauma. 1