Stress dynamically modulates neuronal autophagy to gate depression onset - Yang et al., 2025

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Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders. As a key modulator of brain homeostasis, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.

LINK (Nature)

 

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Interesting links between chronic stress, depression, and autophagy, bringing in mOTR and the anti-depressive effects of rapamycin.

 

[rvallee]

"Stress" being very loosely applied here. This is actually torture:

To decipher how stress affects and eventually dampens LHb autophagy, we measured LHb autophagy function in mice treated with many stressors (restraint, social defeat or footshock), which engage distinct sensory modalities (physical, psychosocial or noxious), either acutely or chronically (Fig. 1e). These chronic stress protocols are all well-accepted animal models of depression29,30,36.

Most people do not get tortured, daily or otherwise. This has very little to do with what most people mean when they talk about stress, most of which amounts to having too much to do, and little rest, or disliking most or part of their daily routine. Which is not torture. Given how little actual quality of life and liberty most people have, it's actually normal for most people to dislike most or part of their lives, as they have very little say in what goes in it, while most of it consists of obligations and boring annoyances.

I can read and accept that this is a well-accepted animal model of depression. However it makes no sense, since obviously if you cease the torture, the "depression" will end almost immediately, which is not true for most of what is labeled depression. This is mostly just torturing animals and writing things down about it.

Frankly, aside from having more things being written down with more formal language, this model really isn't much different from the Stanford prison experiment, with mice.