As a common mental illness, depression affects nearly 300 million people worldwide. On average, one in every 20 adults experiences depression. Research has found that frequent and persistent stress is the most common trigger for depression. Understanding the underlying mechanisms of depression is of guiding significance for effective stress management, as well as the prevention and treatment of depression.

In a research paper just published in Cell, Professor Hu Hailan's team from the School of Medicine at Zhejiang University delved into the neural mechanisms of how excessive stress leads to depression. They discovered for the first time the persistent "neural aftershocks" triggered by stress in key brain regions, revealed the key mechanisms behind stress-induced depression at the molecular, cellular, and neural circuit levels, and pointed out potential targets for regulating depression.

In previous work, Professor Hu Hailan's team had noticed that the lateral habenula (LHb) is a brain region closely related to depressive behavior. The habenula is a nucleus located deep in the mammalian brain. When an animal encounters stress, fear, or frustration, the LHb is often activated and participates in the encoding of negative emotions. In 2018, the research team found in a mouse depression model that depressive-like behavior stems from the burst firing of neurons in the LHb.

This phenomenon prompted the research team to ask: Why do these LHb neurons exhibit abnormal activity?

In the newly published work, the research team identified a key player that interacts with neurons in the LHb: astrocytes. Astrocytes account for about 40% of the total number of brain cells in the human brain. Although they are numerous, their "presence" was once very low because these cells do not fire like neurons. For a long time, they were thought to only provide protection and support for neurons and not participate in the complex functions of the brain. It was only in the last 30 years that the functions of astrocytes, such as regulating the development of neuronal synapses and the plasticity of neurons, have gradually received attention.

The development of technology has provided scientists with powerful tools to understand the functions of astrocytes. Since the intracellular calcium ion concentration changes significantly when astrocytes are active, researchers can judge their activity based on the changes in calcium signals. However, it is still challenging to observe astrocytes in the brains of live mice. Fortunately, after trying various viral vector tools and imaging parameters, when the calcium signals finally emerged clearly from a noisy background, "they (astrocytes) were like stars twinkling in the night sky," described Xin Qianqian, a doctoral student and co-first author of the paper.

▲Recording astrocytes in different brain regions of live mice through calcium signals (Image source: Reference [1])

When the researchers simultaneously monitored multiple brain regions in mice, they found that when mice encountered acute stress - such as a sudden electric shock to the soles of their feet during free movement - the calcium signals of astrocytes in the LHb rose first, indicating that they are the first astrocytes in the brain to receive stress.

When the researchers continued to observe the populations of neurons and astrocytes in the LHb through calcium signal changes, they unexpectedly found that after a brief acute stress, if the observation time was long enough - extended from 5 seconds to 50 seconds - the neurons in the LHb actually had two bursts. The second signal, although weak, lasted for a long time. In the words of the researchers, it was equivalent to the "neural aftershock" caused by stress.

This kind of neural aftershock has not been reported in the literature before, but in fact, we may not be unfamiliar with it in our daily experience - when encountering various stresses, the brain's stress response does not stop immediately after the stress is relieved, just like when a stone is thrown into a calm lake, the ripples gradually disappear after a while.

▲Acute stress triggers two activations of calcium signals in neurons of the lateral habenula (Image source: Reference [1])

Meanwhile, the activity signals of LHb astrocytes appeared between the two bursts of neurons. Does this mean that the neural aftershock caused by stress is the result of a direct "dialogue" between LHb neurons and astrocytes? With further exploration, the researchers found that the situation was not that simple.

In fact, stress signals are like "boomerangs." When stress arrives, the first burst of LHb neurons will remotely activate the noradrenergic neurons in the locus coeruleus (LC), causing the latter to quickly secrete norepinephrine, commonly known as the "stress hormone." These norepinephrine are transported throughout the brain. When they return to the LHb, the astrocytes there are activated and then release glial transmitters, causing the second long-term activation of LHb neurons.

Thus, a stress stimulus lasting only 1 second, with the help of LHb astrocytes, ultimately triggers a continuous activity of LHb neurons and norepinephrine signals for about 1 minute.

▲When stress arrives, neurons in the lateral habenula, noradrenergic neurons in the locus coeruleus, and astrocytes in the lateral habenula interact across brain regions to "broadcast" stress information (Image source: Reference [1])

This unique response mechanism lays a hidden danger for the accumulation of long-term stress to trigger depressive emotions. The results of animal behavior experiments show that about 20 random stress stimuli can trigger depressive-like behavior in mice.

At the same time, these results suggest that the impact of stress on the brain can be adjusted by regulating LHb astrocytes: when the researchers activated the LHb astrocytes in mice, their psychological defenses seemed to weaken significantly, and a few stress stimuli produced depressive emotions; on the contrary, when the LHb astrocytes were selectively "turned off," the mice still maintained stable emotions even when the stress stimulus exceeded the threshold.

For us, the stress from various aspects such as learning, work, and social interaction in daily life may be difficult to avoid, and many people may experience anxiety, negativity, or depressive emotions from time to time. This research work brings a lot of inspiration on how to effectively manage stress and prevent and treat depression.

On the one hand, the brain needs some time to recover, and it takes time or methods to "digest" stress. On the other hand, "In our experiments, we found that the molecules and related receptors that regulate the activity of astrocytes have the potential to become targets for intervening in depression. For example, using drugs that target norepinephrine receptors to block the activation of astrocytes when facing stress may prevent depression," Professor Hu Hailan pointed out. "These results provide new inspiration for preventing depression and optimizing clinical drug use strategies."

[1]Qianqian Xin et al.，Neuron-astrocyte Coupling in Lateral Habenula Mediates Depressive-like Behaviors.Cell(2025)Doi:https://doi.org/10.1016/j.cell.2025.04.010

[2]Yan Yang et al.，Ketamine blocks bursting in the lateral habenula to rapidly relieve depression.Nature(2018)DOI:http://www.nature.com/doifinder/10.1038/nature25509

[3]Yiyan Dong et al.，Stress relief as a natural resilience mechanism against depression-like behaviors.Cell(2023).DOI:10.1016/j.neuron.2023.09.004