Respiratory compromise is the leading cause of morbidity and mortality following cervical spinal cord injury (SCI). Accordingly, identifying treatments to enhance the ability to breathe is a high priority. We are addressing this goal by examining neuronal replacement strategies using embryonic cell transplants. Such transplants offer an opportunity to study the functional integration of """"""""donor"""""""" neurons within the injured spinal cord. Serotonin (5-hydroxytryptamine;5-HT) plays an important role in recovery of breathing after cervical SCI. For example, respiratory recovery after SCI correlates with 5-HT immunoreactivity on phrenic motoneurons (PhrMNs) and 5-HT receptor agonists also enhance recovery. Similarly, phrenic recovery is impaired or abolished by 5-HT antagonists or ablation of serotonergic raphe neurons. Previous studies of locomotor recovery after SCI have used 5-HT cell transplants to enhance 5-HT innervation of lumbar motor pools. These 5-HT grafts can establish topographically appropriate connections and are associated with improved locomotion. Because 5-HT is critical to recovery of breathing after SCI, and also plays an essential role in initiating phrenic motor plasticity, we propose to examine the impact of cervical 5-HT cell transplant on respiratory motor recovery after cervical SCI. We hypothesize that embryonic raphe cell transplants will innervate surviving PhrMNs and improve phrenic motor output via 5-HT-dependent mechanisms. Following a cervical (C2) hemisection lesion (C2HS), ipsilateral bulbospinal pathways are disrupted leading to inactivation of PhrMNs and paralyzing the ipsilateral hemidiaphragm. Contralateral phrenic motoneurons remain active due to intact bulbospinal projections. Phrenic motoneurons ipsilateral to C2HS can be recruited via bulbospinal pathways that cross the spinal midline caudal to the injury (i.e. crossed-spinal pathways). These pathways are initially ineffective, but their synaptic efficacy gradually increases over a period of weeks to months, resulting in a partial recovery of the previously paralyzed ipsilateral hemi- diaphragm. We propose to use the C2HS model in conjunction with cervical raphe cell transplants to test our hypothesis. There have been few unequivocal demonstrations of functional recovery following cell replacement that occur via defined mechanisms. Accordingly, these studies are a proof-of-principle exploration of the potential for a phenotypically defined embryonic cell transplant (i.e. 5-HT) to enhance respiratory recovery after cervical SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS063659-01A2
Application #
7808996
Study Section
Special Emphasis Panel (ZRG1-F01-W (20))
Program Officer
Kleitman, Naomi
Project Start
2010-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
1
Fiscal Year
2009
Total Cost
$32,711
Indirect Cost
Name
University of Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Dougherty, B J; Gonzalez-Rothi, E J; Lee, K Z et al. (2016) Respiratory outcomes after mid-cervical transplantation of embryonic medullary cells in rats with cervical spinal cord injury. Exp Neurol 278:22-6
Dougherty, B J; Lee, K Z; Gonzalez-Rothi, E J et al. (2012) Recovery of inspiratory intercostal muscle activity following high cervical hemisection. Respir Physiol Neurobiol 183:186-92
Dougherty, Brendan J; Lee, Kun-Ze; Lane, Michael A et al. (2012) Contribution of the spontaneous crossed-phrenic phenomenon to inspiratory tidal volume in spontaneously breathing rats. J Appl Physiol (1985) 112:96-105