We are working a novel approach to promote regrowth of damaged descending bulbospinal respiratory axons and reinnervation of their correct phrenic motor neuron (PhMN) targets after cervical spinal cord injury (SCI). Cervical SCI, which occurs in more than half of all human cases, can be extremely debilitating if the neural circuitry responsible for controlling respiratory function is affected. PhMNs located at cervical levels C3-C5 directly control activation of the diaphragm, which is the major inspiratory muscle. PhMNs are mono-synaptically innervated by bulbospinal projections of respiratory neurons located in a brainstem nucleus called the rostral Ventral Respiratory Group (rVRG). Cervical SCI can result in persistent diaphragm compromise because of damage to these descending rVRG axons, denervation and silencing of spared PhMNs, and consequent paralysis of the hemi-diaphragm. In a rat model of unilateral C2/3 hemisection SCI, we are expressing the axon guidance molecule, brain-derived neurotrophic factor (BDNF), in PhMNs to direct regenerating ipsilateral and/or sprouting contralateral rVRG axons towards PhMNs with the goal of achieving targeted restoration of the critical rVRG-PhMN-diaphragm circuit. Specifically, we are employing anatomically-targeted delivery of adeno-associated virus serotype 2 (AAV2) to the ipsilateral C3-C5 spinal cord to achieve BDNF expression throughout the denervated PhMN pool. Using neuroanatomical tract tracing and in vivo electrophysiological approaches, we are exploring the effects of this strategy on rVRG axon regrowth and collateral sprouting, synaptic reconnection with PhMNs, and restoration of ipsilateral hemi-diaphragm activity. Given our findings that rVRG neurons express the BDNF receptor, tropomyosin-related kinase B (TrkB), and that we can efficiently transduce PhMNs using this AAV2-based approach, we hypothesize that BDNF will promote robust PhMN reinnervation by injured rRVG axons and diaphragmatic respiratory recovery.
*B. CHARSAR1, M. URBAN1, B. GHOSH1, G. M. SMITH2, A. C. LEPORE1;
1Thomas Jefferson Univ., Philadelphia, PA; 2Temple Univ., Philadelphia, PA
B. Charsar: None. M. Urban: None. B. Ghosh: None. G.M. Smith: None. A.C. Lepore: None.
RESPIRATORY MOTOR NEURON PROTECTION FOLLOWING CERVICAL SPINAL CORD INJURY (NIH RePorter LINK)