Project Grant F31NS151431

A MOTOR CORTICAL CIRCUIT FOR ONLINE REACHING CONTROL - PROJECT SUMMARY/ABSTRACT SKILLED FORELIMB CONTROL IS A DEFINING FEATURE OF HUMAN BEHAVIOR, ALLOWING US TO REACH FOR, GRASP, AND MANIPULATE OBJECTS IN THE WORLD WITH PRECISION AND INTENT. THIS CONTROL DEPENDS CRITICALLY ON MOTOR CORTEX AND IS DISRUPTED IN DISORDERS OF CORTICAL FUNCTION, SUCH AS STROKE OR TRAUMATIC INJURY. THEREFORE, THERE IS AN ESSENTIAL NEED TO UNDERSTAND THE ROLE OF MOTOR CORTEX IN SKILLED FORELIMB BEHAVIORS AND HOW ITS CONSTITUTIVE CELLULAR COMPONENTS ACHIEVE ITS CIRCUIT FUNCTION. REACHING CONTROL DEPENDS ON ONGOING SOMATOSENSORY FEEDBACK, AND RECORDINGS IN PRIMATES HAVE DEMONSTRATED THAT MOTOR CORTEX RESPONDS RAPIDLY TO UNEXPECTED PROPRIOCEPTIVE DISTURBANCES DURING REACHING. FURTHER STUDIES HAVE HYPOTHESIZED THAT MOTOR CORTEX PRIORITIZES ONLY CERTAIN ASPECTS OF FEEDBACK BASED ON THEIR RELEVANCE FOR ACHIEVING OVERARCHING BEHAVIORAL GOALS. ACCORDINGLY, THESE STUDIES HAVE SUGGESTED THAT DURING REACH EXECUTION, MOTOR CORTEX PROVIDES FEEDBACK CONTROL TO UPDATE COMMANDS ONLINE, CORRECTING FEEDBACK ERRORS IN TASK-RELEVANT DIMENSIONS WHILE ALLOWING NATURAL VARIABILITY IN DIMENSIONS THAT DO NOT IMPACT BEHAVIORAL SUCCESS. HOWEVER, CAUSAL EVIDENCE FOR THIS HYPOTHESIS IS LACKING, AND VIRTUALLY NOTHING IS KNOWN ABOUT HOW THE CELL TYPES THAT COMPRISE MOTOR CORTEX ACHIEVE THIS FUNCTION. WE HAVE DEPLOYED AN ANALOGOUS SKILLED REACHING BEHAVIOR IN THE MOUSE AND IDENTIFIED A MOTOR CORTICAL NODE IN SECONDARY MOTOR CORTEX, MOS-C, UPON WHICH THIS BEHAVIOR DEPENDS. THUS, WE ESTABLISHED A GENETICALLY TRACTABLE SYSTEM TO UNCOVER THE CORTICAL CIRCUIT AND CELL-TYPE MECHANISMS THAT MAY UNDERLY REACHING CONTROL. MY OVERARCHING HYPOTHESIS IS THAT MOS-C ACTS AS A FEEDBACK CONTROLLER FOR REACHING THAT MONITORS THE ONGOING HAND STATE FOR ONLINE REACHING REFINEMENT AND ENDPOINT PRECISION. TO TEST THIS HYPOTHESIS, I WILL PURSUE THE FOLLOWING AIMS. AIM 1 WILL INTERROGATE THE CONTROL RULES OF SKILLED REACHING VIA MECHANICAL LIMB PERTURBATIONS, AIM 2 WILL DELINEATE THE PATTERNS IN MOS-C POPULATION ACTIVITY THAT SUPPORT ONGOING REACHING CONTROL, AND AIM 3 WILL DISCOVER CELL-TYPE SPECIFIC NEURAL DYNAMICS IN MOS- C DURING ONLINE CONTROL. MY APPROACH INCLUDES QUANTITATIVE ANALYSES OF NOVEL BEHAVIORAL VARIANTS OF REACHING WITH PERTURBATIONS, TEMPORALLY PRECISE, CLOSED-LOOP CAUSAL MANIPULATIONS OF CORTICAL ACTIVITY WITH OPTOGENETICS, AND HIGH-DENSITY IN VIVO ELECTROPHYSIOLOGY RECORDINGS OF MARKER-DEFINED PROJECTION NEURON TYPES DURING BEHAVIOR. THESE STUDIES MAY REVEAL THE CELL TYPE AND NEURAL CIRCUIT MECHANISMS IN MOTOR CORTEX THAT EXERT ONLINE CONTROL OF A SKILLED, COMPLEX, MOTOR BEHAVIOR. MY SPONSOR, DR. Z. JOSH HUANG, PH.D., IS AN EXPERT IN THE ASSEMBLY AND FUNCTION OF MAMMALIAN CEREBRAL CORTICAL CIRCUITS. CONSISTENT WITH HIS LONG-ESTABLISHED TRACK RECORD OF MENTORSHIP, THE PROPOSED STUDIES AND TRAINING PLAN WILL PROVIDE ME WITH THE CRITICAL SCIENTIFIC AND PROFESSIONAL SKILLS FOR A FUTURE CAREER AS A NEUROLOGIST-SCIENTIST FOCUSED ON CIRCUIT MECHANISMS AND DISORDERS OF MOVEMENT.