Project Grant 2402645

COORDINATION OF PLASTICITY BETWEEN DISCRETE SYNAPSES IN REWARD CIRCUITS -THE BRAIN HAS THE AMAZING ABILITY TO BRING INFORMATION TOGETHER TO MAKE ASSOCIATIONS, WHICH IS IMPORTANT FOR LEARNING HOW TO GAIN THINGS THAT ARE BENEFICIAL OR PLEASURABLE AND AVOID THINGS THAT ARE HARMFUL. FORMING LEARNED ASSOCIATIONS BETWEEN REWARDING STIMULI LIKE FOOD AND THE CIRCUMSTANCES UNDER WHICH THOSE STIMULI ARE ENCOUNTERED IS NECESSARY FOR SURVIVAL, YET HOW THE BRAIN ESTABLISHES AND MAINTAINS THESE ASSOCIATIONS REMAINS ELUSIVE. NEURONS IN THE BRAIN COMMUNICATE WITH ONE ANOTHER TO REGULATE BEHAVIOR, AND ONE NEURON OFTEN RECEIVES MULTIPLE INPUTS FROM OTHER NEURONS, WHICH UNDERLIES THE BRAIN?S ABILITY TO BRING TOGETHER INFORMATION. THE ABILITY TO MODIFY THE COMMUNICATION BETWEEN NEURONS IS A CORE MECHANISM BY WHICH MOMENTARY EXPERIENCES CAN BE TRANSFORMED INTO LONG-LASTING MEMORIES. HOWEVER, INVESTIGATIONS OF THE CHANGES IN NEURONAL COMMUNICATION THAT MEDIATE BEHAVIORS LIKE LEARNING AND MEMORY HAVE LARGELY FOCUSED ON ONE SET CONNECTIONS AT A TIME LEAVING A SIGNIFICANT GAP IN OUR UNDERSTANDING OF HOW DIFFERENT INPUTS CONVERGE TO INTEGRATE INFORMATION. THE PROPOSED WORK WILL UTILIZE CUTTING-EDGE APPROACHES TO MANIPULATE DIFFERENT NEURONAL CONNECTIONS TO DETERMINE HOW TWO DIFFERENT INPUTS INTERACT WITHIN A SINGLE NEURON. THE RESULTS OF THIS STUDY WILL ANSWER THE FUNDAMENTAL QUESTION: HOW DOES INFORMATION COME TOGETHER IN THE BRAIN? THESE FINDINGS HAVE SIGNIFICANT IMPLICATIONS FOR HOW WE UNDERSTAND BRAIN FUNCTION AND HOW THE BRAIN BRINGS TOGETHER INFORMATION TO REGULATE BEHAVIOR. IN ADDITION TO SCIENTIFIC ADVANCEMENT, EXECUTION OF THIS WORK WILL FOSTER THE DEVELOPMENT OF TRAINEES FROM DIVERSE BACKGROUNDS THROUGH HANDS-ON RESEARCH OPPORTUNITIES AND PROFESSIONAL DEVELOPMENT. THE MAIN OBJECTIVE IN THIS PROPOSAL IS TO DETERMINE THE MECHANISMS RESPONSIBLE FOR MEDIATING AND COORDINATING PLASTICITY AT HIPPOCAMPUS (HIPP)- NUCLEUS ACCUMBENS (NAC) SYNAPSES. THIS IS A KEY SITE OF CONVERGENCE BETWEEN SPATIAL AND CONTEXTUAL INFORMATION AND REWARD PROCESSING WHERE PLASTICITY IS A CRITICAL MEDIATOR OF MOTIVATED BEHAVIOR. HIPP INPUT CONSISTS OF TWO INDEPENDENT PATHWAYS EMANATING FROM DORSAL (DHIPP) AND VENTRAL (VHIPP) SUBREGIONS WITH THE PREVAILING BELIEF THAT THEIR INNERVATION OF AND INFLUENCES ON NAC FUNCTION ARE LARGELY DISTINCT. HOWEVER, PRELIMINARY DATA DEMONSTRATE DHIPP AND VHIPP INNERVATE OVERLAPPING REGIONS IN THE NAC. INDIVIDUAL NEURONS IN THESE AREAS OF OVERLAP CAN RESPOND TO BOTH DHIPP AND VHIPP INPUT, AND PLASTICITY AT ONE SYNAPSE MODULATES RESPONSES IN THE OTHER. THESE OBSERVATIONS CHALLENGE THE CONVENTIONAL BELIEF THAT THESE TWO PATHWAYS ARE ENTIRELY INDEPENDENT AND RAISE NEW QUESTIONS REGARDING THE MECHANISMS UNDERLYING PLASTICITY AT DHIPP-NAC AND VHIPP-NAC SYNAPSES. VIRAL-MEDIATED APPROACHES WILL BE USED TO SPECIFICALLY LABEL AND MANIPULATE DHIPP-NAC AND VHIPP-NAC PATHWAYS IN THE MOUSE BRAIN TO TEST THE CENTRAL HYPOTHESIS THAT DHIPP AND VHIPP PATHWAYS CONVERGE IN THE NAC, AND INTERACTIONS BETWEEN SYNAPSES COORDINATE PLASTICITY WITHIN INDIVIDUAL NEURONS. SUCCESSFUL COMPLETION OF THE PROPOSED WORK WILL ESTABLISH NOVEL MECHANISMS UNDERLYING ACTIVITY-DEPENDENT SYNAPTIC PLASTICITY AND THEIR COORDINATION WITHIN INDIVIDUAL NEURONS THAT WILL BE KEY TO DEFINING NEURONAL MECHANISMS THAT UNDERLIE MOTIVATED BEHAVIORS. OUR MULTIDIMENSIONAL PERSPECTIVE WILL PROVIDE NOVEL INSIGHT INTO THE COMPLEX MECHANISMS RESPONSIBLE FOR MEDIATING REWARD LEARNING WITH SUBSTANTIAL IMPLICATIONS FOR ADVANCING KNOWLEDGE OF THE FUNDAMENTAL PRINCIPLES OF BRAIN FUNCTION. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.