Coping with stress: the essential role of brain autophagy in emotional homeostasis

Catabolism of neuronal postsynaptic proteins, such as glutamate receptors, has been reported to be enhanced with aging in mouse models [1]. Disruptions of this delicate protein synthesis/degradation balance in the brain, such as occurs during prolonged stress, can dysregulate neuronal activity, leading to psychiatric disorders, including depression [2–4]. The lateral habenula (LHb) is the primary brain region associated with negative emotional states and the most vulnerable target of stress [5]. In their recent study, Yang and colleagues report that chronic stress disrupts the autophagy pathway, a major catabolic process, essential for protein degradation and recycling, whereas its function is restored through the use of antidepressant drugs [6].

The authors first asked whether autophagy has a potential role in the action of antidepressant drugs such as paroxetine and ketamine. To address this question, they examined autophagy levels from several stress-related brain regions of depression mouse models that received chronic restraint stress (CRS). Their findings indicate that the antidepressant treatment stimulates autophagy only in the LHb, leaving other stress-related brain regions unaffected. More specifically, they observed a decrease in the protein level of the autophagic marker SQSTM1/p62 due to its degradation through the autophagy pathway, while the protein level of BECN1, which is involved in autophagosome formation, increases. These findings suggest that LHb autophagy is a common target of these antidepressants.

To elucidate the physiological role of autophagy in depression, the researchers examined the transcriptional profiles of various brain regions in naïve and CRS mouse models. The data indicated that CRS mice exhibit compromised levels of autophagy-related genes in the LHb after completing a depression-like behavioral test, suggesting a direct correlation between impaired LHb autophagy function and depression. However, when investigating the impact of multiple stressors applied either acutely or chronically to LHb autophagy, the researchers discovered that the effects of stress on the LHb autophagy vary depending on the stress duration. More specifically, whereas LHb autophagy is suppressed in chronically stressed mouse models, acute stress enhances the autophagy pathway, as indicated by the observed decrease in the protein level of SQSTM1, an increase in BECN1 and MAP1LC3/LC3, and a rise in the number of autophagosomes. Next, the researchers investigated the molecular cascade associated with acute and chronic stress, focusing on the AMPK and MTOR signaling pathways; two main pathways known to modulate autophagy levels during stress [7]. Specifically, AMPK signaling is required for the initiation of LHb autophagy during acute stress, whereas chronic stress activates MTOR, suppressing autophagy. Treating CRS mice with rapamycin, a well-established MTOR inhibitor, assuages the depression-like status by enhancing LHb autophagy to similar levels as those observed with the antidepressant drugs paroxetine and ketamine. In contrast, treatment of CRS mice that are genetically autophagy-impaired with either rapamycin or antidepressants does not alleviate the antidepressant behavior, confirming that the autophagy pathway is the mechanistic target of the antidepressant drugs. To further investigate this finding, the researchers utilized a selective agonist of BECN1, the Tat-beclin 1 peptide (tBP), to activate BECN1 in the LHb of chronic stress-induced mouse models. The results confirmed their findings, showing that LHb autophagy activation alleviates the depression-like state of the chronically stressed mice.

Moreover, as the LHb hyperactivity is a hallmark of depression-like behavior, because depression animal models show a drastic enhancement of burst firing, the researchers next investigated the impact of tBP-induced autophagy on LHb neuronal activity. The data indicated that tBP has an easing effect on neuronal burst firing activity and weakened excitability in a dose-dependent manner. Furthermore, the researchers observed that tBP-induced autophagy is activated in neurons that are more active. This observation led them to investigate glutamate receptor (GluR) levels in CRS mice. Indeed, they found that GluR levels are elevated in depression-like mouse models and are decreased following perfusion of tBP, suggesting that LHb autophagy activation targets GluRs, primarily the post-synaptic ones. In line with this finding, autophagic degradation of GluRs results in silencing effects on neuronal hyperactivity, as evidenced by the reduced burst-firing activity. In contrast, the co-perfusion of tBP with an endocytosis blocker or a specific blocker of GRIA2/GluA2 endocytosis does not alleviate the depression-like phenotype. These findings highlight the essential role of GluR endocytosis in LHb autophagy and further support the notion that GluRs are targets of LHb autophagy, alleviating the depression-like state.

Next, the scientists aimed to determine the effects of impaired LHb autophagy in the pathogenesis of the depression-like state in naïve mouse models. Thus, performing a conditional knockout of the Atg7 gene specifically at LHb, along with decreased autophagy levels, they observed the development of a depressive-like behavior. More specifically, the atg7^LHb−/− mice exhibit neuronal hyperactivity, increased excitatory neurotransmission, and elevated protein levels of the membrane GluR protein subunits, underscoring the significance of LHb autophagy in mitigating neuronal hyperactivity and alleviating the depressive phenotype. Moreover, the researchers demonstrate that LHb autophagy, specifically GluR degradation, in addition to controlling neuronal excitability and synaptic transmission, also regulates the rate and magnitude of synaptic plasticity.

Overall, this study by Yang and colleagues provides comprehensive evidence that LHb autophagy is essential for maintaining emotional homeostasis and for equalizing stress-induced synaptic protein levels, in particular those of glutamate receptors. Interestingly, acute stress transiently induces LHb autophagy, but chronic stress suppresses autophagy through the activation of the MTOR signaling pathway. The MTOR inhibitor rapamycin can restore autophagy, easing the depression-like behavior in chronically stressed mice. However, the lower sucrose preference in CRS mouse models and the loss of appetite in humans with depressive disorders have not been reported to enhance LHb autophagy, suggesting that MTOR inhibition can trigger autophagy, but this depends on the signal. Collectively, the findings of this study emphasize the importance of balanced autophagy levels in maintaining emotional health and open novel avenues for future research in this field.

Funding Statement

This work was supported by NIH grant [GM131919].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Abbreviations

LHb

Lateral Habenula

CRS

Chronic Restraint Stress

GluR

Glutamate Receptor