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Results for “chronic unpredictable mild stress”

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PubMed2025

Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San in a chronic unpredictable mild stress mouse model of depression.

OBJECTIVE: To reveal the antidepressant mechanisms of Jiawei DanZhiXiaoYaoSan (,JD) in chronic unpredictable mild stress (CUMS)-induced depression in mice. METHODS: Using the CUMS mouse model of depression, the antidepressant effects of JD were assessed using the sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Tandem mass tag (TMT)-based quantitative proteomic analysis of the brain was performed following JD treatment. Hierarchical clustering, Gene Ontology function annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interactions (PPIs) were used to analyze differentially expressed proteins (DEPs), which were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: Behavioral tests confirmed the anti-depressant effects of JD, and bioinformatics analysis revealed 59 DEPs, including 33 up-regulated and 26 down-regulated proteins, between the CUMS and JD-M groups. KEGG and PPI analyses revealed that neuro-filament proteins and the Ras signaling pathway may be key targets of JD in the treatment of depression. qRT-PCR and Western blotting results demonstrated that CUMS reduced the protein expression of neurofilament light (NEFL) and medium (NEFM) and inhibited the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2), whereas JD promoted the phosphorylation of ERK1/2 and up-regulated the protein expression of NEFL and NEFM. CONCLUSIONS: The antidepressant mechanism of JD may be related to the up-regulation of p-ERK1/2 and neurofilament proteins.

Animals↗

PubMed1992

Suppression of sucrose drinking by chronic mild unpredictable stress: a methodological analysis.

Previous studies have demonstrated that chronic exposure of rats to a melange of ultra-mild stressors causes an antidepressant-reversible decrease in the intake of palatable weak sucrose solutions, as well as other evidence of insensitivity to rewards. In the present study, we analyzed some of the behavioral requirements for the suppression of consummatory behaviour by chronic mild stress. Rats exposed to our standard chronic mild stress protocol and tested following 20 h food and water deprivation showed a decrease in intake of 1% sucrose, but not of water or chow. The effect on sucrose intake was also present, but smaller, in non-deprived animals, and wa seen in both singly- and pair-housed animals. Experiments designed to identify the crucial elements of the stress procedure showed that one element, paired housing (in animals normally housed singly) was particularly potent. However, no one element was either necessary to cause the decrease in sucrose intake, or sufficient to maintain the impairment for longer than 4 weeks: Variety and frequency of microstressors appeared to be the essential features of procedures causing a prolonged anhedonia.

Adrenal Glands↗

PubMed1992

Decreased reactivity to sweetness following chronic exposure to mild unpredictable stress or acute administration of pimozide.

Consumption of a palatable wet mash was examined in rats subjected chronically (4-10 weeks) to unpredictable mild stress. Intake of mash containing 0, 10%, or 20% additional sucrose was normal in stressed animals. In control animals, the addition of 30% or 40% sucrose caused a decrease in the quantity of mash consumed, but increased the rate of eating. Both the increase in eating rate and the decrease in intake, at high sucrose concentration, were markedly attenuated in stressed animals (which therefore had higher intakes of very sweet mash and lower rates of eating, relative to control animals). Like chronic mild stress, the dopamine receptor antagonist pimozide (0.2 mg/kg) also increased the intake of a wet mash with 30% added sucrose, while decreasing the rate of consumption. Stressed animals were relatively insensitive to pimozide, though there were significant additive effects on duration of eating (increased) and on postprandial resting (suppressed). The failure of stressed animals to adapt their intake to increases in sweetness, and the similarities between the effects of chronic mild stress and acute pimozide, are compatible with the hypothesis that animals exposed to chronic mild stress are anhedonic.

Animals↗

PubMed2025

Corticotropin-releasing hormone inhibits autophagy by suppressing PTEN to promote apoptosis in dermal papilla cells.

BACKGROUND: Stress-related hair loss is on the rise, largely due to escalating levels of stress-related corticotropin-releasing hormone (CRH) through poorly defined mechanisms. CRH-mediated activation of corticotropin-releasing hormone receptors (CRHRs) on dermal papilla cells (DPCs) is a likely cause of stress-related hair loss. The aim of the study is to elucidate the key mechanisms of alopecia caused by CRH and provide potential new targets for the treatment of stress-related hair loss. METHODS: 4D label-free quantitative proteomics of DPCs and the chronic unpredictable mild stress mouse (CUMS) model were used to explore the relationship and mechanism between CRH, DPCs and hair regeneration. RESULTS: CRH initially downregulated PTEN to suppress autophagy, leading to DPC apoptosis. Overexpression of PTEN enhanced autophagy and mitigated CRH-dependent DPC apoptosis. CRH inhibited PTEN and activated the PI3K/AKT/mTOR pathway, whereas rapamycin inhibited this pathway and activated autophagy, consequently lowering apoptosis, suggesting that increased susceptibility to apoptosis is caused by decreased autophagy. CUMS-induced hair growth disruption is accompanied by an increase in CRHRs and a decrease in PTEN levels within the dermal papilla. Intracutaneous injection of CRH impeded hair regeneration and decreased PTEN in mice, concurrent with inhibition of autophagy and increased apoptosis. CONCLUSIONS: These findings indicate that PTEN loss coupled with PI3K/AKT/mTOR-mediated autophagy inhibition and apoptosis in DPCs is a key mechanism of stress-related hair loss induced by CRH and suggests that topical activation of PTEN or enhancement of autophagy, e.g. through rapamycin, may have a therapeutic effect on stress-induced hair loss disorders such as alopecia.

Animals↗

PubMed2026

13C Stable Isotope Tracing-Based MFA Reveals the Contribution of Glucose to Glycolytic and TCA Fluxes and Its Application in Depression Research.

Metabolomics is widely applied to dissect metabolic pathways and their correlations with biological phenotypes. Unlike genomics and proteomics, metabolites exhibit substantial heterogeneity in chemical structure, physicochemical properties, and biological origin. Accordingly, pathway enrichment and annotation relying merely on alterations in metabolite abundance are prone to incomplete coverage, ionization bias, and ambiguous annotation, which inevitably impair the accuracy of pathway interpretation. Metabolic flux analysis (MFA) coupled with stable isotope-resolved metabolomics (SIRM) offers a powerful quantitative framework for tracing in vivo carbon flow and estimating reaction fluxes across key metabolic nodes. Glucose metabolism lies at the core of systemic energy homeostasis; however, most current investigations are confined to cell lines or in vitro systems, and a simple, easy-to-implement computational pipeline for in vivo glucose flux analysis in animal models is still lacking. Herein, we established an in vivo 13C-labeling-based MFA workflow to trace and resolve the systemic metabolic fate of glucose in rats. The pipeline covers tracer administration, sample preparation, LC-MS detection, isotopologue data acquisition and correction, construction of a glucose-metabolism-related metabolite database, MFA model establishment, and metabolic flux quantification. By infusing rats with [U-13C6]-glucose and [U-13C3]-sodium L-lactate, we precisely characterized the in vivo metabolic fates of circulating glucose and lactate and quantified their respective contributions to glycolytic flux and tricarboxylic acid (TCA) cycle flux. We further applied this workflow to profile energy metabolic reprogramming in depression. The results revealed a systemic shift toward aerobic glycolysis in rats exposed to chronic unpredictable mild stress (CUMS). Overall, the expanded application of this MFA strategy can provide mechanistic and quantitative insights into the regulation of metabolic pathways.

Animals↗

PubMed1992

Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline.

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 micrograms/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.

Animals↗

PubMed1992

Antidepressant-like effects of dopamine agonists in an animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synpases. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, intermittent administration of DA agonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three to four twice-weekly injections of quinpirole (100-200 micrograms/kg) or bromocriptine (2.5 mg/kg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raclopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.

Animals↗