A new study published in Nature suggests that the immune system may play a more direct role in shaping fear and stress responses than previously thought — and that psychedelic compounds like psilocybin and MDMA may offer a way to therapeutically modify this neuroimmune pathway. Researchers found that a specific set of brain-immune interactions involving astrocytes, neurons, and inflammatory monocytes contributes to fear-related behavior in mice under chronic stress. The study also provides initial evidence that psychedelic treatments can disrupt this signaling cascade, reducing fear and inflammation, with parallel patterns found in human tissue.

Scientists have long known that the immune system communicates with the brain, especially during psychological stress. Immune cells can release molecules that cross into the brain and alter its activity, sometimes worsening symptoms of mental health conditions such as depression and anxiety. But many of the specific pathways and mechanisms by which these signals affect behavior have remained unclear.

The new study was designed to explore how chronic stress might disrupt communication between the brain and immune system — particularly in the amygdala, a region known to be involved in emotional processing and fear. The team of researchers from Brigham and Women’s Hospital, Massachusetts General Hospital, and Harvard Medical School focused on astrocytes, a type of glial cell that supports and regulates neurons. Prior work has suggested that astrocytes may help dampen inflammatory signals in the brain, and the researchers suspected they might be key players in mediating the behavioral effects of chronic stress.

In addition, the team was interested in whether psychedelic compounds, known to influence mood and perception, might interact with this brain-immune circuit. Psychedelics have recently attracted attention for their potential to treat depression and posttraumatic stress disorder, but the biological mechanisms behind these effects are not fully understood. (← missing period added)

“We are interested in trying to understand how interactions between the brain and body might contribute to psychiatric disorders. Importantly, these interactions have not been studied in deep mechanistic detail before. Hence, we hope that if we uncover new mechanisms that control this communication network, we can develop novel therapies for diseases like depression,” explained Michael Wheeler, an assistant professor of neurology at Harvard Medical School based out of Brigham and Women’s Hospital.

To examine the effects of stress on fear behavior, the researchers subjected mice to 18 days of restraint stress and assessed their responses using behavioral tests such as contextual fear conditioning and the elevated plus maze. Mice exposed to chronic stress displayed significantly more fear-related behaviors, including freezing, compared to unstressed controls. Blood samples revealed increased levels of corticosterone and several inflammatory cytokines, including interleukin-1 beta, suggesting an activated stress and immune response.

The researchers then analyzed astrocytes in the amygdala using single-cell RNA sequencing. They discovered a distinct population of astrocytes that expanded in response to chronic stress. These stress-sensitive astrocytes had lower expression of a receptor known as EGFR, or epidermal growth factor receptor. EGFR has been previously linked to anti-inflammatory functions, and its downregulation suggested that these astrocytes might be less able to buffer against inflammation under stress.

To test the causal role of EGFR in these cells, the researchers used a gene-editing approach to reduce EGFR expression specifically in amygdala astrocytes. Mice with this targeted knockdown showed exaggerated fear responses even after just seven days of stress — a time point that normally does not produce significant behavioral changes. Additional molecular analyses revealed increased inflammation and signs of heightened neuronal activity, suggesting that loss of EGFR made astrocytes less effective at regulating stress-induced brain signaling.

The research team also found that astrocyte-neuron communication was altered in stressed animals. Loss of EGFR in astrocytes led to changes in neurons expressing a transcription factor called NR2F2, which was linked to increased excitatory signaling and fear behavior. Suppressing NR2F2 in neurons reduced fear responses, providing further evidence that this pathway plays a functional role.

Beyond changes within the brain itself, the researchers found that stress affected the immune system in peripheral tissues. Mice subjected to chronic stress had increased numbers of inflammatory monocytes in the meninges — the protective membranes surrounding the brain. These monocytes, known for their pro-inflammatory properties, were not seen in elevated numbers in the spleen or lymph nodes, suggesting a specific recruitment to the brain’s outer layers.

To probe the importance of these cells, the team conducted several experiments. Transferring monocytes into the meninges of stressed mice amplified fear behavior and reduced EGFR-related gene activity in the amygdala. Conversely, depleting these monocytes reduced fear responses and boosted protective signaling in astrocytes. The researchers also showed that monocytes could release inflammatory molecules like interleukin-1 beta that may reach the brain through leaky barriers during chronic stress.

Together, these results suggest a signaling loop in which chronic stress draws inflammatory immune cells to the meninges, where they influence brain astrocytes and neurons, ultimately shaping behavior.

“Our study shows that dialogue between the brain and body is a crucial driver of behavior, meaning that environmental changes that impact cells in our body can start to modify brain circuits implicated in mood disorders,” Wheeler told PsyPost.

With this brain-immune-fear circuit in place, the researchers turned to psilocybin and MDMA. These compounds were administered to mice following chronic stress exposure. Both psychedelics reduced fear-related behaviors and decreased the number of inflammatory monocytes in the meninges. At the molecular level, psychedelics restored EGFR signaling in astrocytes and dampened the inflammatory transcriptional programs seen in monocytes.

In cell culture experiments, psilocybin and MDMA also reduced the expression of pro-inflammatory genes in mouse and human immune cells treated with stress-related hormones. These effects were blocked by antagonists of serotonin receptors, indicating that serotonin signaling — a known target of psychedelics — may help mediate these immune changes.

“We were surprised to find that psychedelic compounds also impacted cell types that don’t directly contribute to hallucinations — in this particular case, immune cells that typically fight off infections,” Wheeler said. “Those findings told us that perhaps psychedelic therapy may have broader therapeutic applicability beyond mental health diseases.”

The team explored whether these results might apply to people by analyzing human amygdala tissue from individuals with major depressive disorder. They found that a subset of astrocytes in patients with depression had lower EGFR expression and that a group of excitatory neurons expressed elevated levels of NR2F2 and other genes linked to fear-related circuitry. These patterns mirrored what was observed in the stressed mice, providing a tentative bridge from animal models to human disease.

“If we suspect that psychedelics are candidate molecules to control not just inflammatory signals in the brain, but tissue plasticity more broadly through their control of neural-immune interactions, we might be able to find use for them in completely new diseases where neural-immune communication is disturbed — for example, inflammatory diseases,” Wheeler explained.

Still, the researchers caution that these results are early and based largely on animal studies. Further work is needed to determine how these mechanisms operate in humans and whether they can be effectively targeted in clinical settings.

“We aren’t suggesting that psychedelics are a panacea for every disease,” Wheeler said. “But rather, we think that they may have applicability in unanticipated diseases marked by similar inflammatory mechanisms as mental health disorders. In other words, diseases that are not brain diseases — something akin to chronic inflammation. There is still a substantial amount of mechanistic work needed to determine their utility in these and other disorders, but we are excited at this possibility.”

“We want to understand the extent to which our findings apply to humans, so we are collaborating with colleagues at Massachusetts General Hospital on a clinical trial to understand how psilocybin therapy impacts the immune system. Likewise, we want to test our ideas that psychedelics may modify tissue plasticity in inflammatory diseases, to see what use cases they may have outside of the brain.”

“We think that harnessing the therapeutic power of the immune system in psychiatry could potentially usher in revolutionary therapies,” Wheeler added. “We hope that the mechanisms we defined in this study are early steps in this process.”