Project Grant R03NS139043

DEVELOPING GENETIC ACCESS TO GROUP II PROPRIOCEPTIVE MUSCLE AFFERENTS - SUMMARY THE PROPRIOCEPTIVE SENSE LARGELY DERIVES FROM TWO SPECIALIZED RECEPTOR ORGANS IN SKELETAL MUSCLE: MUSCLE SPINDLES (MSS) AND GOLGI TENDON ORGANS (GTOS). THE AFFERENTS ASSOCIATED WITH THESE SENSORY END ORGANS ARE GROUPS IA AND II MS-AFFERENTS AND GROUP IB GTO AFFERENTS, WHICH RELAY INFORMATION ABOUT LIMB MOVEMENT AND POSITION (MS), OR MUSCLE LOAD (GTO) FROM THE PERIPHERAL RECEPTORS TO THE SPINAL CORD AND BRAINSTEM. MS AFFERENTS ARE THE PRIMARY KINESTHETIC SENSORS THAT ENHANCE THEIR FIRING RATES WITH INCREASES IN MUSCLE LENGTH, WHICH IN TURN SERVES AS AN INDIRECT READOUT OF JOINT POSITION. WHILE MS GROUP IA AFFERENT CAN RELAY DYNAMIC CHANGES, MS GROUP II AFFERENTS ARE, ON AVERAGE, MORE SENSITIVE FOR STATIC STRETCH WHEN COMPARED TO GROUP IA AFFERENTS AND ARE FAR MORE NUMEROUS. THESE OBSERVATIONS HAVE LED TO THE IDEA THAT GROUP II AFFERENTS ARE THE MAIN MEDIATORS OF LIMB AND BODY POSITION SENSE. GROUP II AFFERENTS THEREFORE NOT ONLY PLAY A KEY ROLE IN VARIOUS MOTOR FUNCTIONS, BUT ALSO ARE CENTRAL TO THE SENSE OF SELF AND AGENCY, THE SENSE OF BEING IN CONTROL OF ONE'S ACTIONS. DESPITE THEIR IMPORTANCE, SYSTEMATIC ANALYSES OF GROUP II FUNCTION OR THEIR DOWNSTREAM NEURAL CIRCUITS REMAINS SCARCE. HISTORICALLY, A KEY DIFFICULTY IN STUDYING GROUP II AFFERENTS HAS BEEN THE INABILITY TO CLEARLY DISTINGUISH THEM FROM MS GROUP IA AFFERENTS THROUGH PHYSIOLOGICAL OR GENETIC MEANS. MOST STIMULI THAT ACTIVATE GROUP II'S WILL ALSO ACTIVATE GROUP IA'S AND GENETIC REPORTERS FOR INDIVIDUAL PROPRIOCEPTOR SUBTYPES WERE NOT YET IDENTIFIED. IN RECENT YEARS, HOWEVER, MY LAB IDENTIFIED EXPRESSION OF NEUREXOPHILIN 1 (NXPH1), A MEMBER OF THE NEUREXOPHILIN FAMILY OF SECRETED GLYCOPROTEINS AS A UNIVERSAL MARKER FOR MS GROUP II AFFERENTS. ADDITIONAL EXPRESSION ANALYSES INDICATE THAT THE NXPH1 LOCUS OFFERS A UNIQUE OPPORTUNITY TO STUDY THE DEVELOPMENT, CIRCUITRY AND FUNCTION OF MOUSE GROUP II PROPRIOCEPTIVE MUSCLE AFFERENTS. TOWARDS THIS GOAL, THIS PROPOSAL WILL DEVELOP AND VALIDATE A NOVEL NXPH1:CRE ANIMAL MODEL TO ENABLE THE SELECTIVE MANIPULATION OF ADULT GROUP II MUSCLE SPINDLE AFFERENTS. THESE EXPERIMENTS WILL PROVIDE THE RESEARCH COMMUNITY WITH A NEW GENETIC MOUSE MODEL THAT WILL BE ESSENTIAL FOR THE STUDY OF GROUP II MUSCLE AFFERENTS IN HEALTH AND DISEASE.