Publication Date

2012

Document Type

Dissertation

Committee Members

Timothy Cope (Advisor), Robert Fyffe (Committee Member), David Goldstein (Committee Member), T. Richard Nichols (Committee Member), Mark Rich (Committee Member)

Degree Name

Doctor of Philosophy (PhD)

Abstract

Peripheral nerve regeneration fails to restore complete normal function after surgical repair of severed nerves, and this failure has primarily been attributed to errors in connecting with peripheral targets. However, recent evidence suggests that central deficits remain even after peripheral target reinnervation is largely successful. It has long been established that regeneration fails to restore the stretch reflex despite observation that many of the neural components are intact. Regenerated Ia afferents are largely successful in reinnervating muscle spindles, are capable of encoding stretch, and elicit EPSPs in homonymous motoneurons, while regenerated motor pools are capable of responding to uninjured sources of excitatory input. We now know this areflexia is due in part to a retraction of Ia afferent collaterals from motor pools in lamina IX (Alvarez et al., 2011). However, Ia afferents project not only to homonymous motoneurons but also to heteronymous synergist motor pools, even ones that are injury-spared. Ia afferents also project to antagonist motor pools through an interposed inhibitory interneuron. Therefore stretch of a muscle is capable of producing reflex contraction of both itself and synergist muscles while producing reflex inhibition of antagonist muscles. The function of these heteronymous projections after regeneration, however, remains unknown. The goal of this thesis is to determine the limitations of recovery of spinal circuit function after peripheral nerve regeneration by direct examination of stretch-evoked reflexes among synergists and antagonists. Direct examination of the force response to stretch in vivo is extremely valuable as changes in behavior, the muscle response to stretch, after peripheral nerve regeneration must necessarily reflect changes in the underlying circuitry. We found that heteronymous stretch reflexes initiated by reinnervated muscle were dramatically decreased in both regenerated and injury-spared synergist motoneuronal pools. Additionally, both homonymous and heteronymous stretch reflexes were reduced in an injury-spared synergist after regeneration. These results give physiological evidence for retraction of regenerated Ia afferents from all synergist motor pools, and this retraction may extend to afferents that are injury-spared. Dysfunction also extends to antagonist stretch-evoked reflexes as we found a shift from net inhibition to net excitation of the injury-spared muscle due to reinnervated antagonist stretch. This shift is readily explained by the differential preservation of synapses located in lamina where interneurons mediating these responses are presumably located (Alvarez et al., 2011). Therefore functional deficits after peripheral nerve regeneration extend to heteronymous connections of Ia afferents with synergists and antagonists, both reinnervated and injury-spared. Taken together, these findings suggest that there is a profound discoordination of spinal reflexes and reorganization of spinal circuits after peripheral nerve regeneration.

Page Count

184

Department or Program

Biomedical Sciences

Year Degree Awarded

2012

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