Chronic stress disables the brain’s defenses

It has long been known that stress and depression are closely related. However, exactly how the brain reacts at the cellular level to acute and prolonged overload remained unclear. Scientists from Zhejiang University in China have found a specific mechanism that explains why brief stress can even mobilize forces, and chronic – on the contrary, leads to deterioration of mental state.

The lateral habenula, a region of the brain responsible for controlling emotions and susceptibility to stress, played a major role in this story. As experiments on mice have shown, it is here that a special process is triggered – autophagy, “self-cleaning” of cells, which protects neurons from overload.

Interestingly, brief stress, such as restricted mobility or loneliness, activates this function. Neurons get rid of excess proteins, rebalance and become more stable. Under prolonged stress, however, autophagy in the habenula is virtually shut down. This leads to an accumulation of glutamate receptors – substances that increase excitation in the brain and can upset emotional balance.

The authors conducted a whole series of experiments, including genetically turning off the genes responsible for autophagy, and recorded the behavior of mice. Animals became lethargic, less social, and when injected with a peptide that activates autophagy, these signs disappeared – and the effect persisted for up to a week.

Additionally, we tested the effects of popular antidepressants – from paroxetine to ketamine. All of them activated “self-cleaning” in the habenula, but did not touch other parts of the brain. This allowed the authors to conclude: it is this mechanism that underlies their action, not just correction of the balance of neurotransmitters.

The researchers paid special attention to two signaling systems: AMPK, activated under brief stress, and mTOR, activated under prolonged stress. The former triggers autophagy, the latter blocks it. This “switch” determines whether the brain can withstand stress or collapse into depression.

Thus, the lateral habenula turned out to be not just a participant, but a real “switch” between stress and depression. This means that the fight against mental disorders can become much more effective.