Role of serotonergic IL-1R1 in modulating physiological and behavioral responses to peripheral inflammation

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Project Summary/Abstract Serotonergic circuits are involved in complex behaviors linked to mood, reward, appetite, and social behavior. Dysfunction of these circuits is believed to support multiple neuropsychiatric disorders including anxiety, depression, autism, and schizophrenia. Although often treated monolithically, serotonergic projections arise from subpopulations of neurons that confer distinct behavioral outcomes. A subset of serotonin (5-HT) neurons support the transduction of peripheral innate immune system activation into changes in discrete behaviors, though mechanistic details of this are poorly understood. A better understanding of the location, function and behavioral output of these neurons will help elucidate the comorbidity observed between immune system dysfunction and neuropsychiatric disorders. Activation of the innate immune system rapidly increases the activity of the presynaptic 5-HT transporter (SERT), which contributions to 5-HT neurotransmission. In vitro and ex vivo studies support a role for signaling by the inflammatory cytokine, IL-1β, through its receptor IL-1R1, to influence SERT via p38α MAPK. The distribution of serotonergic IL-1R1, their ability to support cell autonomous modulation of 5-HT neurons, and the necessity/sufficiency of IL-1R1 in the functional manifestations of serotonergic signaling is unknown. Resolving these issues will improve our understanding of how the peripheral immune system communicates activation to the CNS and thereby establishes adaptive behavioral responses as a means of coping with global states of inflammation. The current proposal aims to 1) quantify and validate patterns of serotonergic IL-1R1 expression and immune system-related activation, 2) determine the projection sites of serotonergic IL-1R1-expressing neurons, 3) determine the necessity/sufficiency of serotonergic IL-1R1 in mediating inflammation-induced changes in in vivo CNS SERT activity and 5-HT release, and 4) investigate behaviors demonstrated to depend on serotonergic IL-1R1 activation. The proposed studies will make use of recently-developed mice that have IL-1R1 eliminated from 5-HT neurons, as well as mice that lack whole-body IL-1R1, but have a functional tagged IL-1R1 restored in 5-HT neurons. These aims will elucidate a fundamental pathway by which the function of 5-HT neurons is modulated by peripheral inflammation and clarify links between observations of elevated inflammatory markers and neuropsychiatric disorders. Moreover, they may establish the rationale for the development of novel medications that target anatomically and functionally discrete aspects of serotonergic neuromodulation. My training plan, which provides opportunities to develop as an independent investigator, primarily focuses on the above research, along with activities related to career development including RCR training, participation at scientific meetings, neuroscience community engagement and outreach, and junior scientist mentorship. My project will be pursued under the mentorship of Dr. Randy Blakely and a senior Advisory Committee at the FAU Brain Institute and supported by the advanced technology core facilities and neuroscience research community of FAU, Scripps Florida, and the Max Planck Florida Institute.