Project Grant F32NS146047

UNDERSTANDING HOW STRESS-INDUCED GUT DYSBIOSIS CONTRIBUTES TO DEVELOPMENT OF MIGRAINE - PROJECT SUMMARY/ ABSTRACT MIGRAINE IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. OVER 70% OF INDIVIDUALS REPORT THAT STRESS IS A MIGRAINE TRIGGER. DESPITE THIS HIGH PREVALENCE, THE MECHANISMS UNDERLYING STRESS-INDUCED MIGRAINE ARE POORLY UNDERSTOOD. STRESS CAN ALTER THE COMPOSITION OF GUT MICROBIAL COMMUNITIES, MICROBIAL METABOLITES, AND METABOLITES PRODUCED BY THE HOST. THUS, STRESS-INDUCED CHANGES IN THE GUT MICROBIOME MAY CONTRIBUTE TO MIGRAINE SUSCEPTIBILITY. MY PRELIMINARY DATA DIRECTLY SUPPORT THIS HYPOTHESIS; I FOUND THAT FECAL MICROBIOTA TRANSPLANT FROM RESTRAINT STRESSED ANIMALS PRIMES NAIVE ANIMALS TO A SUBTHRESHOLD MIGRAINE TRIGGER. NOW, WE WILL DETERMINE HOW STRESS-INDUCED CHANGES IN THE BIOLOGICAL/OR CHEMICAL FACTORS OF THE GASTROINTESTINAL TRACT CONTRIBUTE TO MIGRAINE BEHAVIOR AND PHYSIOLOGY. THE PROPOSED RESEARCH PROJECT AIMS TO ADDRESS THIS QUESTION THROUGH THREE AIMS. IN AIM 1 WE WILL EXAMINE THE EXTENT TO WHICH THE STRESSED GUT MICROBIOME ALTERS EXCITABILITY AND SENSITIZES PRIMARY SENSORY NEURONS TO MIGRAINE TRIGGERS BY PERFORMING WHOLE-CELL PATCH CLAMP ELECTROPHYSIOLOGY AND CALCIUM IMAGING ON BOTH SENSORY NEURONS ISOLATED FROM STRESSED FMT RECIPIENTS AND NAIVE SENSORY NEURONS INCUBATED IN STRESSED FECAL MATERIAL. IN AIM 2 WE WILL DETERMINE IF CALCITONIN-GENE RELATED PEPTIDE (CGRP) SIGNALING CONTRIBUTES TO STRESSED FMT MIGRAINE PATHOLOGY. FIRST, WE WILL MEASURE CGRP RELEASE FROM SENSORY NEURONS ISOLATED FROM STRESS AND CONTROL FMT RECIPIENTS (2A). THEN WE WILL PERFORM BEHAVIOR ON STRESS FMT RECIPIENTS FOLLOWING CGRP ANTAGONIST ADMINISTRATION (2B). IN AIM 3 WE WILL IDENTIFY MICROBIAL METABOLITES ASSOCIATED WITH STRESS-INDUCED CHANGES IN THE GUT MICROBIOME. UNDERSTANDING HOW THE GUT MICROBIOME CONTRIBUTES TO MIGRAINE SUSCEPTIBILITY MAY LEAD TO INDIVIDUALIZED-MICROBIAL BASED TREATMENT WHICH WILL HELP REDUCE THE BURDEN OF THIS NEUROLOGICAL DISEASE. UNDER THE MENTORSHIP OF DR. KATE SADLER AND DR. GREG DUSSOR AT THE CENTER FOR ADVANCED PAIN STUDIES AT UNIVERSITY OF TEXAS AT DALLAS, I AM CONFIDENT THAT I HAVE THE RESOURCES NECESSARY TO COMPLETE THE DESCRIBED RESEARCH TRAINING PLAN. ADDITIONALLY, THROUGH COMPLETING THESE AIMS, I WILL REACH MY TRAINING GOALS THAT INCLUDE 1) BECOMING AN EXPERT IN PERIPHERAL NERVOUS SYSTEM ANATOMY AND PHYSIOLOGY, 2) GAINING A COMPREHENSIVE UNDERSTANDING OF MIGRAINE PATHOLOGY, 3) STRENGTHENING MY LEADERSHIP AND MENTORSHIP SKILLS, AND 4) EFFECTIVELY DISSEMINATING RESEARCH THROUGH SCIENTIFIC WRITING AND PRESENTATIONS.