Phrenic Afferents and Neuromuscular Plasticity Following Spinal Cord Injury

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PROJECT SUMMARY/ABSTRACT CANDIDATE: Dr. Streeter’s career objective is to improve human medicine through translational, basic science by establishing an independent research program focused on mechanisms of respiratory control, and developing therapeutic strategies to treat pulmonary insufficiencies that occur during neuromuscular impairments. The research and career development plans have been carefully designed to provide the necessary skills for Dr. Streeter to establish a novel, independent line of research and include the following objectives: 1) acquire core knowledge in respiratory neurobiology and cardiovascular control, 2) gain further expertise in research methodology, techniques, and scientific writing, and 3) develop academic leadership skills. ENVIRONMENT: Drs. Fuller and Davenport are exceptional mentors, with a track record of successful mentees. Dr. Fuller has expertise in spinal cord injury (SCI) and neuroplasticity, and Dr. Davenport is an authority on phrenic afferents and respiratory control. Both have NIH funding and productive laboratories, and will provide the resources to assist the candidate in her research project. The sponsoring institution, the University of Florida, is an ideal place to conduct the mentored studies due to outstanding faculty mentors, top- notch facilities, and opportunities within the Center for Respiratory Research and Rehabilitation. RESEARCH: The proposed research will determine the contribution of phrenic afferents to respiratory control in spinal intact and injured rodents. Cervical SCI disrupts descending drive to the primary inspiratory muscle, the diaphragm, and results in a profound breathing impairment. Diaphragm (phrenic) sensory afferent neurons are a novel target due to their role in the regulation of respiratory activity. The fundamental goal of this proposal is to determine the functional contribution of phrenic afferents to respiratory motor output following cervical SCI. Three specific aims are proposed in rats with sub-acute (3-4 wks) cervical SCI: AIM 1: To test the hypothesis that acute activation of phrenic afferents increases phrenic motor output; AIM 2: To test the hypothesis that repeated activation of phrenic afferents induces phrenic motor plasticity associated with altered functional connectivity in the spinal cord; AIM 3: To test the hypothesis that activation of phrenic afferents during the clinically used strategy of diaphragm pacing, improves respiratory neuromuscular control. Since individuals with cervical SCI are also at the highest risk for developing abhorrent driven cardiovascular responses (e.g., autonomic dysreflexia) and activation of phrenic afferents can be powerful regulator of heart rate and arterial blood pressure, we will evaluate these variables during each aim. The added focus on cardiovascular regulation provides an additional career development opportunity for Dr. Streeter, and we recruited an expert in this area (Dr. Hayward) to serve on the mentoring team. We propose to use an established rodent model of cervical SCI (C2 hemisection) and a multi-disciplinary approach including in vivo neurophysiology, electrical stimulation, multi-electrode recordings, immunohistochemistry and chronic EMG recordings/stimulation.