Therapeutic Potential of Hypoxia on Urinary and Respiratory Function after SCI

Project Summary Spinal cord injury (SCI) damages axonal connections between the spinal cord and brain resulting in reduction or loss of motor, sensory, and autonomic function below the level of the injury. While most SCIs are incomplete, spontaneous functional recovery resulting from neural plasticity occurs albeit this recovery is rarely complete. Thus, efforts aimed at enhancing the extent of functional recovery by augmenting neural plasticity following SCI are essential, and a variety of therapies focusing on this goal have been implemented. Amongst the therapies investigated, exposure to acute intermittent hypoxia (AIH) has been shown to elicit functional improvements in both respiratory and non-respiratory motor spinal systems following incomplete SCI in rodents and humans, with repetitive or daily AIH (dAIH) producing persistent functional improvements that may last one week or more. These observations suggest that respiratory and somatic motor systems are affected by AIH in similar ways. The effects of AIH on autonomic dysfunction, including lower urinary tract (LUT) dysfunction, following SCI are less well understood or altogether unknown. Moreover, the impact of AIH on recovery of respiratory function, including expiratory motor output, following mid-thoracic SCI have not been examined. This R21 application proposes an exploratory/developmental project that is designed to investigate the therapeutic potential of acute intermittent hypoxia (AIH) as a tool for improving lower urinary tract (LUT) and respiratory dysfunction following mid-thoracic SCI. In young adult female rats, LUT and respiratory motor function will be measured before and after SCI produced by mid-thoracic moderate contusion or complete spinal cord transection. In Specific Aim 1, at 1-week (immediate) versus 4-week (delayed) following SCI, LUT and respiratory-related motor activities will be measured and quantified in response to and for 2-hours following AIH or sham gas treatment. In Specific Aim 2, beginning four weeks after SCI, rats will receive dAIH or dSHAM gas treatment for one week and then monitored at 1-day versus 1-week post gas treatment; an additional terminal acute AIH gas exposure experiment will also be conducted at this final time point. Functional outcome measures will be acquired at regular time points before SCI, during the 4-week recovery period following SCI, and at specific time points post-AIH/SHAM gas treatment, and will include residual urine volume (manual bladder expression); frequency and volume of spontaneous voids (metabolic chamber); bladder pressure threshold, frequency of subthreshold bladder contractions, duration and frequency of external urethral sphincter (EUS) bursting, detrusor-sphincter dyssynergia (cystometry with EUS EMG recording); and rate and depth of breathing (plethysmography and respiratory-related motor activities). It is anticipated that AIH and dAIH treatments will lead to improved LUT function (e.g., reduced detrusor-sphincter dyssynergia and residual urine volume) and enhanced respiratory motor output following SCI. If successful, this approach could be an effective non-invasive intervention to improve bladder control and respiratory dysfunction in individuals with spinal cord injury.