Project Grant K01AI182449

BRAIN AND BEHAVIORAL ALTERATIONS IN A NONHUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION: MPFC-AMYGDALA CIRCUITRY, NEUROINFLAMMATION, AND SOCIOEMOTIONAL DEVELOPMENT - PROPOSAL SUMMARY EXPOSURE TO VIRAL OR BACTERIAL INFECTIONS DURING PREGNANCY INCREASES RISK FOR OFFSPRING NEURODEVELOPMENTAL DISORDERS, INCLUDING AUTISM AND SCHIZOPHRENIA. GESTATIONAL BIOMARKERS INDICATE THAT THE MATERNAL IMMUNE RESPONSE PLAYS A CRITICAL ROLE IN ALTERED FETAL NEURODEVELOPMENT. OUR ABILITY TO MITIGATE THE HARMFUL EFFECTS OF MATERNAL IMMUNE ACTIVATION (MIA) ON OFFSPRING NEURODEVELOPMENT IS LIMITED BY OUR INCOMPLETE MECHANISTIC UNDERSTANDING OF THE NEUROBIOLOGICAL CHANGES ASSOCIATED WITH PRENATAL EXPOSURE TO MIA. WHILE RODENT STUDIES HAVE SHOWN SIMILARITIES BETWEEN ALTERATIONS IN BRAIN AND BEHAVIORAL DEVELOPMENT IN MIA-EXPOSED OFFSPRING AND CHANGES OBSERVED IN HUMAN NEURODEVELOPMENTAL DISORDERS, THERE ARE LIMITATIONS IN TRANSLATING THESE FINDINGS TO HUMAN NEUROANATOMY AND PHYSIOLOGY. IT IS THEREFORE NECESSARY TO EXPAND THIS RESEARCH TO A PRECLINICAL MODEL MORE CLOSELY RELATED TO HUMANS, SUCH AS NONHUMAN PRIMATES (NHPS). MY PRIMARY MENTOR'S LABORATORY (BAUMAN) HAS DEVELOPED THE FIRST VIRAL-MIMIC BASED RHESUS MACAQUE MODEL OF MIA EXPOSURE IN PREGNANCY. FOR THIS K01 CAREER DEVELOPMENT AWARD, I PROPOSE TO LEVERAGE THE ENTIRETY OF BIOBEHAVIORAL DATA AVAILABLE FOR THE NHP MIA MODEL TO EXAMINE THE EFFECTS OF NEUROIMMUNE CHANGES ON BEHAVIORAL AND BRAIN ALTERATIONS IN MIA-EXPOSED NHPS. MY OUTSTANDING MENTORSHIP TEAM WILL PROVIDE FOUNDATIONAL TRAINING IN IMMUNOLOGY (VAN DE WATER) AND THE USE OF NHP MODELS (BAUMAN) TO ACCELERATE COMPLEX TRANSLATIONAL BIOMEDICAL RESEARCH IN NEURODEVELOPMENTAL DISORDERS (SCHUMANN). THIS AWARD, WHICH REPRESENTS A CRITICAL NEXT STEP IN MY DEVELOPMENT AS AN INDEPENDENT RESEARCH SCIENTIST, PROVIDES AN OPPORTUNITY TO MAKE USE OF MY UNIQUE SKILL SET IN HUMAN AND NHP CELLULAR AND MOLECULAR NEUROANATOMY, WHILE EXPANDING THE BREADTH OF MY RESEARCH FOCI IN THE UNIQUE INSTITUTIONAL ENVIRONMENT PROVIDED BY UC DAVIS AND THE CALIFORNIA NATIONAL PRIMATE RESEARCH CENTER. OUR RESEARCH WILL CONTRIBUTE TO OUR UNDERSTANDING OF THE BEHAVIORAL AND NEUROBIOLOGICAL CHANGES ASSOCIATED WITH PRENATAL EXPOSURE TO MIA. SPECIFICALLY, WE WILL APPLY NOVEL BEHAVIORAL PHENOTYPING PARADIGMS TO EVALUATE ALTERATIONS IN SOCIOEMOTIONAL BEHAVIOR IN THE MIA-EXPOSED NHP (AIM 1A). WE WILL LONGITUDINALLY MAP THE DEVELOPMENT OF THE AMYGDALA IN MIA-EXPOSED NHPS AND CONTROLS TO UNDERSTAND THE COURSE OF MIA- INDUCED STRUCTURAL BRAIN CHANGES (AIM 1B). USING POSTMORTEM TISSUE COLLECTED FROM SUBJECTS AT TWO CRITICAL AGE TIME POINTS, WE WILL EXAMINE NEUROIMMUNE PROTEOMIC ALTERATIONS IN THE AMYGDALA AND MEDIAL PREFRONTAL CORTEX (AIM 2A). USING MARKERS FOR NEUROIMMUNE TARGETS IDENTIFIED IN AIM 2A, WE WILL MAP THE EXPRESSION OF NEUROIMMUNE TRANSCRIPTS IN SPECIFIC CELL TYPES IN BRAIN TISSUE SECTIONS (AIM 2B). TOGETHER, THESE DATA BUILD A COMPREHENSIVE PICTURE OF MIA-INDUCED CHANGES IN NHP BRAIN CIRCUITRY, TOWARD THE ULTIMATE GOAL OF IDENTIFYING PATHWAYS OF VULNERABILITY AND CRITICAL PERIODS FOR NOVEL, TARGETED INTERVENTIONS AND BIOTHERAPEUTICS.