Project Grant F31DA062444

FUNCTIONS AND MECHANISMS OF CRYM-POSITIVE ASTROCYTES IN THE NUCLEUS ACCUMBENS - PROJECT SUMMARY/ABSTRACT ASTROCYTES ARE UBIQUITOUS CNS CELLS THAT MAKE EXTENSIVE CONTACTS WITH NEURONS. ASTROCYTES SERVE DIVERSE ROLES, INCLUDING ION HOMEOSTASIS, NEUROTRANSMITTER CLEARANCE, AND CONTRIBUTIONS TO NEUROVASCULAR COUPLING, WHICH POSITION THEM AS CRITICAL COMPONENTS OF NEURAL CIRCUITS THAT CONTRIBUTE TO BRAIN PHYSIOLOGY AND DISEASE. ONCE THOUGHT OF AS HOMOGENEOUS, RECENT STUDIES HAVE HIGHLIGHTED ASTROCYTE HETEROGENEITY ACROSS AND WITHIN BRAIN REGIONS. AS TOOLS TO STUDY ASTROCYTES HAVE IMPROVED, ONE IMPORTANT GOAL IS TO DETERMINE IF DEFINED POPULATIONS OF ASTROCYTES REGULATE BEHAVIORS ASSOCIATED WITH THE BRAIN REGION THEY ARE LOCATED IN. AN IDEAL POPULATION TO EXPLORE THIS LARGER QUESTION IS THE NEWLY DISCOVERED SUBPOPULATION OF CRYM+ ASTROCYTES WITHIN THE NUCLEUS ACCUMBENS (NAC), A STRUCTURE WITHIN THE VENTRAL STRIATUM THAT IS WELL CHARACTERIZED IN THE CONTEXT OF REWARDING BEHAVIORS AND ADDICTION. THE FOCUS OF THIS APPLICATION IS THUS TO DETERMINE THE ROLE(S) OF CRYM+ ASTROCYTES IN BEHAVIORS RELEVANT TO THE NAC. CRYM ENCODES THE PROTEIN M- CRYSTALLIN THAT WAS RECENTLY IDENTIFIED IN A SPECIFIC POPULATION OF CENTRAL STRIATAL ASTROCYTES TO REGULATE PERSEVERATIVE BEHAVIORS OF MICE. THE CURRENT APPLICATION SEEKS TO ELUCIDATE THE FUNCTIONS OF CRYM+ NAC ASTROCYTES (~45%) USING INTEGRATED MOLECULAR, CELLULAR, AND PHYSIOLOGICAL ASSESSMENTS DURING NATURAL BEHAVIORS AND A MODEL OF FENTANYL-EVOKED OPIOID USE DISORDER (OUD). I WILL TEST THE HYPOTHESIS THAT ASTROCYTES IN THE NAC HAVE SEPARABLE PROPERTIES RELATIVE TO THE DORSAL STRIATUM, CONTRIBUTE TO GOAL- DIRECTED BEHAVIORS, AND THAT THEY ARE ALTERED IN A CLINICALLY RELEVANT MODEL OF OPIOID USE DISORDER (OUD) WHERE GOAL-DIRECTED BEHAVIORS ARE DISRUPTED. THIS HYPOTHESIS IS BASED ON EXCITING PRELIMINARY DATA DESCRIBED IN THE APPLICATION, INCLUDING DATA SHOWING THAT CRYM EXPRESSION IS DECREASED IN NAC ASTROCYTES IN THE OUD MODEL. I WILL TEST THIS HYPOTHESIS WITH THREE SPECIFIC AIMS. AIM 1 WILL CHARACTERIZE BASIC BIOLOGICAL PROPERTIES OF ASTROCYTES IN THE NAC. AIM 2 WILL ASSESS FUNCTIONS OF CRYM+ NAC ASTROCYTES DURING GOAL-DIRECTED BEHAVIORS. AIM 3 WILL DETERMINE HOW NAC ASTROCYTES ARE ALTERED IN A MODEL OF FENTANYL- EVOKED OUD. THE AIMS ARE LOGICALLY RELATED TO ADDRESS MY HYPOTHESIS BUT ARE NOT INTERDEPENDENT SO THAT SUCCESS IN ANY ONE IS NOT CONTINGENT ON THE OTHER. THE COMPLETION OF THE PROPOSED EXPERIMENTS WILL PROVIDE ME WITH RIGOROUS TRAINING IN STATE-OF-THE-ART METHODS AND ALLOW ME TO DIRECTLY ADDRESS THE FUNCTIONS OF A MOLECULARLY DEFINED POPULATION OF ASTROCYTES IN THE NAC.