NEURAL MECHANISM OF IMPAIRED SATIATION AFTER MAGEL2 MUTATION - PROJECT SUMMARY SATIATION IS AN IMPORTANT ASPECT OF INTEROCEPTION THAT TRANSLATES GUT SIGNALS, SUCH AS CHOLECYSTOKININ (CCK), INTO EATING SUPPRESSION. INSATIABLE APPETITE IS ASSOCIATED WITH DEVELOPMENTAL GENETIC DISEASES INCLUDING PRADER-WILLI SYNDROME (PWS) AND SHAFER-YOUNG SYNDROME (SYS). PARADOXICALLY, INDIVIDUALS WITH PWS HAVE HIGHER LEVELS OF PLASMA CCK BUT CONSUME MORE FOOD, SUGGESTING THAT THE NEURAL MECHANISM RESPONSIBLE FOR DETECTING SATIATION SIGNALS IS IMPAIRED AND CANNOT CONVERT SATIATION INFORMATION INTO EATING SUPPRESSION. HOWEVER, HOW THE NEURAL CIRCUIT THAT REGULATES SATIATION IS IMPAIRED IN THESE DISEASES IS STILL UNKNOWN. PWS AND SYS SHARE A COMMON MUTATION IN THE MAGEL2 GENE, SUGGESTING THAT THE MUTATION OF THIS GENE MIGHT IMPAIR THE SATIATION CIRCUIT. CONSISTENT WITH THIS, OUR PRELIMINARY RESULTS INDICATE THAT CCK FAILS TO SUPPRESS FOOD INTAKE IN MAGEL2-NULL MICE. OUR PREVIOUS STUDIES HAVE IDENTIFIED A SPECIFIC POPULATION OF NEURONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) MARKED BY THE EXPRESSION OF PROTEIN KINASE C-DELTA, WHICH PLAYS A CRITICAL ROLE IN DETECTING CCK. SILENCING THESE NEURONS PREVENTS THE EATING SUPPRESSION CAUSED BY CCK AND ACTIVATION OF THESE NEURONS SUPPRESSES FOOD INTAKE. HERE, WE FOUND THAT THE RESPONSE OF CEA PKC-D NEURONS TO CCK IS REDUCED IN MAGEL2 NULL MICE. THEREFORE, WE HYPOTHESIZE THAT THE NEURAL CIRCUITS INVOLVING CEA PKC-D NEURONS ARE IMPAIRED AFTER MAGEL2 MUTATION. IN THIS PROPOSAL, WE AIM TO DETERMINE HOW THE CEA PKC-D NEURONS ARE AFFECTED BY THE MAGEL2 MUTATION, USING RECENTLY DEVELOPED IN VIVO CALCIUM IMAGING AND ELECTROPHYSIOLOGY APPROACHES (AIM 1). BECAUSE THE TOTAL NUMBER OF CEA PKC-D NEURONS IS NOT AFFECTED BY MAGEL2-MUTATION, WE WILL ALSO TEST THE HYPOTHESIS THAT ACTIVATION OF CEA PKC- D NEURONS SUPPRESSES APPETITE IN MAGEL2-NULL MICE (AIM 2). SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL HELP US UNDERSTAND HOW SATIATION AND APPETITE ARE REGULATED IN THE BRAINS OF INDIVIDUALS WITH PWS AND SYS. ADDITIONALLY, IT MAY SUGGEST NOVEL DRUGGABLE TARGETS IN THE BRAIN TO CONTROL INSATIABLE APPETITE AND OBESITY IN THESE DISEASES, ULTIMATELY IMPROVING THE QUALITY OF LIFE.