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Home Science & Environment Medical Research

Acute and chronic stress have markedly different impacts on neural repair in a depression-linked brain region

April 12, 2025
in Medical Research
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Chronic stress blocks neural repair in a depression-linked brain region, overlapping with antidepressant drug activity
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Chronic stress blocks neural repair in a depression-linked brain region, overlapping with antidepressant drug activity
Hypothesized model. Credit: Nature (2025). DOI: 10.1038/s41586-025-08807-4

Researchers at Zhejiang University found that acute stress increases natural repair mechanisms in the brain, while chronic stress suppresses them. Autophagy was most affected in the lateral habenula, a brain region linked to emotional regulation. Several antidepressant drugs were tested and found to reverse this suppression, pointing to autophagy in the lateral habenula as a common therapeutic pathway in these treatments.

Major depressive disorder affects approximately 10.6% of people worldwide and ranks among the most debilitating psychiatric illnesses. Stress, a ubiquitous component of daily life, has long been identified as a key contributor to depression.

While moderate short-term stress can support survival, sustained stress can destabilize emotional regulation. How the brain adapts or fails to adapt at the cellular level to stress remains unresolved.

Autophagy, the cellular process of degrading and recycling internal components, has gained increasing attention in neuroscience. Autophagy regulates protein turnover in neurons and has been implicated in neurological conditions such as Alzheimer’s and Parkinson’s diseases. Yet, the role of autophagy in stress-related psychiatric disorders remains unclear.

In the study, “Stress dynamically modulates neuronal autophagy to gate depression onset,” published in Nature, researchers conducted in vivo and in vitro experiments to determine whether and how autophagy in the lateral habenula mediates the effects of stress and antidepressants.

Experiments were conducted in mouse models subjected to various forms of acute and chronic stress, including restraint, social defeat, and footshock.

Autophagic activity was measured across multiple brain regions using techniques such as bulk RNA sequencing, single-nucleus RNA sequencing, immunostaining, electron microscopy, western blot analysis, and behavioral testing. Researchers also used genetic tools to selectively knock out or silence autophagy-related genes, including Atg7, Atg5, and Beclin-1, in specific brain regions.

Systemic administration of antidepressants including paroxetine, ketamine, and rapamycin was used to evaluate whether these treatments modulated autophagy in stress-exposed animals. Researchers also directly infused a Beclin-1 activating peptide into the lateral habenula to test whether enhancing autophagy in this brain region could reverse depression-like behaviors.

RNA sequencing of six emotion-related brain regions in chronically stressed mice showed that genes related to autophagy were downregulated most strongly in the lateral habenula of mice exposed to chronic restraint stress. Single-nucleus RNA sequencing confirmed that this suppression occurred specifically in neurons.

Other stress-sensitive brain regions, including the ventral hippocampus, ventral tegmental area, and medial prefrontal cortex, did not show the same pattern.

Acute stress increased autophagy markers in the lateral habenula, as measured by increased LC3 puncta, decreased p62 protein levels, and higher autophagosome counts under electron microscopy. Chronic stress produced the opposite effect.

Western blot analysis showed that chronic stress elevated mTOR signaling, which is known to inhibit autophagy, while acute stress activated AMPK signaling, which promotes it. These pathways operate independently.

Systemic treatment with antidepressants increased autophagy activity in the lateral habenula. Protein markers for autophagy improved after treatment with paroxetine, ketamine, or rapamycin, but remained unchanged in eight other brain regions. Blocking autophagy with a selective inhibitor negated the behavioral effects of antidepressants and prevented normalization of synaptic function.

Mice lacking autophagy-related genes in the lateral habenula showed depression-like behaviors, including increased immobility in the forced swim test and reduced social interaction. Enhancing autophagy using a Beclin-1 activating peptide reversed these behaviors within 30 minutes of treatment and maintained effects for up to seven days. Infusing the peptide during chronic stress exposure also prevented the onset of depression-like behaviors.

Protein analysis revealed that chronic stress led to an accumulation of glutamate receptor subunits in the lateral habenula. These receptors were selectively degraded when autophagy was restored.

Synaptic activity recordings showed that enhancing autophagy reduced excitatory transmission and normalized neuronal firing patterns in this region. Blocking receptor endocytosis eliminated these effects. Autophagy seemed to be activated “on-demand” in highly active neurons.

Authors concluded that autophagy in the lateral habenula serves as a cellular mechanism that maintains emotional stability under stress by degrading excessive glutamate receptors. Acute stress activates this system through AMPK signaling, while chronic stress shuts it down through mTOR activation.

Disruption of autophagy in this region contributes directly to depression-like behaviors. Reinstating autophagic function, either pharmacologically or genetically, was sufficient to reverse or prevent these effects.

These findings identify lateral habenula autophagy as a causal gatekeeper in the transition from stress to depression, and a shared mechanism by which multiple antidepressant treatments exert their effects. Targeting this process could lead to faster-acting antidepressants.

More information:
Liang Yang et al, Stress dynamically modulates neuronal autophagy to gate depression onset, Nature (2025). DOI: 10.1038/s41586-025-08807-4

Alberto Corona et al, Chronic stress drives depression by disrupting cellular housekeeping, Nature (2025). DOI: 10.1038/d41586-025-00910-w

© 2025 Science X Network

Citation:
Acute and chronic stress have markedly different impacts on neural repair in a depression-linked brain region (2025, April 12)
retrieved 12 April 2025
from https://medicalxpress.com/news/2025-04-acute-chronic-stress-impacts-neural.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.



Chronic stress blocks neural repair in a depression-linked brain region, overlapping with antidepressant drug activity
Hypothesized model. Credit: Nature (2025). DOI: 10.1038/s41586-025-08807-4

Researchers at Zhejiang University found that acute stress increases natural repair mechanisms in the brain, while chronic stress suppresses them. Autophagy was most affected in the lateral habenula, a brain region linked to emotional regulation. Several antidepressant drugs were tested and found to reverse this suppression, pointing to autophagy in the lateral habenula as a common therapeutic pathway in these treatments.

Major depressive disorder affects approximately 10.6% of people worldwide and ranks among the most debilitating psychiatric illnesses. Stress, a ubiquitous component of daily life, has long been identified as a key contributor to depression.

While moderate short-term stress can support survival, sustained stress can destabilize emotional regulation. How the brain adapts or fails to adapt at the cellular level to stress remains unresolved.

Autophagy, the cellular process of degrading and recycling internal components, has gained increasing attention in neuroscience. Autophagy regulates protein turnover in neurons and has been implicated in neurological conditions such as Alzheimer’s and Parkinson’s diseases. Yet, the role of autophagy in stress-related psychiatric disorders remains unclear.

In the study, “Stress dynamically modulates neuronal autophagy to gate depression onset,” published in Nature, researchers conducted in vivo and in vitro experiments to determine whether and how autophagy in the lateral habenula mediates the effects of stress and antidepressants.

Experiments were conducted in mouse models subjected to various forms of acute and chronic stress, including restraint, social defeat, and footshock.

Autophagic activity was measured across multiple brain regions using techniques such as bulk RNA sequencing, single-nucleus RNA sequencing, immunostaining, electron microscopy, western blot analysis, and behavioral testing. Researchers also used genetic tools to selectively knock out or silence autophagy-related genes, including Atg7, Atg5, and Beclin-1, in specific brain regions.

Systemic administration of antidepressants including paroxetine, ketamine, and rapamycin was used to evaluate whether these treatments modulated autophagy in stress-exposed animals. Researchers also directly infused a Beclin-1 activating peptide into the lateral habenula to test whether enhancing autophagy in this brain region could reverse depression-like behaviors.

RNA sequencing of six emotion-related brain regions in chronically stressed mice showed that genes related to autophagy were downregulated most strongly in the lateral habenula of mice exposed to chronic restraint stress. Single-nucleus RNA sequencing confirmed that this suppression occurred specifically in neurons.

Other stress-sensitive brain regions, including the ventral hippocampus, ventral tegmental area, and medial prefrontal cortex, did not show the same pattern.

Acute stress increased autophagy markers in the lateral habenula, as measured by increased LC3 puncta, decreased p62 protein levels, and higher autophagosome counts under electron microscopy. Chronic stress produced the opposite effect.

Western blot analysis showed that chronic stress elevated mTOR signaling, which is known to inhibit autophagy, while acute stress activated AMPK signaling, which promotes it. These pathways operate independently.

Systemic treatment with antidepressants increased autophagy activity in the lateral habenula. Protein markers for autophagy improved after treatment with paroxetine, ketamine, or rapamycin, but remained unchanged in eight other brain regions. Blocking autophagy with a selective inhibitor negated the behavioral effects of antidepressants and prevented normalization of synaptic function.

Mice lacking autophagy-related genes in the lateral habenula showed depression-like behaviors, including increased immobility in the forced swim test and reduced social interaction. Enhancing autophagy using a Beclin-1 activating peptide reversed these behaviors within 30 minutes of treatment and maintained effects for up to seven days. Infusing the peptide during chronic stress exposure also prevented the onset of depression-like behaviors.

Protein analysis revealed that chronic stress led to an accumulation of glutamate receptor subunits in the lateral habenula. These receptors were selectively degraded when autophagy was restored.

Synaptic activity recordings showed that enhancing autophagy reduced excitatory transmission and normalized neuronal firing patterns in this region. Blocking receptor endocytosis eliminated these effects. Autophagy seemed to be activated “on-demand” in highly active neurons.

Authors concluded that autophagy in the lateral habenula serves as a cellular mechanism that maintains emotional stability under stress by degrading excessive glutamate receptors. Acute stress activates this system through AMPK signaling, while chronic stress shuts it down through mTOR activation.

Disruption of autophagy in this region contributes directly to depression-like behaviors. Reinstating autophagic function, either pharmacologically or genetically, was sufficient to reverse or prevent these effects.

These findings identify lateral habenula autophagy as a causal gatekeeper in the transition from stress to depression, and a shared mechanism by which multiple antidepressant treatments exert their effects. Targeting this process could lead to faster-acting antidepressants.

More information:
Liang Yang et al, Stress dynamically modulates neuronal autophagy to gate depression onset, Nature (2025). DOI: 10.1038/s41586-025-08807-4

Alberto Corona et al, Chronic stress drives depression by disrupting cellular housekeeping, Nature (2025). DOI: 10.1038/d41586-025-00910-w

© 2025 Science X Network

Citation:
Acute and chronic stress have markedly different impacts on neural repair in a depression-linked brain region (2025, April 12)
retrieved 12 April 2025
from https://medicalxpress.com/news/2025-04-acute-chronic-stress-impacts-neural.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.


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