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The Effects of Nervous System Injury on Sensory and Motor Function


In this thesis, I will discuss three studies in relation to the recovery of function after nervous system injury in hopes of answering a vital question. How do manipulations of specific inhibitors of regeneration affect the functional recovery of rodents after SCI, and what circuit-level change(s) might underlie these functional changes?

Our first study investigates the mechanism of peripheral conditioning by using a demyelinating reagent, ethidium bromide (EtBr), to test whether demyelination, rather than mechanical nerve crush of axons is sufficient to induce the regeneration-promoting, conditioning effect. After assessing regeneration, as well as functional recovery through behavioral studies, we found that demyelination is a likely contributor to the conditioning effect. These studies provide the framework for further investigation into the mechanisms of the conditioning effect.

The second study combines our novel EtBr-mediated conditioning paradigm with inhibition of the repulsive axon guidance molecule Wnt. In these studies, bone marrow stromal cells (BMSCs) secreting the Wnt inhibitor frizzled-related peptide 2 (SFRP2), were grafted at a cervical level 1 (C1) lesion site caudal to main body of dorsal funiculi, second order, sensory neurons. In our studies, better sensory functional recovery was observed in animals with SFRP2 treatment compared to naive animals. Circuit level analysis demonstrated that axons of conditioned sensory neurons sprouted and made new connections with a small subset of dorsal column neurons, caudal to the main body of dorsal column nuclei. Transient silencing or re-transection of this remodeled circuit at thoracic level 10 (T10) resulted in the loss of recovered sensory function, indicating that this remodeled circuit is sufficient to confer the observed recovery of sensory function.

Our third study aims to minimize the effect of Wnt signaling in a newly generated line of related to receptor tyrosine kinase (Ryk) conditional knockout (cKO) mice. Ryk is a repulsive receptor of Wnt, and we studied corticospinal axon plasticity in this mouse model. After C5 dorsal column lesion, better motor-related function recovery was observed in Ryk cKO mice. Circuit level analysis showed increased collateral sprouting with Ryk deletion in motor cortex. Secondary lesion at C3 resulted in a loss of both the enhanced recovery mediated by Ryk deletion, as well as a loss of corticospinal axon collaterals between levels C3 and C5. Whereas after lesioning of the corticospinal motor axons at the level of the pyramid (pyramidotomy), functional recovery was lost completely, implicating a role for the remodeled corticospinal tract in the recovery of motor function.

These studies indicate that, while regeneration is not easily achieved, local sprouting and axon plasticity might offer more attainable circuit changes after spinal injury. We have found that this plasticity leads to significant motor and sensory functional recovery in rodents, and may be a potential avenue for mediating recovery for approximately 280,000 patients affected by SCI in the United States.

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