Stress, activating the hypothalamic-pituitary-adrenal (HPA) axis and releasing glucocorticoids (GCs), has both beneficial and detrimental effects. While normal stress is adaptive, chronic stress is a major risk factor for mood disorders like major depressive disorder. Chronic stress causes genomic and neuronal changes, particularly in the medial prefrontal cortex (mPFC), leading to persistent depressive behavior and HPA axis dysregulation. Paradoxically, some studies suggest that glucocorticoids can have acute antidepressant effects under certain conditions. This study investigates the hypothesis that short-term stress, rather than strengthening pre-existing stress responses, can actually resolve them, leading to a reversal of depressive-like behavior. Behavioral appraisals, such as cognitive reappraisal and cognitive behavioral therapy (CBT), are used clinically to treat emotional dysfunction, but their underlying neural mechanisms are poorly understood. This study uses repeated short-term restraint stress (RS5) as a model to explore the potential of behavioral interventions to modify pre-existing stress responses and alleviate depressive symptoms.

The literature establishes a strong link between chronic stress and mood disorders. Chronic stress leads to structural and functional changes in brain regions, including the mPFC, impacting glutamate transmission and neuronal activity. The dysregulation of the HPA axis is also a key feature of chronic stress-induced depression. While the pro-depressive effects of chronic stress and prolonged GC exposure are well-documented, the literature also shows evidence of acute antidepressant effects of glucocorticoid receptor agonists, raising questions about the context-dependent nature of GC action. The precise mechanisms by which behavioral appraisals like CBT exert their therapeutic effects remain largely unknown, creating a need for further research into the neural underpinnings of such interventions.

The study used male C57BL/6 and ICR mice. Mice were subjected to chronic restraint stress (CRST) for 14 days to induce depressive-like behaviors, assessed through the sociability test (SIT), sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST). Repeated short-term restraint stress (RS5; 5 min/day for 14 days) was then applied to the CRST mice. Other groups received RS10 and RS15 protocols (10 and 15 min/day, respectively). The effects of RS5 were also investigated in the chronic social defeat stress (CSDS) model and in ICR mice with maternal stress. Serum corticosterone levels were measured to assess HPA axis function. Low-dose corticosterone injections were used to mimic RS5 effects. c-Fos staining mapped brain region activation, while microarray analysis identified gene expression changes in the prelimbic cortex (PL). Chemogenetic techniques (using DREADDs) and optogenetics were employed to manipulate PL neuron activity and their projections to the bed nucleus of the stria terminalis (BNST), basolateral amygdala (BLA), and nucleus accumbens (NAcc). Adrenalectomy (ADX) was used to study the role of the HPA axis in RS5 effects. Immunohistochemistry, Western blot analysis, and siRNA-mediated knockdown were used to analyze molecular changes. Principal component analysis (PCA) and K-means clustering analyzed behavioral and physiological data.

Repeated short-term restraint stress (RS5) reversed pre-existing depressive-like behaviors in mice subjected to CRST, comparable to the effects of the antidepressant imipramine. This effect was also observed in the CSDS model and in ICR mice with maternal stress. RS5 normalized the dysregulation of the HPA axis, including basal corticosterone levels and CRH/AVP expression in the PVN. Low-dose corticosterone injections mimicked the anti-depressive effects of RS5. The anti-depressive effects of RS5 required activation of the HPA axis. RS5 activated specific brain regions, particularly the PL, IL, vSub, dBNST, and PVN. Microarray analysis showed RS5 reversed CRST-induced gene expression changes in the PL, particularly affecting genes involved in stress and glucocorticoid responses. RS5 restored GR expression and normalized Fkbp5 levels in the PL. Increased p-CaMKIIα levels in the PL were associated with CRST, while RS5 reversed this change. Chemogenetic inhibition of PL neurons or their projections to the dBNST, BLA, or NAcc blocked RS5's anti-depressive effects. Specifically, the PL→dBNST circuit was crucial for RS5's effects on basal corticosterone levels. Optogenetic manipulation of the PL→NAcc pathway confirmed the chemogenetic findings.

The study's findings challenge the traditional view of GCs as mere stress mediators, suggesting they can act as stress modifiers. RS5, by activating the HPA axis and causing a surge of GCs, resolves pre-existing maladaptive stress responses rather than amplifying them. The specific duration and intensity of the short-term stress are critical; only RS5, not RS10 or RS15, produced anti-depressive effects, implying a therapeutic window for this approach. The intricate involvement of PL neurons and their projections to various limbic structures underscores the complexity of the brain's stress response system. The results highlight the potential of repeated short-term stress as a novel therapeutic strategy for depression, requiring precise control of stressor parameters. The study also identifies key molecular and neural pathways, emphasizing the role of the PL, its downstream projections, GR, and CaMKIIα in stress coping and potential therapeutic targets.

This research demonstrates that repeated short-term stress, via a glucocorticoid-dependent mechanism involving the prelimbic cortex and its projections to other limbic regions, can resolve pre-existing stress-induced depressive-like behaviors in mice. This novel therapeutic strategy provides a potential alternative approach to treat depression. Further research is needed to optimize the parameters of this approach and explore its translational potential to humans.

The study uses animal models, which may not fully capture the complexity of human depression. The specific mechanisms underlying the interaction between short-term stress and the HPA axis need further elucidation. The generalizability of these findings to different stress paradigms or subtypes of depression needs to be determined through future studies.