Scientists identify skull-to-brain immune pathway linking chronic stress to depression

A new study published in Nature Communications provides evidence that chronic stress triggers the release of immune cells from bone marrow in the skull, which then travel to the protective layers surrounding the brain. These immune cells, known as neutrophils, appear to contribute to behavioral symptoms commonly associated with depression and anxiety. The findings, based on extensive research in mice, highlight a previously unrecognized link between the body’s immune response and stress-related mental health symptoms.

The research was led by Stacey Kigar, a postdoctoral research associate at the University of Cambridge, in collaboration with colleagues at the National Institute of Mental Health in the United States. The study adds to a growing body of work suggesting that inflammation may play a key role in depression.

People experiencing depression often report persistent sadness, low energy, reduced interest in previously enjoyable activities, sleep disturbances, and changes in appetite. While psychological and social factors contribute to its development, biological processes are also involved. In recent years, researchers have increasingly focused on how the immune system may influence the onset and persistence of depressive symptoms, particularly under conditions of chronic stress.

The researchers behind the new findings were motivated by accumulating evidence that the immune system plays an active role in mental health. Chronic inflammation has been associated with both major depressive disorder and ongoing psychosocial stress. Neutrophils—white blood cells that act as rapid responders to injury and infection—have been found at elevated levels in the blood of people with depression. These cells are known to respond to inflammatory signals, including those from type I interferons, a family of proteins involved in antiviral defense and immune regulation.

Previous work by the same research group had already shown that depleting B cells in mice, or subjecting them to chronic social stress, could lead to higher expression of interferon-related genes in the meninges. But it was not clear how neutrophils were being recruited to this region, or what role they might play in stress-induced behavioral changes.

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One recently described mechanism involves immune cells traveling directly from skull bone marrow through small vascular channels into the meninges, bypassing the bloodstream entirely. The team aimed to test whether this pathway might be activated by chronic stress, and if so, whether it could influence behavior.

“Depression affects many people and can be debilitating; I have seen it negatively impact loved ones first-hand,” Kigar told PsyPost. “Many people I talk to intuitively understand that stress and the onset of depression are linked, but there is still a narrative out there suggesting susceptibility to stress is somehow a personal failing, and that a person suffering from depression should be able to ‘pull themselves up by their bootstraps.'”

“My goal as a scientist has been to help demystify the black box of mental health research a bit by pinning down specific biological mechanisms that link environmental factors like stress to adverse outcomes like depression. In doing so, I hope we will shift the broader societal narrative on mental health away from one of personal weakness to one of legitimate biomedical concern.”

For their study, the researchers used a well-established model of chronic stress called chronic social defeat. In this paradigm, male mice are repeatedly exposed to brief but intense encounters with aggressive counterparts, leading to a range of behavioral changes. These behaviors—such as reduced interest in social interaction or exploration of new environments—are considered indicators of anxiety-like and depression-like states in mice.

The team subjected groups of mice to one, two, four, eight, or fourteen days of this stress protocol and examined both behavior and immune cell activity in various tissues. Behavioral tests included urine scent marking (a measure of sexual motivation), open field and light-dark box tests (to assess anxiety), and social interaction with unfamiliar mice. Only mice exposed to the full fourteen-day stress procedure showed significant increases in neutrophils in the meninges, while neutrophil levels in the blood rose after just one day of stress.

Advanced imaging of the skull and meninges revealed that many of these neutrophils originated from bone marrow in the skull. The researchers used genetically modified mice whose neutrophils glowed under a microscope to visually trace the route these cells took through bone channels into the meningeal tissue. They found that stressed mice had more neutrophils present in these skull-to-meninges channels, and that the composition of neutrophils in the meninges resembled those in bone marrow rather than those in the bloodstream. This pointed to the skull as a likely source of these stress-related immune cells.

Using single-cell RNA sequencing, the researchers analyzed the gene activity of meningeal immune cells in stressed versus control mice. They discovered that stressed mice had a higher proportion of neutrophils in the meninges, and that these cells expressed high levels of genes related to type I interferon signaling. These gene expression patterns indicated a heightened inflammatory response specific to this immune pathway. Notably, the effect was not seen in other immune cells such as monocytes, further pointing to a unique role for neutrophils.

The presence of more neutrophils in the meninges was associated with behavioral changes. Mice with higher numbers of these immune cells in meningeal tissue showed stronger signs of anxiety and anhedonia—the reduced ability to experience pleasure. The researchers also noted that the buildup of neutrophils in the meninges lasted longer than similar increases in the blood, suggesting a prolonged immune presence near the brain.

“We were surprised to find that following exposure to chronic stress, neutrophils in the brain’s protective tissues (meninges) showed a type I interferon signature,” Kigar explained. “While we had assumed chronic stress would change neutrophils in some way, we weren’t sure how; with this finding, things began to click. Type I interferons are given to patients with life-threatening viral infections; they boost an immune response and help clear the infection, but a well-known side effect is depressed mood. Identifying this pathway in meningeal neutrophils (and only neutrophils—none of the other cell types in our experiment showed enrichment of this pathway) was exciting and may help explain interferon-related depression.”

To test whether interferon signaling was essential to these effects, the team administered a drug that blocks the receptor for type I interferons. Mice given this treatment before and during chronic stress exposure showed fewer behavioral signs of stress, particularly in the urine marking and open field tests. At the same time, these mice had reduced numbers of neutrophils in the meninges, but not in the blood, reinforcing the idea that interferon-driven trafficking of neutrophils into brain-adjacent tissue contributes to behavioral symptoms.

“Stress has a demonstrable effect on your body; we can easily detect it using simple tests that count different types of immune cells in your blood,” Kigar told PsyPost. “Specifically, stress leads to greater release of ‘first responder’ cells called neutrophils into the bloodstream. While our bodies are generally good at ‘resetting’ after brief exposures to stress, if stress is prolonged, our ‘reset point’ may change so that we are more prone to an inflammatory state. This appears to alter the type of neutrophil that gets released, not just into the bloodstream, but also in the protective tissues that line the brain—which appears to negatively influence mood.”

While the study used a mouse model, the authors suggest that the findings may help explain how chronic stress promotes mood disorders in humans. Elevated neutrophil levels have already been observed in people with depression, and interferon treatments in clinical settings are known to trigger depressive symptoms. The discovery that skull bone marrow plays a role in immune signaling to the brain opens up new lines of investigation into how psychological stress can influence immune activity in specific anatomical niches.

The study also identifies interferon signaling as a potential target for intervention. Drugs that block this pathway already exist for other conditions, and might be repurposed or refined to address mood symptoms linked to chronic inflammation. However, the researchers acknowledge that further work is needed to determine whether similar immune dynamics occur in humans, and how best to target them without disrupting the immune system more broadly.

One key limitation of the study is its focus on male mice. Depression is more common in women, and some previous research suggests that female immune responses to stress and inflammation may differ in important ways.

“Though depression is more common in women, our study used only male mice, as we were unsuccessful in our attempts to adapt the chronic stressor for use in females,” Kigar noted. “There is some evidence to suggest women respond to interferon therapy more strongly than men, which might mean this pathway would be more active in women exposed to chronic stress. Future studies are needed to address this potential sex difference.”

Despite these limitations, the research provides a detailed map of how chronic social stress can trigger a cascade of immune events—beginning in the skull and ending in behavior—that may help shape our understanding of stress-related mental health disorders. The study raises the possibility that part of the brain’s response to adversity comes not from within the brain itself, but from the immune system just outside it.

The study, “Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling in male mice,” was authored by Stacey L. Kigar, Mary-Ellen Lynall, Allison E. DePuyt, Robert Atkinson, Virginia H. Sun, Joshua D. Samuels, Nicole E. Eassa, Chelsie N. Poffenberger, Michael L. Lehmann, Samuel J. Listwak, Ferenc Livak, Abdel G. Elkahloun, Menna R. Clatworthy, Edward T. Bullmore, and Miles Herkenham.