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Principal Investigator: Gloria Choi
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $473,814
Funding agency: National Institute of Neurological Disorders and Stroke
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-1β 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-1β 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-1β 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-1β 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.
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