Electrical and Optogenetic Stimulation of Sympathetic Neurons to Stabilize Blood Pressure after Acute Spinal Cord Injury

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Spinal cord injury (SCI) is a life-changing condition that results in permanent motor disability and autonomic dysfunction. Acute blood pressure instability is associated with poor long term neurological recovery. Despite current clinical standards of care, blood pressure instability still occurs in the acute phase, and the in-hospital mortality of patients with acute SCI ranges up to 22%. As a result, it is important to examine the mechanisms of blood pressure control in order to identify potential future therapeutic targets for the clinical management of blood pressure instability. A recent study from our team identified regions of the spinal cord that, when stimulated with epidural electrical stimulation (EES), were able to increase blood pressure in spinal cord injured animals. This region was termed the hemodynamic hotspot. Closed-loop application of EES (eSTIM), showed success in stabilizing blood pressure in the chronic phase of SCI in rats. eSTIM induces pressor responses by activating ChAT+ sympathetic preganglionic neurons (SPNs) in the intermediolateral column that innerve the splanchnic vasculature. My thesis aimed to investigate whether blood pressure stability can be restored in mice during the acute phase of SCI using eSTIM, and to develop a method to precisely modulate blood pressure using closed-loop red-shifted optogenetic stimulation to target ChAT+ SPNs. I showed that blood pressure stability is severely disrupted following acute SCI, and that eSTIM can stabilize blood pressure and prevent blood pressure drop during orthostatic challenge in acutely injured mice. I developed a method to stimulate deeper neurons in the spinal cord hemodynamic hotspot using optogenetics and showed that the optogenetic activation of neurons at the hemodynamic hotspot was able to increase blood pressure. The closed-loop optogenetic stimulation of ChAT+ SPNs was able to stabilize blood pressure in the acute phase of SCI. The methods established in this study will pave the way for future studies that aim to investigate the roles of various spinal cord neurons in blood pressure regulation by precise modulation of specific cell subtypes.
Spinal cord injury, optogenetics, neuroprosthetic, spinal cord, sympathetic
Tso, M. (2023). Electrical and optogenetic stimulation of sympathetic neurons to stabilize blood pressure after acute spinal cord Injury (Unpublished master's thesis). University of Calgary, Calgary, AB.