Depression is one of the most common and disabling mental health conditions in the world, affecting over 10% of people globally.
Stress plays a major role in the development of depression, but exactly how it affects the brain at a cellular level has remained unclear—until now.
A new study from researchers at Zhejiang University has shed light on a key process in the brain that may help explain how stress leads to depression and how antidepressants work to reverse it.
The researchers focused on a process called autophagy, which is the brain’s way of cleaning out damaged parts of cells and recycling them.
This natural “self-cleaning” system is essential for keeping brain cells healthy.
While scientists have known that autophagy plays a role in diseases like Alzheimer’s and Parkinson’s, its role in depression has not been well understood.
In this study, researchers looked at a part of the brain called the lateral habenula, which helps regulate emotions and has been linked to depression.
They found that short-term (or “acute”) stress actually boosts autophagy in this brain region, helping the brain stay balanced. But when stress continues for a long time (known as “chronic” stress), autophagy in the lateral habenula shuts down—and this can lead to depression.
To explore this further, the scientists used different types of stress on mice, such as restraining them or exposing them to mild shocks. They then used a range of tools—like gene editing, brain scans, and protein testing—to study what was happening in the brain.
What they discovered was striking: chronic stress reduced autophagy-related gene activity only in the lateral habenula, not in other emotion-related brain regions.
At the molecular level, they found that chronic stress increased a signaling pathway known as mTOR, which is known to block autophagy. Acute stress, on the other hand, activated a different pathway called AMPK, which promotes autophagy. These two pathways seemed to work separately and had opposite effects on the brain’s clean-up system.
The researchers also tested common antidepressants—including paroxetine (a traditional antidepressant), ketamine (a fast-acting one), and rapamycin (which affects autophagy directly). All of these drugs boosted autophagy in the lateral habenula and improved depression-like behaviors in the mice.
But when the researchers blocked autophagy, the antidepressants stopped working. This shows that boosting autophagy might be the key to how these drugs help people feel better.
To take things a step further, the scientists tried enhancing autophagy directly using a special protein called Beclin-1. When they delivered this protein straight into the lateral habenula, the mice quickly recovered from depression-like symptoms—within just 30 minutes—and the effect lasted for up to a week.
Giving the treatment before the mice were stressed also prevented them from developing depressive behaviors in the first place.
The study also found that when autophagy was blocked, certain glutamate receptors (which affect how brain cells communicate) built up in the lateral habenula. When autophagy was restored, these receptors were broken down, which helped calm the brain’s activity and improve mood.
In short, the researchers discovered that autophagy acts like an emotional “safety valve” in the lateral habenula. When stress is short-lived, the brain increases autophagy to stay balanced.
But if stress continues, this protective system breaks down, allowing depression to take hold. Importantly, helping this cleanup process work again—whether through drugs or direct intervention—can reverse the damage and restore emotional balance.
This study offers a breakthrough in our understanding of how stress triggers depression and how antidepressants work at a deep, cellular level.
The key finding is that autophagy in the lateral habenula plays a crucial role in regulating emotional health. When this system fails under chronic stress, depression symptoms appear. But if autophagy can be restored, the symptoms can be prevented or reversed.
What makes this discovery especially powerful is that it connects several known antidepressants to the same biological pathway—autophagy in the lateral habenula—suggesting a common therapeutic mechanism. This could open the door to a new generation of faster and more effective treatments for depression that target this process directly.
In a field where most antidepressants take weeks to work, the fact that enhancing autophagy could show effects within 30 minutes is especially exciting. This points to potential new treatments that work quickly, even for people who haven’t responded to existing medications.
Overall, this research could reshape how we understand and treat depression. By focusing on how the brain’s natural repair system is affected by stress, it offers real hope for developing faster-acting and more targeted antidepressant therapies in the future.
If you care about mental health, please read studies about 6 foods you can eat to improve mental health, and B vitamins could help prevent depression and anxiety.
For more health information, please see recent studies about how dairy foods may influence depression risk, and results showing Omega-3 fats may help reduce depression.
The research findings can be found in Nature.
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