Project Grant F31NS147560

DETERMINING THE ROLE OF THE PARABRACHIAL NUCLEUS IN CHEMOSENSITIVITY AND EPILEPSY - ABSTRACT SUDDEN UNEXPECTED DEATH IN EPILEPSY (SUDEP) IS THE LEADING CAUSE OF DEATH IN PATIENTS WITH REFRACTORY EPILEPSY. SUDEP IS SECOND ONLY TO STROKE IN YEARS OF POTENTIAL LIFE LOST TO NEUROLOGICAL DISEASE, THEREFORE REPRESENTING A MAJOR PUBLIC HEALTH ISSUE. VICTIMS ARE OFTEN FOUND ALONE, MAKING THE EVENTS PRIOR TO DEATH ELUSIVE AND DIFFICULT TO DEFINE. ALTHOUGH SUDEP IS A DIAGNOSIS OF EXCLUSION, SEVERAL ETIOLOGIES HAVE BEEN PROPOSED FOR SUDEP. THE FIELD HAS INCLUDING CARDIAC AND RESPIRATORY DYSREGULATION FOLLOWING SEIZURE TERMINATION AS CRITICAL CONTRIBUTORS TO A POTENTIALLY FATAL OUTCOME. AN ADDITIONAL ETIOLOGY THAT IS POSTULATED IS POST-SEIZURE, OR POST-ICTAL, IMPAIRED AROUSAL. SEIZURES IMPAIR ONE'S ABILITY TO APPROPRIATELY RESPOND TO STIMULI. THIS IS INCLUSIVE OF STIMULUS THAT NORMALLY RESULTS IN AROUSAL. AMONG AROUSAL STIMULI, ONE THAT IS PARTICULARLY RELEVANT TO SUDEP IS CO2. CO2 RISES FOLLOWING SEIZURES AND IS PART OF THE SEIZURE CESSATION MECHANISM. SEIZURES ARE FREQUENTLY ASSOCIATED WITH ICTAL AND POST- ICTAL CENTRAL AND OBSTRUCTIVE APNEAS. AN APNEIC EPISODE FURTHER EXACERBATES THE ACCUMULATION OF CO2. IMPAIRMENT OF THE CO2-AROUSAL MECHANISM IS PROPOSED AS AN ETIOLOGICAL FACTOR IN ANOTHER SUDDEN DEATH ENTITY, SUDDEN INFANT DEATH SYNDROME, WHICH HAS MANY PARALLELS WITH SUDEP. INVESTIGATING THE MODULATION OF CHEMOSENSITIVE POPULATIONS FOR PROPER CO2-AROUSAL PROVIDES AN INITIAL COURSE OF ACTION IN UNDERSTANDING WHAT POPULATIONS ARE IMPAIRED IN THE CONTEXT OF SEIZURES AND EPILEPSY. THE LONG-TERM GOAL OF THIS PROJECT IS TO IDENTIFY HOW CO2-AROUSAL CAN BE PROMOTED AND WHAT POPULATIONS ARE ASSOCIATED WITH NEGATING SEIZURE-INDUCED DEATH. IN AIM 1, WE WILL DETERMINE THE CHEMOSENSITIVE PROPERTIES OF THE CALCITONIN GENE-RELATED PEPTIDE-EXPRESSING SUBPOPULATION IN THE EXTERNAL LATERAL REGION OF THE PARABRACHIAL NUCLEUS (PBELCGRP) BY EVALUATING CO2-AROUSAL DURING OPTOGENETIC INHIBITION. WE WILL TEST WHETHER SUPPRESSING PBELCGRP NEURONAL ACTIVITY PROLONGS AROUSAL LATENCY TO A CO2 STIMULUS. PROLONGED CO2-AROUSAL LATENCY WOULD PROVIDE ADDITIONAL EVIDENCE THAT PBELCGRP NEURONS CONTRIBUTE CRITICALLY TO THE ASCENDING AROUSAL SYSTEM THAT MEDIATES HOMEOSTATIC RESPONSES TO HYPERCAPNIA. IN AIM 2, WE WILL DETERMINE WHETHER OPTOGENETIC ACTIVATION OF THE PBELCGRP NEURONS REDUCES SEIZURE-INDUCED DEATH BY PROMOTING RECOVERY OF RESPIRATORY AND BEHAVIORAL FUNCTION IN A MOUSE MODEL OF SEIZURE-INDUCED DEATH. THIS MODEL, WHICH EXHIBITS A DEATH PHENOTYPE RESEMBLING SEIZURE-INDUCED RESPIRATORY ARREST, ALLOWS US TO COMPARE FINDINGS BETWEEN MICE THAT DIE AND THOSE THAT SURVIVE, MAKING THESE STUDIES HIGHLY RELEVANT TO SUDEP. SIGNIFICANT REDUCTION IN MORTALITY WOULD ESTABLISH THE PBELCGRP SUBPOPULATION AS A LOCATION FOR INTERVENTION AND FURTHER INVESTIGATION TO PROMOTE RECOVERY. COMBINED WITH PREVIOUS WORK, WE WILL HAVE A POWERFUL, RIGOROUS, AND TRANSLATABLE APPROACH TO IDENTIFY CONVERGENT AND DIVERGENT MECHANISMS ACROSS MODELS FOR HOW IMPAIRED CO2- AROUSAL CONTRIBUTES TO SUDEP RISK AND WHAT POPULATIONS CAN MITIGATE THIS RISK. THE PROPOSED WORK WILL HAVE AN IMMEDIATE POSITIVE IMPACT AS IT WILL FORM THE INITIAL FOUNDATION TO EXPAND UPON FOR FUTURE RESEARCH OF POST-ICTAL IMPAIRED AROUSAL IS A CONTRIBUTING MECHANISM OF SUDEP.