Project Grant F31AG101973

THE IMPACT OF AGING ON NEURAL MECHANISMS UNDERLYING SICKNESS SYMPTOMS AND DELIRIUM - PROJECT SUMMARY/ABSTRACT IN RESPONSE TO AN INFECTION, A STEREOTYPED SET OF SYMPTOMS ARE INDUCED TO FIGHT OFF PATHOGENS AND PROMOTE SURVIVAL. THESE RESPONSES ARE MEDIATED BY SPECIFIC NEURONAL POPULATIONS IN THE BRAIN THAT DETECT AND RESPOND TO IMMUNE MEDIATORS. THE SEVERITY OF AND RECOVERY FROM THESE SYMPTOMS MAY DEPEND ON SEVERAL FACTORS, INCLUDING GENETIC PREDISPOSITIONS, BIOLOGICAL SEX, IMMUNE HISTORY, AND AGE. IN AGED POPULATIONS, THESE TYPICALLY ADAPTIVE SYMPTOMS BECOME MORE SEVERE AND DETRIMENTAL, LEADING TO INCREASED MORTALITY. MOREOVER, AGED POPULATIONS EXHIBIT ADDITIONAL SYMPTOMS SUCH AS COGNITIVE IMPAIRMENT, INCLUDING DELIRIUM. WHILE PRIOR STUDIES HAVE LARGELY FOCUSED ON IMMUNE DYSFUNCTION WITH AGE, EMERGING EVIDENCE SUGGESTS THAT BRAIN REGIONS WITH IMMUNE-SENSITIVE NEURONAL CIRCUITS UNDERGO AGE-RELATED CHANGES, INCLUDING INCREASES IN NEUROINFLAMMATION AT THE CELLULAR AND MOLECULAR LEVELS. IMMUNE-RESPONSIVE CIRCUITS MAY BE PARTICULARLY SENSITIVE TO NORMAL AGE-RELATED NEUROINFLAMMATION, LEADING TO EXACERBATED SICKNESS SYMPTOMS; HOWEVER, IT IS STILL UNCLEAR HOW SICKNESS- GENERATED CIRCUITS CHANGE WITH AGE, WHETHER THIS CHANGE IS CORRELATED WITH SICKNESS BEHAVIORS OR INCREASES IN NEUROINFLAMMATORY MARKERS. THIS PROJECT AIMS TO ELUCIDATE THE NEURAL MECHANISMS OF AGE-RELATED CHANGES IN SICKNESS AND COGNITIVE SYMPTOMS AND THE CONTRIBUTION OF CHANGES IN IMMUNE-GENE EXPRESSION UNDERLYING INCREASED ACTIVITY IN IMMUNE-SENSITIVE POPULATIONS. I HYPOTHESIZE THAT AGING INCREASES SICKNESS SYMPTOM SEVERITY THROUGH INCREASED ACTIVITY LEVELS AND INCREASED IMMUNE GENE EXPRESSION IN SICKNESS-GENERATING NEURONS. THIS PROPOSAL WILL CHARACTERIZE THE SEVERITY OF SICKNESS BEHAVIORS AND COGNITIVE IMPAIRMENT AND IDENTIFY REGIONS WITH ALTERED SICKNESS-RELATED ACTIVITY PATTERNS AND NEURAL DYNAMICS IN AGING. IT WILL ADDITIONALLY REVEAL THE CHANGES IN IMMUNE-GENE EXPRESSION IN CRITICAL SICKNESS REGIONS THAT MAY IMPACT THE ACTIVITY OF IMMUNE-SENSITIVE NEURONS. THESE RESULTS WILL PROVIDE CRITICAL INSIGHT INTO THE IMPACT OF AGING ON IMMUNE-RESPONSIVE CIRCUITS AND THE NEUROPATHOLOGY OF DELIRIUM. IT WILL ALSO LAY THE GROUNDWORK FOR FUTURE STUDIES INTO THE UPSTREAM CELLULAR AND MOLECULAR PATHWAYS LINKING NEUROINFLAMMATION TO SICKNESS SEVERITY AND COGNITIVE IMPAIRMENT. THIS PROJECT WILL ALSO PROVIDE EXCELLENT MULTIDISCIPLINARY TRAINING IN NEUROIMMUNOLOGY, SYSTEMS AND BEHAVIORAL NEUROSCIENCE, AND AGING. THIS TRAINING PLAN WILL PROVIDE THE CONCEPTUAL, TECHNICAL, AND PROFESSIONAL SKILLS NECESSARY FOR A CAREER AS AN INDEPENDENT INVESTIGATOR AND WILL PROVIDE OPPORTUNITIES FOR NETWORKING AND COLLABORATIVE RESEARCH. THIS RESEARCH WILL BE CONDUCTED IN AN ENVIRONMENT WITH INVESTIGATORS SKILLED IN THE FIELDS AND TECHNIQUES NECESSARY TO MAKE THE PROJECT SUCCESSFUL, AND AT AN INSTITUTION WITH ALL THE NECESSARY EQUIPMENT AND FACILITIES TO PERFORM THIS RESEARCH IN A RIGOROUS AND REPRODUCIBLE MANNER.