Project Grant R03NS147206

STIMULATING BULBOSPINAL PLASTICITY TO IMPROVE BAROREFLEX REGULATION OF SYMPATHETIC CARDIOVASCULAR ACTIVITY AFTER SPINAL CORD INJURY. - PROJECT SUMMARY/ABSTRACT SPINAL CORD INJURY (SCI) CAN DISRUPT THE AUTONOMIC NERVOUS SYSTEM'S ABILITY TO REGULATE BLOOD PRESSURE, OFTEN LEADING TO ORTHOSTATIC HYPOTENSION, A CONDITION CHARACTERIZED BY A SIGNIFICANT DROP IN BLOOD PRESSURE UPON STANDING OR SITTING UP. THIS OCCURS DUE TO IMPAIRED SYMPATHETIC NERVOUS SYSTEM REGULATION OF THE BAROREFLEX, CAUSING REDUCED VASOCONSTRICTION AND INADEQUATE BLOOD FLOW TO THE BRAIN. CONSIDERING THAT THE MOST SIGNIFICANT RATE OF IMPROVEMENT IN LOCOMOTOR FUNCTION OCCURS WITHIN THE FIRST SIX MONTHS AFTER SCI, AFTER WHICH PROGRESS PLATEAUS, THE ABILITY TO FULLY PARTICIPATE IN EARLY AND EFFECTIVE PHYSICAL THERAPY IS IMPERATIVE. AS SUCH, ORTHOSTATIC HYPOTENSION IS A SIGNIFICANT BARRIER FOR THOSE WITH SCI. SYMPATHETIC REGULATION OF THE BAROREFLEX IS DERIVED FROM PREGANGLIONIC NEURONS LOCATED IN THE LATERAL HORN OF THE THORACIC AND UPPER LUMBAR SPINAL CORD. THE ROSTROVENTROLATERAL MEDULLA (RVLM) IS LOCATED BILATERALLY WITHIN THE BRAIN STEM MEDULLA AND PLAYS A PRINCIPAL ROLE IN BAROREFLEX REGULATION. THE RVLM SENDS DESCENDING PROJECTIONS DOWN BOTH SIDES OF THE SPINAL CORD TO REGULATE THE ACTIVITY OF SYMPATHETIC PREGANGLIONIC NEURONS AND, THEREFORE, BAROREFLEX BLOOD PRESSURE REGULATION. USING A LEFT SURGICAL HEMISECTION MODEL IN THE RAT, WE HAVE PREVIOUSLY SHOWN THAT BAROREFLEX REGULATION IS MEDIATED MAINLY, ALTHOUGH NOT EXCLUSIVELY, BY IPSILATERAL RVLM-SPINAL PATHWAYS. WE HAVE DEMONSTRATED IN THE RAT THAT BAROREFLEX REGULATION IS SIGNIFICANTLY IMPAIRED ONE WEEK AFTER LEFT THORACIC HEMISECTION, AND MODEST IMPROVEMENT IS OBSERVED AFTER EIGHT WEEKS. THIS IMPROVEMENT IS LIKELY MEDIATED BY INCREASED EFFICIENCY OF THE REMAINING DESCENDING CONTRALATERAL PATHWAYS THAT CROSS THE SPINAL CORD CAUDAL TO THE HEMISECTION. WHEREAS ELECTRICAL STIMULATION TO THE SPINAL CORD HAS SHOWN PROMISING RESULTS IN IMPROVING BOTH LOCOMOTOR AND AUTONOMIC ACTIVITY, THE MECHANISM OF ACTION IS NOT FULLY KNOWN. SPECIFICALLY, IT IS ALSO NOT KNOWN IF FOCAL STIMULATION OF THE DESCENDING SPINAL PATHWAYS FROM RVLM TO REGULATE SYMPATHETIC PREGANGLIONIC NEURONS CAN IMPROVE BAROREFLEX REGULATION OF BLOOD PRESSURE. THIS PROPOSAL AIMS TO CHARACTERIZE THE POTENTIAL BENEFICIAL EFFECT OF FOCAL CHEMOGENETIC STIMULATION OF BRAIN STEM NEURONS TO IMPROVE NEURAL CONTROL OF BLOOD PRESSURE AFTER SCI. WE HYPOTHESIZE THAT CHRONIC STIMULATION OF THE REMAINING PATHWAYS THAT CROSS THE SPINAL CORD BELOW THE LESION CAN ENHANCE THE RECOVERY OF BAROREFLEX FUNCTION. TO TEST THIS HYPOTHESIS, WE WILL USE A RETROGRADE CRE-DEPENDENT EXPRESSION OF DESIGNER RECEPTOR EXCLUSIVELY ACTIVATED BY A DESIGNER DRUG (DREADDS) APPROACH TO PROVIDE CHRONIC AND TARGETED CHEMOGENETIC STIMULATION OF RVLM NEURONS THAT SPECIFICALLY SEND SPINAL PROJECTIONS TO SYMPATHETIC PREGANGLIONIC NEURONS AFTER LEFT SPINAL HEMISECTION IN THE RAT. AFTER THE STIMULATION TREATMENT PERIOD, WE WILL PERFORM IN-VIVO ELECTROPHYSIOLOGY TO TEST THE POTENTIAL RECOVERY OF SYMPATHETIC BAROREFLEX REGULATION COMPARED WITH UNTREATED CONTROLS AND HISTOLOGICAL ANALYSIS OF SPINAL PATHWAYS TO OBSERVE POTENTIAL NEUROPLASTICITY. THUS, THIS SMALL RESEARCH PROJECT AIMS TO PROVIDE PROOF OF CONCEPT DATA FOR A NOVEL APPROACH TO STIMULATE SYMPATHETIC NEURONS AND IMPROVE NEURAL CONTROL OF BLOOD PRESSURE AFTER SCI.