Abstract
Sick animals exhibit behavioral changes that extend beyond physiological symptoms, such as appetite loss and hypoactivity, and include a decline in social interactions. While social isolation during sickness has been recognized to have the evolutionary benefit of staving off disease spread, the molecular and neural mechanisms underlying this response remain unclear. Cytokines-immune-derived signaling molecules-have emerged as neuromodulators impacting brain function during inflammation. Through behavioral screening, we identify a unique role for the cytokine interleukin-1β (IL-1β) in promoting social withdrawal during sickness. IL-1β directly modulates the activity of IL-1R1-expressing neurons in the dorsal raphe nucleus (DRN) (IL-1R1(DRN)). Activation of these neurons is sufficient to elicit social withdrawal, while their inhibition or genetic deletion of IL-1R1 rescues self-imposed social isolation during systemic inflammation. Our findings reveal a neural mechanism that actively promotes social disengagement in sick animals, highlighting the role of IL-1R1(DRN) neurons in driving these behavioral adaptations.