Project Grant 2452718

CONTROL OF DENTATE GYRUS FUNCTION AND CONTEXT DISCRIMINATION BY CCK+ INTERNEURONS -EFFICIENT MEMORY PROCESSES RELY ON OUR BRAIN'S ABILITY TO STORE SIMILAR EXPERIENCES AS DISTINCT MEMORIES. THIS PROCESS, PERFORMED IN PART BY A STRUCTURE IN THE BRAINS OF MAMMALS CALLED HIPPOCAMPUS, FACILITATES MEMORY DISCRIMINATION AND IS AFFECTED IN BRAIN DISORDERS LIKE DEMENTIA AND POST-TRAUMATIC STRESS DISORDERS. AS A RESULT, ANIMALS AND PEOPLE SUFFERING FROM THESE DISORDERS EXPERIENCE DIFFICULTIES RECALLING OR ACCURATELY RETRIEVING MEMORIES. OUR UNDERSTANDING OF HOW THE HIPPOCAMPUS ENCODES SIMILAR EXPERIENCES AS DISTINCT MEMORIES, ALLOWING FOR EASY DISCRIMINATION DURING RECALL, IS STILL LIMITED. RECENT ADVANCEMENTS IN NEUROSCIENCE SUGGEST THAT COORDINATED ACTIVITY BETWEEN EXCITATORY AND INHIBITORY NEURONS ENABLES A SPECIFIC COMPUTATION KNOWN AS PATTERN SEPARATION WITHIN THE HIPPOCAMPAL CIRCUIT. THIS COMPUTATION TRANSFORMS SIMILAR INPUT PATTERNS INTO HIGHLY DISSIMILAR OUTPUT PATTERNS AND IS THOUGHT TO BE THE BASIS FOR MEMORY DISCRIMINATION. IN THE PROPOSED RESEARCH, THE INVESTIGATORS AIM TO DETERMINE THE CONTRIBUTION OF A SPECIFIC TYPE OF INHIBITORY NEURONS CALLED CHOLECYSTOKININ-EXPRESSING (CCK) NEURONS TO THE HIPPOCAMPAL CIRCUIT?S FUNCTION. THEIR LONG-TERM GOAL IS TO ENHANCE OUR UNDERSTANDING OF CRITICAL COMPUTATIONS, LIKE PATTERN SEPARATION, PERFORMED BY THIS BRAIN REGION, WHICH ARE CRUCIAL FOR MEMORY DISCRIMINATION. AS PART OF THIS PROJECT, THE INVESTIGATORS ALSO PROVIDE A STRONG EDUCATIONAL AND TRAINING ENVIRONMENT TO STUDENTS AND NEW GENERATIONS OF SCIENTISTS WITH A STRONG EMPHASIS IN RECRUITING AND TRAINING MINORITIES AND UNDER-REPRESENTED GROUPS IN STEM, AND THEY PARTICIPATE IN OUTREACH PROGRAMS, SUCH AS THE BIG BROTHER BIG SISTER EVENT ORGANIZED BY THE RENO MUSEUM OF NATURAL HISTORY, WHICH THEY USE AS A PLATFORM TO SHARE THEIR RESEARCH WITH THE GENERAL PUBLIC AND STUDENTS OF ALL AGES. THE INVESTIGATORS AIM TO DETERMINE THE CONTRIBUTION OF CCK NEURONS TO HIPPOCAMPAL CIRCUIT FUNCTION, FOCUSING ON THE PLASTICITY OF CCK NEURONS DURING THE DEVELOPMENTAL PERIOD OF JUVENILE MICE. THEIR PREVIOUS WORK DEMONSTRATES THAT ENVIRONMENTAL ENRICHMENT (EE) LEADS TO INCREASED SYNAPSES FORMED BY CCK NEURONS IN THE DENTATE GYRUS, SUGGESTING THEIR INVOLVEMENT IN THE MATURATION OF HIPPOCAMPAL FUNCTION AND PATTERN SEPARATION. FOR THE PROPOSED WORK, THEY USE AN EE PARADIGM IN MICE AND TAKE ADVANTAGE OF VIRAL MEDIATED GENE DELIVERY TECHNIQUE COMBINED WITH OPTOGENETIC APPROACHES TO MANIPULATE THE ACTIVITY OF THE CCK NEURONS. THEY DETERMINE HOW THE REMODELING OF THE INHIBITORY CCK NETWORK ADJUSTS THE COMPUTATION IN THE DG. IN THE FIRST OBJECTIVE OF THE PROJECT, THEY DETERMINE THE CONTRIBUTION OF CCK NEURONS TO FEEDBACK AND FEEDFORWARD INHIBITORY MICROCIRCUITS, BOTH OF WHICH CAN IMPACT PATTERN SEPARATION. IN THE SECOND OBJECTIVE, THEY MEASURE THE CHANGE IN PATTERN SEPARATION AND FILTERING PERFORMANCE OF THE DG INDUCED BY THE EE USING A NOVEL IN-VITRO ELECTROPHYSIOLOGICAL PROTOCOL. TOGETHER THEIR RESEARCH AIMS TO UNRAVEL THE MECHANISMS UNDERLYING PATTERN SEPARATION BY EXPLORING THE INVOLVEMENT OF CCK NEURONS IN THE HIPPOCAMPAL CIRCUIT. BY INCREASING OUR UNDERSTANDING OF THESE FUNDAMENTAL COMPUTATIONS, THEY WILL SHED LIGHT ON THE PROCESSES THAT SUPPORT EFFICIENT MEMORY FUNCTIONING AND POTENTIALLY CONTRIBUTE TO THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES FOR MEMORY-RELATED DISORDERS. THIS PROJECT IS JOINTLY FUNDED BY THE MODULATION PROGRAM OF THE NEURAL SYSTEMS CLUSTER IN THE BIO DIRECTORATE AND THE ESTABLISHED PROGRAM TO STIMULATE COMPETITIVE RESEARCH (EPSCOR). 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.