Summary: New research pinpoints the immune-to-brain pathway responsible for the loss of social motivation during illness. The study shows that the immune signaling molecule interleukin-1 beta (IL-1β) binds to IL-1R1 receptors on neurons in the dorsal raphe nucleus (DRN), activating a neural circuit to the lateral septum that drives social withdrawal.
This mechanism operates independently of general sickness-related lethargy, demonstrating that social withdrawal during infection is an active, regulated behavior rather than a passive side effect. The work clarifies a precise neural route by which the immune system reshapes behavior in response to systemic inflammation.
Key Facts:
- Immune–brain connection: IL-1β acts directly on IL-1R1-expressing neurons in the dorsal raphe nucleus to suppress social behaviors.
- Identified circuit: The DRN-to-intermediate lateral septum projection reproduces the full social withdrawal response.
- Separate from lethargy: Interfering with this circuit blocks social withdrawal without reversing illness-induced lethargy, indicating distinct mechanisms.
Source: Picower Institute at MIT
Overview
Across species, infection commonly leads animals to withdraw from social contact. This behavioral change reduces the spread of disease and conserves energy for recovery, but the underlying molecular and neural mechanisms have been unclear. A team at the Picower Institute for Learning and Memory at MIT, together with collaborators, dissected the pathway linking immune signaling to social behavior and demonstrated causality using multiple techniques.
Published Nov. 25 in Cell, the study focused on the cytokine interleukin-1 beta (IL-1β). By testing many immune signaling molecules directly in the brain, the researchers identified IL-1β as uniquely capable of reproducing the social withdrawal typically produced by systemic immune challenges such as LPS. They then mapped where IL-1β’s receptor, IL-1R1, is expressed across brain regions and identified a population of IL-1R1-expressing neurons in the dorsal raphe nucleus (DRN) as a critical site of action.
The DRN is well positioned to respond to circulating immune signals because of its proximity to cerebrospinal fluid pathways and because it contains neurons that influence social behavior, including many serotonin-producing cells. The investigators showed that IL-1β activates IL-1R1-positive DRN neurons, that artificial activation of these neurons produces social withdrawal, and that silencing them prevents social withdrawal induced by IL-1β or systemic immune challenge. Importantly, manipulating these neurons did not abolish the general reduction in activity (lethargy) caused by immune activation, indicating that social disengagement and hypoactivity are mediated by separate mechanisms.
Mapping the downstream circuit
To discover which downstream connections mediate the behavioral change, the team traced projections from the IL-1R1-expressing DRN neurons to several brain regions implicated in social behavior. Using optogenetics to activate specific axonal projections, they found that only stimulation of the projection from the DRN to the intermediate lateral septum fully reproduced the social withdrawal seen after IL-1β or systemic infection. The result confirms that a defined DRN→intermediate lateral septum circuit drives self-imposed social isolation during sickness. The findings were further supported by experiments using a bacterial infection model (salmonella) to evoke similar responses.
The authors conclude that IL-1β acting on IL-1R1-expressing DRN neurons is a primary effector of social withdrawal during systemic immune activation. While this work establishes the cytokine, receptor, neurons, and circuit responsible for social withdrawal in mice, it also raises follow-up questions: Do these IL-1R1-positive DRN neurons influence other sickness behaviors, and what role, if any, does serotonin play in mediating these changes?
Study leaders include Gloria Choi (co-senior author), associate professor at the Picower Institute and MIT’s Department of Brain and Cognitive Sciences, and Jun Huh (co-senior author), associate professor of immunology at Harvard Medical School. The paper’s lead author is Liu Yang, a research scientist in Choi’s lab; other contributors include Matias Andina, Mario Witkowski, Hunter King, and Ian Wickersham.
Funding: The work was supported by the National Institute of Mental Health, the National Research Foundation of Korea, the Denis A. and Eugene W. Chinery Fund for Neurodevelopmental Research, the Jeongho Kim Neurodevelopmental Research Fund, Perry Ha, the Simons Center for the Social Brain, the Simons Foundation Autism Research Initiative, the Picower Institute for Learning and Memory, and the Freedom Together Foundation.
Key Questions Answered:
A: The cytokine IL-1β activates IL-1R1-expressing neurons in the dorsal raphe nucleus, initiating a neural program that suppresses social interaction.
A: The critical pathway identified is the projection from IL-1R1-positive neurons in the dorsal raphe nucleus to the intermediate lateral septum.
A: No. The study demonstrates that social withdrawal is an actively generated neural response that can be dissociated from general sickness-related lethargy.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to clarify the findings.
About this neuroscience and social isolation research news
Author: David Orenstein
Source: Picower Institute at MIT
Contact: David Orenstein – Picower Institute at MIT
Image: Image credited to Neuroscience News
Original Research: Open access. Title: “IL-1R-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness” by Gloria Choi et al., published in Cell.
Abstract
IL-1R-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness
Sick animals show behavioral changes beyond classic physiological symptoms like appetite loss and reduced activity; they also withdraw from social interactions. Although social isolation during illness may have adaptive value by limiting disease transmission, the molecular and neural mechanisms driving this behavior have been unclear. Cytokines—immune-derived signaling molecules—can act as neuromodulators during inflammation. Through behavioral screening, the researchers identified interleukin-1β (IL-1β) as a key cytokine that promotes social withdrawal. IL-1β directly modulates IL-1R1-expressing neurons in the dorsal raphe nucleus (IL-1R1DRN). Activation of these neurons is sufficient to elicit social withdrawal, while their inhibition or genetic deletion of IL-1R1 prevents self-imposed social isolation during systemic inflammation. These findings reveal a neural mechanism that actively promotes social disengagement in sick animals, highlighting the role of IL-1R1DRN neurons in this adaptive behavioral response.