Project Grant R01NS135616

ELUCIDATING NEURAL MECHANISMS UNDERLYING SICKNESS BEHAVIORS - ABSTRACT SICKNESS BEHAVIORS REPRESENT A RANGE OF BEHAVIORAL CHANGES THAT MANIFEST IN RESPONSE TO INFECTION OR INFLAMMATION. THESE CHANGES INCLUDE REDUCED PHYSICAL ACTIVITY, DIMINISHED SOCIAL INTERACTION, AND ALTERED FEEDING BEHAVIOR. IT IS SUGGESTED THAT THESE BEHAVIORAL SHIFTS ARE INTEGRAL TO THE BODY'S IMMUNE RESPONSE AGAINST PATHOGENS, SERVING TO CONSERVE ENERGY, DEPRIVE PATHOGENS OF NUTRIENTS, AND CONTAIN THE INFECTION WITHIN THE HOST'S COMMUNITY. NEVERTHELESS, THE MECHANISMS BEHIND THE INITIATION OF SICKNESS BEHAVIORS AT THE LEVEL OF NEURONS AND NEURAL CIRCUITS REMAIN LARGELY UNEXPLORED. THIS RESEARCH ENDEAVORS TO FILL THIS KNOWLEDGE GAP BY IDENTIFYING A NEURAL SUBSTRATE THAT ACTS AS A POINT OF INTERACTION BETWEEN THE IMMUNE AND NERVOUS SYSTEMS. CYTOKINES, SIGNALING MOLECULES PRODUCED BY VARIOUS IMMUNE CELLS, PLAY A PIVOTAL ROLE IN MOUNTING THE BODY'S IMMUNE RESPONSE AGAINST PATHOGENIC THREATS. A GROWING BODY OF EVIDENCE SUGGESTS THAT CYTOKINES CAN ALSO FUNCTION AS NEUROMODULATORS BY ACTING ON RECEPTORS EXPRESSED ON NEURONS WITHIN THE CENTRAL NERVOUS SYSTEM. IL-1B IS ONE SUCH CYTOKINE THAT HAS BEEN STRONGLY ASSOCIATED WITH THE GENERATION OF SICKNESS BEHAVIORS. IN SUPPORT OF THIS IDEA, OUR DATA HAS REVEALED ENRICHMENT OF ITS RECEPTOR, IL-1R1, WITHIN THE DORSAL RAPHE NUCLEUS (DRN), A BRAIN REGION WELL-KNOWN FOR ITS INVOLVEMENT IN REGULATING BEHAVIORS ALTERED DURING SICKNESS. THESE OBSERVATIONS SUGGEST THAT IL-1B MIGHT ACT DIRECTLY ON IL-1R1-EXPRESSING NEURONS OF THE DRN (IL-1R1DRN) TO PROMOTE THE EXPRESSION OF SICKNESS BEHAVIORS. IN THIS APPLICATION, WE WILL TEST THIS HYPOTHESIS USING A RANGE OF MOLECULAR, GENETIC, AND SYSTEMS NEUROSCIENCE METHODS. SPECIFICALLY, IN AIM 1, WE WILL COMPREHENSIVELY EXAMINE IL-1R1 EXPRESSION IN THE DRN AND MONITOR THE ACTIVITY OF DRN NEURONS IN RESPONSE TO IL-1B AND INFLAMMATION. IN AIM 2, WE WILL MANIPULATE THE ACTIVITY OF IL-1R1DRN NEURONS TO INVESTIGATE THEIR ROLE IN MODULATING SICKNESS BEHAVIORS. WE WILL ALSO EXPLORE WHETHER IL-1 RECEPTOR EXPRESSION ITSELF IN THE DRN IS ESSENTIAL FOR GENERATING SICKNESS BEHAVIORS. FINALLY, IN AIM 3, WE WILL IDENTIFY DOWNSTREAM TARGETS OF IL-1R1DRN NEURONS THAT MEDIATE SICKNESS BEHAVIORS WHILE SIMULTANEOUSLY ASKING WHETHER IL-1R1DRN RELIES ON A SINGLE TARGET TO INDUCE ALL SICKNESS BEHAVIORS OR IF IT UTILIZES DIFFERENT TARGETS FOR GENERATING DISTINCT TYPES OF SICKNESS BEHAVIORS. IN SUMMARY, OUR STUDY WILL IDENTIFY IL-1R1DRN AND ITS ASSOCIATED TARGETS AS THE PRIMARY NEURAL CIRCUITS INFLUENCED BY THE PRO-INFLAMMATORY CYTOKINE IL-1B IN DRIVING BEHAVIORAL CHANGES DURING SICKNESS. SUCCESSFUL COMPLETION OF THIS RESEARCH WILL OFFER NEURAL CIRCUIT-FOCUSED INSIGHTS INTO HOW CHANGES IN THE IMMUNE SYSTEM UNDER INFLAMMATORY CONDITIONS CAN LEAD TO CORRESPONDING ALTERATIONS IN BEHAVIOR.