Chemogenetic stimulation of sympathetic preganglionic neurons and serotonergic reorganization after spinal cord injury - Project Summary/Abstract This proposal aims to characterize the potential beneficial effect of focal chemogenetic stimulation of sympathetic preganglionic neurons in the recovery of sympathetic regulation of blood pressure after left surgical hemisection in the rat. Spinal cord injury (SCI) can cause serious cardiovascular dysfunction. One of the most common dysfunctions is orthostatic hypotension, which is the inability to achieve an upright posture without fainting. Sympathetic regulation of blood pressure is driven by preganglionic neurons located in the lateral horn of the thoracic and upper lumbar spinal cord. Orthostatic hypotension after SCI is caused by a loss of supraspinal regulation of spinal sympathetic preganglionic neurons. Considering that the most significant rate of improvement in motor function occurs within the first six months after the SCI, after which progress plateaus, early and effective physical therapy is imperative. As such, orthostatic intolerance is a significant barrier for those with SCI to participate fully in rehabilitation, thereby impeding recovery. We have previously mapped the spinal pathways in the rat responsible for baroreflex-mediated activation of sympathetic preganglionic neurons to regulate blood pressure. We observed that over eight weeks, rats recover some degree of baroreflex function after severe SCI as long as some baroreflex-related spinal pathway is spared. This recovery is likely due to an increased efficacy of the remaining spinal pathways after the injury. Considering that approaches for the repair and/or regeneration after SCI have been elusive, this discovery provides an opportunity to determine the mechanistic action in the neuroplasticity after SCI for improving sympathetic regulation of blood pressure. Advances in rehabilitation, particularly spinal cord stimulation, have improved sympathetic regulation of blood pressure. While the mechanism of action is not fully known, animal models suggest that plasticity is due to engaging previously dormant neural tissue. However, it is unknown if it activates sympathetic preganglionic neurons directly or indirectly via stimulation of spinal networks that synapse on sympathetic preganglionic neurons. This is important because a better understanding of the neural mechanisms will provide better- targeted therapeutics. We propose using a novel targeted chemogenetic approach in transgenic rats to exclusively stimulate only sympathetic postganglionic neurons independent of the surrounding spinal network. In doing so, we will determine if chronic focal stimulation of sympathetic preganglionic neurons after SCI improves the recovery of sympathetic baroreflex function. We will also determine if this stimulation improves the reorganization of spinal networks involved in the sympathetic regulation of blood pressure. Thus, the goal of this small research project is to provide proof of concept for a novel approach to stimulate sympathetic neurons after SCI. This project will provide a data-derived path for more extensive studies to better understand the regulation of sympathetic activity and neuroplasticity, improve blood pressure regulation, and ultimately improve the ability to participate in rehabilitation after SCI.
