How Chronic Stress Increases Risk of Depression
Description
STORY AT-A-GLANCE
Chronic stress triggers a neutrophil invasion into brain-protective layers, driving depression-like behaviors through immune activation rather than just hormonal changes
Stress-induced immune signals hijack brain reward circuits, reducing dopamine and shifting neural activity toward threat detection over pleasure-seeking behaviors
Prolonged stress damages brain mitochondria, reducing cellular energy production while creating an inflammatory feedback loop that worsens mood and cognitive function
Interferon pathways and inflammatory cytokines like IL-6 cross into the brain, directly altering neuron firing patterns in emotional regulation centers
Natural interventions including healthy carbohydrates, regular exercise, positive thinking, creativity, and physical touch help counter stress-induced immune activation and protect mental health
Depression is one of the most common psychiatric conditions in America, affecting 21 million people each year.1 While factors such as the current state of your gut health influence your mental state, chronic stress is also a key driver behind depression.
According to a new study published in Nature Communications, long-term stress repeatedly activates the body's stress-response systems, pushing the immune system into a state of chronic low-grade inflammation. As noted by Stacey Kigar, Ph.D., one of the study authors:
"There's a significant proportion of people for whom antidepressants don't work, possibly as many as one in three patients. If we can figure out what's happening with the immune system, we may be able to alleviate or reduce depressive symptoms."
Following the hypothesis above, learning how the immune system works under chronic stress is key to discovering new treatments that can benefit patients experiencing this issue. Note, however, that within this field of study, animal testing is used due to ethical concerns.2 That said, the knowledge gleaned from the analysis will still positively impact mental health care.
Immune Cells at the Brain's Border Are Driving Stress
According to the study, repeated social stress sets off a specific immune reaction that alters behavior. Researchers used a well-established model called chronic social defeat stress, which mimics the emotional toll of repeated social pressure, and tracked what happened in the protective layers around the brain — the meninges.3
Summary of the findings — Chronic stress triggered a surge of neutrophils (the immune system's first responders) into the brain. The researchers theorized that this rush was not just a bystander effect, but a driver of the depression- and anxiety-like behaviors seen in the test subjects.
<label class="hide-text" contenteditable="false">Text within this block will maintain its original spacing when published</label>The mice in this experiment were healthy before stress exposure, which means the changes seen were a direct result of the stressful environment. The stressed group displayed strong signs of anhedonia (the loss of pleasure), avoiding social contact and even ignoring sexual cues. They were also more anxious, exploring less and staying away from lit areas in behavior tests.
<label class="hide-text" contenteditable="false">Text within this block will maintain its original spacing when published</label>Interestingly, about 30% of the mice were resilient, showing normal behavior despite exposure to stress, giving researchers a comparison group that helped separate stress-specific immune effects from random variation.
A closer analysis of the findings — The researchers found a 5.6-fold increase in blood neutrophils and a 1.3 to 1.7-fold increase in meningeal neutrophils in stressed mice. This was not a random spike — the more neutrophils a mouse had, the more withdrawn and anxious it became. Mice with the highest levels of these immune cells showed the strongest reduction in social approach behavior and pleasure-seeking.
<label class="hide-text" contenteditable="false">Text within this block will maintain its original spacing when published</label>The effect was not fleeting, too. Meningeal neutrophil levels stayed elevated for at least 24 hours after stress ended and only returned to normal after about a week, whereas blood neutrophil levels normalized much faster. This suggests that the immune footprint caused by stress lingers near the brain even after the stressful situation is over.
Where neutrophils came from and where they went — Instead of traveling from distant bone marrow in the limbs, many neutrophils came directly from reservoirs in the skull bone marrow and slipped into the meninges through tiny vascular channels.
<label class="hide-text" contenteditable="false">Text within this block will maintain its original spacing when published</label>In other words, stress triggers a very localized immune response right next to the brain, which suggests why mood and behavior are so sensitive to chronic social pressure. These skull-derived neutrophils were genetically more similar to immature bone marrow neutrophils than to circulating blood neutrophils, meaning they were fresh and primed for action.
Meningeal neutrophils were in a hyperactive state with a strong "interferon signature" — They were responding to Type I interferons, immune messengers known to induce depressive symptoms even in healthy people. These neutrophils had reduced major histocompatibility complex (MHC) II expression, a molecule needed to present antigens to T cells, which means they also disrupt normal immune regulation near the brain.
<label class="hide-text" contenteditable="false">Text within this block will maintain its original spacing when published</label>The researchers even identified that some of these neutrophils were physically larger — a sign of immaturity and heightened activity — and nearly tripled in number in the stressed animals compared to controls.
Blocking interferon signaling with an antibody against the interferon-α/β receptor (IFNAR) reversed many of the stress effects — Mice treated with this antibody showed restored pleasure-seeking behavior and fewer meningeal neutrophils.
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