Project Grant R01AG082975

NEUROINFLAMMATION, PERINEURAL NETS, AND POSTOPERATIVE DELIRIUM - THE AGING BRAIN IS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING POSTOPERATIVE DELIRIUM (POD), POSTOPERATIVE NEUROCOGNITIVE DISORDER (PNCD), AND ALZHEIMER'S DISEASE. POD OCCURS IN 9-50% OF OLDER PATIENTS UNDERGOING ANESTHESIA AND SURGERY AND IS ASSOCIATED WITH A HIGH RISK OF DEVELOPING ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD), GREATER INCIDENCES OF POSTOPERATIVE COMPLICATIONS, WORSE CLINICAL OUTCOMES, AND HIGHER MORTALITY. HEIGHTENED NEUROINFLAMMATION IS ONE OF THE KEY DRIVERS UNDERLYING AGE-RELATED POD. EXISTING RESEARCH ON POD PRIMARILY FOCUSES ON GLIAL CELLS AND NEURONS, WITH LITTLE ATTENTION PAID TO THE EXTRACELLULAR MATRIX(ECM). CELLS IN THE BODY CONSTANTLY COMMUNICATE WITH OTHER CELLS AND WITH ECM. IT HAS BECOME INCREASINGLY RECOGNIZED THAT ECM PROVIDES NOT ONLY ESSENTIAL PHYSICAL SCAFFOLDING FOR THE CELLULAR CONSTITUENTS BUT ALSO INITIATES CRUCIAL BIOCHEMICAL AND BIOMECHANICAL CUES THAT ARE OF UTMOST FUNCTIONAL IMPORTANCE. HOWEVER, WHETHER ECM IS IMPLICATED IN POD HAS YET TO BE EXAMINED. PERINEURAL NETS (PNNS) ARE ECM WITH CHONDROITIN SULFATE PROTEOGLYCAN-CONTAINING STRUCTURES SURROUNDING THE SOMA AND DENDRITES OF VARIOUS TYPES OF MAMMALIAN NEURONS. WE FOUND THAT OLDER MICE DISPLAYED ACCENTUATED NEUROINFLAMMATION CHARACTERIZED BY INCREASED IBA-1 EXPRESSION AS WELL AS DECREASED PNNS USING WFA STAINING. MICROGLIA DEPLETION USING PLX3397 PREVENTED THE DEGRADATION OF PNNS AND DETERRED THE OCCURRENCE OF POD, SUGGESTING MICROGLIA-MEDIATED PNNS DEGRADATION AS A NEUROINFLAMMATION MECHANISM UNDERLYING POD. TO DIRECTLY INTERROGATE NEURONAL ACTIVITIES IN POD, WE ESTABLISHED INTRAVITAL MULTI-PHOTON MICROSCOPY IN THE HIPPOCAMPUS. OLDER MICE AFTER ANESTHESIA AND SURGERY DEMONSTRATED EXAGGERATED EXCITATORY NEURON ACTIVITIES. IN CONTRAST, PARVALBUMIN (PV) INTERNEURONS, A KEY SUBTYPE OF INHIBITORY NEURONS WHICH ARE OFTEN SURROUNDED BY PNNS, DISPLAYED DECREASED NEURONAL ACTIVITIES IN OLDER MICE AFTER ANESTHESIA AND SURGERY, REVEALING EXCITATORY/INHIBITORY IMBALANCE LINKED TO POD. BASED ON THESE RESULTS, WE HYPOTHESIZE THAT NEUROINFLAMMATION ACCOMPANIED BY ANESTHESIA AND SURGERY PROMOTES PNNS DEGRADATION WHICH LEADS TO NEURONAL DYSFUNCTION AND AGE-RELATED POD DEVELOPMENT. WE PLAN TO CARRY OUT THREE INTERRELATED BUT NOT INTERDEPENDENT AIMS TO RIGOROUSLY TEST THIS HYPOTHESIS. AIM 1: TO INVESTIGATE THE KINETICS OF NEUROINFLAMMATION-MEDIATED PNNS DEGRADATION AFTER ANESTHESIA AND SURGERY. AIM 2: TO EXAMINE IF DEPLETING PNNS SURROUNDING PV INTERNEURONS COULD PRECIPITATE POD. AIM 3: TO PREVENT POD BY ATTENUATING NEUROINFLAMMATION-INDUCED PNNS DEGRADATION. TAKEN TOGETHER, THIS PROPOSAL USES MULTIDISCIPLINARY TOOLS INCLUDING INTRAVITAL MULTI-PHOTON IMAGING, GENETIC MANIPULATION (MICROGLIA DEPLETION, NEURON-SPECIFIC CHABC, HAPLN1 EXPRESSION, ETC.), BIOCHEMISTRY, AND ANIMAL BEHAVIOR, TO DISSECT A PREVIOUSLY UNKNOWN ROLE FOR PNNS (ECM) IN THE PATHOGENESIS OF POD, WHICH PROVIDES NOVEL MECHANISTIC INSIGHTS AND THERAPEUTIC TARGETS FOR POD, A CONDITION RELATED TO ADRD.