Stress dynamically modulates neuronal autophagy to gate depression onset

Area of Science:

• Neuroscience
• Cellular Biology
• Psychiatry

Background:

• Chronic stress significantly alters brain homeostasis, often leading to depressive disorders.
• The role of brain autophagy in mediating the effects of stress remains largely unknown.

Purpose of the Study:

• To investigate the engagement of brain autophagy in stress dynamics.
• To explore the lateral habenula (LHb) as a potential target for antidepressant therapies.

Main Methods:

• Examined autophagy levels in the LHb under acute and chronic stress conditions.
• Assessed the effects of genetic manipulation and pharmacological interventions on autophagy and stress behaviors.
• Investigated the molecular mechanisms by which LHb autophagy influences neuronal function.

Main Results:

• Acute stress activates autophagy, while chronic stress suppresses it, primarily in the LHb.
• Antidepressant drugs restore LHb autophagy function.
• Genetic deletion of LHb autophagy increases stress susceptibility; enhancing it yields rapid antidepressant effects.
• LHb autophagy regulates neuronal excitability and synaptic plasticity via glutamate receptor degradation.

Conclusions:

• Autophagy in the lateral habenula plays a critical role in maintaining emotional homeostasis against stress.
• Disrupted LHb autophagy contributes to maladaptation to chronic stress.
• Targeting LHb autophagy with enhancers presents a novel antidepressant strategy.