Project Grant R03MH137614

ROLE OF HYPOTHALAMIC MAGEL2 IN MOTIVATION - PRADER-WILLI SYNDROME (PWS) IS A NEUROGENETIC DISORDER CAUSED BY THE LOSS OF PATERNAL EXPRESSION OF A CLUSTER OF GENES IN THE HUMAN 15Q11-Q13 REGION. AMONG THE GENES IN THE PWS DELETION REGION, THE MAGEL2 GENE IS ONE OF THE GENES RESPONSIBLE FOR THE ETIOLOGY OF PWS. LOSS OF THE MOUSE MAGEL2 GENE RESULTS IN ABNORMALITIES IN GROWTH AND FERTILITY AND INCREASED ADIPOSITY WITH ALTERED METABOLISM IN ADULTHOOD. ALTHOUGH THE EXACT CELLULAR MECHANISMS UNDERLYING THESE ABNORMALITIES ARE NOT YET FULLY DETERMINED, A RECENT STUDY HAS SHOWN DEFICITS IN SECRETORY GRANULE ABUNDANCE AND NEUROPEPTIDE PRODUCTION IN THE HYPOTHALAMUS OF MAGEL2-NULL MICE. MAGEL2-NULL MICE HAVE LOWER LEVELS OF A- MELANOCYTE-STIMULATING HORMONE DERIVED FROM POMC. AS POMC NEURONS ARE PRIMARILY LOCATED IN THE ARCUATE NUCLEUS OF THE HYPOTHALAMUS (ARC), THE HIGHLY EXPRESSING MAGEL2 MRNA, A LOSS OF FUNCTION OF MAGEL WOULD DISRUPT THE CENTRAL MELANOCORTIN SYSTEM. WE HAVE RECENTLY ELUCIDATED THE CRUCIAL FUNCTION OF THE MAGEL2 GENE IN ARCPOMC NEURONS THAT PROJECT TO THE MEA IN REGULATING BODY WEIGHT. DECREASING THE EXPRESSION OF MAGEL2 IN THIS NEURAL CIRCUIT DIMINISHES SUSCEPTIBILITY TO DIET-INDUCED OBESITY, CONSISTENT WITH PREVIOUS INVESTIGATIONS ON PWS MOUSE MODELS, INCLUDING MICE DEFICIENT IN THE MAGEL2 AND SNORD116 GENES, WHEN FED A HIGH-FAT DIET. HOWEVER, THESE PRIOR FINDINGS DIVERGE FROM THE PRIMARY METABOLIC CHARACTERISTICS OF PWS, SUCH AS EXCESSIVE WEIGHT GAIN AND OBESITY. HENCE, IT IS POSSIBLE THAT CENTRAL MAGEL2 MAY EXERT A SIGNIFICANT INFLUENCE ON BEHAVIOR RATHER THAN ENERGY METABOLISM. KEY PHENOTYPIC PWS BEHAVIORS INCLUDE TEMPER OUTBURSTS, ANXIETY, OBSESSIVE-COMPULSIVE BEHAVIORS, AND SOCIAL COGNITION DEFICITS. MY RECENT STUDY FOUND THAT SEX HORMONE LEVELS PLAY A CRUCIAL ROLE IN REGULATING DAILY HOME CAGE ACTIVITY IN FEMALES. KNOCKDOWN OF THE MAGEL2 GENE IN MEA-INNERVATING ARCPOMC NEURONS ELEVATES PLASMA ESTROGEN LEVELS IN FEMALES. BLOCKADE OF THE G PROTEIN-COUPLED ESTROGEN RECEPTOR (GPER) BUT NOT THE NUCLEAR ESTROGEN RECEPTOR-A IN THE BRAIN COMPLETELY ABOLISHES THIS INCREASED HOME CAGE ACTIVITY. IMPORTANTLY, GPER IS HIGHLY EXPRESSED IN THE MEA THAT CONTROLS SOCIAL BEHAVIOR, AGGRESSION, AND ANXIETY-LIKE BEHAVIOR. HENCE, THIS PILOT STUDY AIMS TO DETERMINE THE EFFECT OF THE LOSS OF FUNCTION OF THE MAGEL2 GENE IN ARCPOMC NEURONS INNERVATING THE MEA ON ANXIETY-LIKE BEHAVIOR. THE PRIMARY GOAL OF THIS PILOT STUDY IS TO PRODUCE MORE MEANINGFUL, APPLICABLE RESULTS DEMONSTRATING THAT THE MAGEL2 GENE IN MEA-PROJECTING ARCPOMC NEURONS IS A CRUCIAL FACTOR CONTROLLING THE ABILITY OF ARCPOMC NEURONS TO REGULATE ANXIETY-LIKE BEHAVIOR.