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-1ß, through its receptor IL-1R1, to influence
SERT via p38a 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.