Neuromodulation of somato-sympathetic postganglionic activity after SCI

About This Grant

PROJECT SUMMARY The sympathetic nervous system contributes to organismal stability including via vasomotor control of blood flow by regulation of activity in somato-sympathetic postganglionic neurons (SPNs) - to skin for thermoregulation, and to muscle to meet its changing metabolic demands. Command centers in the brain regulate sympathetic drive via descending projections to thoracolumbar spinal cord sympathetic preganglionic neurons that exit to recruit the SPNs that control end-organ function. Spinal cord injuries (SCIs) that interrupt projections from brain sympathetic command centers may partially or completely impair sympathetic homeostatic modulation of target organ function. This leads to a variety of dysautonomias. For example, people with high-level SCIs have little ongoing below-injury sympathetic activity to skin and muscle, and this impairs thermoregulation and muscle function, respectively. In contrast, individuals with more incomplete or lower-level SCIs may have abnormal skin/muscle sympathetic activity. There is increased recognition that electrotherapeutic strategies like epidural spinal cord stimulation (SCS) may recruit SPNs and improve autonomic function after SCI. However, the clinical literature on SCS-based modulation of autonomic dysfunction after SCI is limited and without large-scale randomized trials. Given the variety of protocols used, variability in SCI patient status, and magnitude effort to undertake such studies, it is timely to develop rigorous animal models using clinically analogous SCS to better understand neuromodulation of autonomic function after SCI to help instruct clinical trials. (1) We developed an in vivo approach that incorporates a modified form of microneurography to undertake the first recordings of somatic SPN activity in mice and are now capable of capturing SPN activity from several hindlimb skin/muscle nerves while simultaneously monitoring changes in hindlimb blood flow regulation with Laser Doppler Flowmetry (LDF). (2) We propose to pair this with SCS-based neuromodulation using scaled electrode parameters to deliver clinically analogous stimulus paradigms to study their capacity to modulate motor/skin SPN activity and blood flow. Simultaneous capture of blood pressure, heart rate, respiratory rate and motor activity will provide important insight into SCS modulation of interrelated to physiological parameters. Experiments will characterize and compare the effects of clinically analogous SCS on SPNs and vasomotor function in naive and two SCI mouse models: (i) the T2 transection model with autonomic dysreflexia / body temperature instability, and (ii) the T10 contusion model with neuropathic pain. In sum, we have developed important methodological innovations in an adult mouse model system that provide a powerful exploratory testing ground to study SCS modulation of skin and muscle SPN activity after SCI.