LINKING STIMULATION PATTERN-DRIVEN AND CELL-SPECIFIC MYELINATION TO COGNITIVE OUTCOMES IN ALZHEIMER'S DISEASE - PROJECT SUMMARY / ABSTRACT ALZHEIMER'S DISEASE (AD) AFFECTS MILLIONS OF AMERICANS AND IS CHARACTERIZED BY EARLY MYELIN LOSS, CIRCUIT INSTABILITY, AND COGNITIVE DECLINE. MYELIN, PRODUCED BY OLIGODENDROCYTES, IS ESSENTIAL FOR MAINTAINING NEURAL CIRCUIT STABILITY, YET CURRENT NEUROMODULATION STRATEGIES FOCUS ALMOST EXCLUSIVELY ON NEURONAL ACTIVITY, OVERLOOKING HOW OLIGODENDROCYTES RESPOND TO STIMULATION. THIS PROJECT TESTS THE CENTRAL HYPOTHESIS THAT DISTINCT PATTERNS OF BRAIN STIMULATION CAN DRIVE OLIGODENDROCYTE CALCIUM ACTIVITY TO PRODUCE SPECIFIC MYELINATION OUTCOMES, AND THAT TARGETING PARTICULAR NEURONAL SUBTYPES WILL DIFFERENTIALLY INFLUENCE MYELINATION AT THE CELL- SPECIFIC AND NETWORK LEVEL, WITH IMPLICATIONS FOR COGNITIVE FUNCTION. AIM 1 WILL DEFINE HOW INTRACORTICAL MICROSTIMULATION PATTERNS EVOKE OLIGODENDROCYTE CALCIUM DYNAMICS AND DRIVE PARADIGM-SPECIFIC MYELIN REMODELING IN VIVO. AIM 2 WILL INVESTIGATE WHETHER STIMULATING INHIBITORY OR EXCITATORY NEURONAL SUBTYPES ALTERS MYELINATION AT THE CELL AND NETWORK LEVEL AND HOW THESE CHANGES AFFECT COGNITION IN A MOUSE MODEL OF AD. BY INTEGRATING LONGITUDINAL IMAGING, ULTRASTRUCTURAL ANALYSIS, AND BEHAVIORAL ASSESSMENT, THIS RESEARCH WILL ELUCIDATE MECHANISMS LINKING NEURONAL ACTIVITY, MYELIN REMODELING, AND CIRCUIT FUNCTION, ESTABLISHING A FOUNDATION FOR FUTURE STRATEGIES TO PRESERVE COGNITIVE FUNCTION IN AD AND RELATED NEURODEGENERATIVE DISEASES.