Project Grant F31MH146025

CYTOKINE MODULATION OF DORSAL RAPHE NUCLEUS NEURONS UNDERLYING DEPRESSIVE-LIKE BEHAVIOR - PROJECT SUMMARY MAJOR DEPRESSIVE DISORDER (MDD) IS A DEBILITATING MENTAL HEALTH DISORDER THAT SEVERELY LIMITS PSYCHOSOCIAL FUNCTION AND GREATLY DIMINISHES ONE'S QUALITY OF LIFE. DESPITE DECADES OF RESEARCH ON MONOAMINERGIC-BASED ANTIDEPRESSANTS, CURRENT MEDICATIONS REMAIN INEFFECTIVE FOR NEARLY ONE-THIRD OF MDD PATIENTS, UNDERSCORING THE NEED TO IDENTIFY NOVEL BIOLOGICAL MECHANISMS UNDERLYING MOOD REGULATION. EMERGING EVIDENCE INDICATES THAT THE IMMUNE SYSTEM PLAYS A CRITICAL ROLE IN MDD PATHOPHYSIOLOGY, BUT HOW IMMUNE DYSREGULATION ALTERS NEURAL CIRCUITS UNDERLYING DEPRESSIVE SYMPTOMS REMAINS POORLY UNDERSTOOD. RECENT STUDIES HAVE REVEALED THAT CYTOKINES, IMMUNE SIGNALING PROTEINS, CAN ALTER NEURAL EXCITABILITY, SYNAPTIC PLASTICITY, AND BEHAVIOR, SUGGESTING THAT CYTOKINES MAY ALSO ACT AS NEUROMODULATORS. ONE SUCH CYTOKINE, INTERLEUKIN-4 (IL-4), HAS EMERGED AS A KEY REGULATOR OF BRAIN FUNCTION. ALTHOUGH TRADITIONALLY THOUGHT OF AS AN ANTI-INFLAMMATORY MOLECULE, ELEVATED IL-4 LEVELS HAVE BEEN IMPLICATED IN MDD. NOTABLY, THE DORSAL RAPHE NUCLEUS (DRN), A MAJOR SOURCE OF NEUROMODULATORY PROJECTIONS AND A REGION HEAVILY IMPLICATED IN MDD, IS ENRICHED IN IL-4 RECEPTOR ALPHA (IL-4RA), AN EXPRESSION PATTERN NOT OBSERVED IN OTHER BRAIN REGIONS. THIS SELECTIVE ENRICHMENT POSITIONS THE DRN AS A UNIQUE SITE WHERE PERIPHERAL IMMUNE SIGNALS MAY DIRECTLY INFLUENCE NEURAL CIRCUITS THAT UNDERLIE MOOD. IN PARTICULAR, THE PROJECTIONS FROM THE DRN TO THE MEDIAL PREFRONTAL CORTEX (DRN-MPFC) ARE ESSENTIAL FOR REGULATING MOOD, MOTIVATION, AND SOCIAL BEHAVIOR, POSITIONING IT AS A LIKELY TARGET OF IL-4 MODULATION. HOWEVER, THE MECHANISMS BY WHICH IL-4 INFLUENCES THE DRN-MPFC CIRCUIT AND ITS CONSEQUENCES ON DEPRESSIVE-LIKE BEHAVIOR REMAIN UNKNOWN. THIS PROJECT TESTS THE CENTRAL HYPOTHESIS THAT IL-4 ACTS AS A NEUROMODULATOR TO DAMPEN ACTIVITY IN THE DRN-MPFC CIRCUIT AND ULTIMATELY DRIVE DEPRESSIVE-LIKE BEHAVIOR. AIM 1 WILL DEFINE HOW IL-4 INFUSION INTO THE DRN AFFECTS DRN-MPFC ACTIVITY DURING DEPRESSIVE-LIKE BEHAVIORAL ASSAYS USING PROJECTION-SPECIFIC FIBER PHOTOMETRY. AIM 2 WILL USE A VIRAL KNOCKDOWN STRATEGY TO SELECTIVELY KNOCK OUT IL-4RA ON NEURONS AND MICROGLIA IN THE DRN AND TEST THEIR NECESSITY FOR IL-4-INDUCED DEPRESSIVE-LIKE BEHAVIOR. THIS PROJECT IS THE FIRST TO INVESTIGATE THE ROLE OF IL-4 SIGNALING IN THE DRN-MPFC CIRCUIT UNDERLYING DEPRESSIVE-LIKE BEHAVIOR. BY LINKING AN IMMUNE CYTOKINE TO A DEFINED MOOD-REGULATING CIRCUIT, THIS WORK ESTABLISHES A NOVEL FRAMEWORK FOR UNDERSTANDING THE NEUROIMMUNE MECHANISMS OF DEPRESSION. THIS RESEARCH WILL SUPPORT MY DEVELOPMENT AS AN INDEPENDENT INVESTIGATOR BY STRENGTHENING MY EXPERTISE IN NEURAL CIRCUIT DISSECTION, IN VIVO IMAGING, AND TRANSLATIONAL MODELS OF DEPRESSION.