IL-1R1-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness, Yang et al, 2025

[leokitten]

Highlights​

• IL-1β uniquely triggers self-imposed social withdrawal during inflammation
• IL-1R1-positive DRN serotonergic neurons mediate social withdrawal
• A peripheral-to-central IL-1β relay sustains prolonged social withdrawal

Summary​

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-1R1DRN). 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-1R1DRNneurons in driving these behavioral adaptations.

https://www.cell.com/cell/abstract/S0092-8674(25)01245-0

 

[leokitten]

Feeling Anti-Social When You’re Sick? Signals to the Brain Are Responsible

Learn how your body uses an immune-to-brain communication line to nudge you away from others when you’re getting sick.

www.discovermagazine.com

 

[jnmaciuch]

This is an interesting paper. I'll note that out of the list of cytokines that they screened, they also found one cytokine (IL-1a) that reduced activity level but did not induce observable social withdrawal. So zeroing in on receptors/neuron populations specifically responsive to both IL-1a and IL-1b would give more insight into which pathway causes hypoactivity during infection.

 

[leokitten]

This is an interesting paper. I'll note that out of the list of cytokines that they screened, they also found one cytokine (IL-1a) that reduced activity level but did not induce observable social withdrawal. So zeroing in on receptors/neuron populations specifically responsive to both IL-1a and IL-1b would give more insight into which pathway causes hypoactivity during infection.

It’s the dorsal raphe nucleus so it’s serotonin neurons

 

[jnmaciuch]

It’s the dorsal raphe nucleus so it’s serotonin neurons

That’s specifically for neurons that were responsive to IL-1b and associated with social withdrawal in this study. If this is the same circuit that causes social withdrawal in human sickness, that's a clue that those neurons are probably not being activated in ME/CFS. pwME often express still having desire for social interaction but simply being prevented from socializing due to the illness (and it’s one of the things often cited to differentiate between ME/CFS and severe depression).

Since IL-1a also caused hypoactivity but no social withdrawal, it indicates that social withdrawal and hypoactivity are actually mediated by two separate circuits or signaling pathways (and they showed this is true in one of their knockout studies that dissociated social withdrawal from reduced locomotion). IL-1b binding to specific DRN neurons triggers both, but IL-1a only triggers the latter. So you could find the "hypoactivity mechanism" by looking at what non-ILR1+ cells get activated by both IL-1b and IL-1a but not any of the other cytokines tested.