Prolonged Maternal Separation Induces the Depression-Like Behavior Susceptibility to Chronic Unpredictable Mild Stress Exposure in Mice

Early life stress is an important determinant for developing depression later in life. It is reported that maternal separation (MS) could trigger stress sensitivity in adulthood when exposed to stress again. However, it could also result in resilience to stress-induced depression. The conclusions are contradictory. To address this issue, C57BL/6N newborn pups were exposed to either daily short MS (MS for 15 min per day; MS15) or prolonged MS (MS for 180 min per day; MS180) from the first day postpartum (PD1) to PD21. Adult mice were then subjected to chronic unpredictable mild stress (CUMS) exposure from PD64 to PD105. The behavior tests such as the forced swimming test (FST), tail suspension test (TST), and open-field test were performed once a week during this time. Besides, the hippocampal neurosteroids, serum stress hormones, and hippocampal monoamine neurotransmitters were measured at PD106. We found that mice in the MS180 group displayed the reduced struggling time and the increased latency to immobility in both FST and TST. However, there was no significant difference in the MS15 group. The levels of hippocampal neurosteroids (progesterone and allopregnanolone) were decreased, and the serum levels of corticosterone, corticotropin-releasing hormone, and adrenocorticotropic hormone were overexpressed in the MS180 group. Besides, the expressions of monoamine neurotransmitters such as 5-hydroxytryptamine and 5-hydroxy indole acetic acid significantly decreased in the MS180 group, but not in the MS15 group. All findings revealed that prolonged MS, rather than short MS, could increase the susceptibility to depression-like behavior when reexposed to stress in adulthood. However, future studies are warranted to identify the underlying neuromolecular mechanism of the MS experience on the susceptibility to adult stress reexposure.

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Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

Frontiers in Physiology ◽

10.3389/fphys.2021.701344 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elizabeth Elliot-Portal ◽

Christian Arias-Reyes ◽

Sofien Laouafa ◽

Rose Tam ◽

Richard Kinkead ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Stress Hormones ◽

Respiratory Control ◽

Early Life Stress ◽

Whole Body ◽

Wild Type ◽

Adult Mice ◽

Respiratory Disturbance

Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

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Impacts of Aerobic Exercise on Depression-Like Behaviors in Chronic Unpredictable Mild Stress Mice and Related Factors in the AMPK/PGC-1α Pathway

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17062042 ◽

2020 ◽

Vol 17 (6) ◽

pp. 2042 ◽

Cited By ~ 2

Author(s):

Jia Luo ◽

Changfa Tang ◽

Xiaobin Chen ◽

Zhanbing Ren ◽

Honglin Qu ◽

...

Keyword(s):

Skeletal Muscle ◽

Aerobic Exercise ◽

Chronic Stress ◽

Control Group ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Atp Content ◽

Related Factors ◽

Significant Difference ◽

The Impact

This study was to study the impact of aerobic exercises on the chronic unpredictable mild stress (CUMS) in mice, and to discuss the possible mechanism from the skeletal muscle AMPK/PGC-1α energy metabolism signaling pathway. The healthy male mice were randomly divided into Control Group (CG), Model Group (MG), and Model Exercise Group (ME).Twelve stress methods were adopted for four weeks (28 days) to establish the depression model. ME was subject to aerobic training plan after the model was established. The weight of the mice was recorded weekly. After the experimental intervention, the three groups of mice were subjected to behavioral assessment tests. Western blotting, RT-PCR, and ELISA were performed to test AMPK, p-AMPK, PGC-1α, and ATP in skeletal muscle. There were no significant difference in body weight between the three groups. CUMS leaded to significant decline in behavioral scores. and the p-AMPK and PGC-1α decreased significantly. But boosted ATP content. Aerobic exercise enhanced the expressions of p-AMPK and PGC-1α, increased the ratio of p-AMPK/AMPK, boosted ATP content. And improved behavioral scores significantly. Chronic stress-induced depression-like behavior was improved significantly by Aerobic exercise. The mechanism of aerobic exercise for improving depressive symptoms in mice with chronic stress depression may be related to influence AMPK/PGC-1α pathway.

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Metabonomic Study on the Antidepressant-Like Effects of Banxia Houpu Decoction and Its Action Mechanism

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/213739 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Zhanqiang Ma ◽

Weiwei Ji ◽

Rong Qu ◽

Mingyan Wang ◽

Wen Yang ◽

...

Keyword(s):

Experimental Model ◽

Antidepressant Effect ◽

Control Group ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Model Group ◽

Action Mechanism ◽

Significant Difference ◽

And Control ◽

Endogenous Metabolites

The aim of this study was to establish an experimental model for metabonomic profiles of the rat’s brain and then to investigate the antidepressant effect of Banxia Houpu decoction (BHD) and its possible mechanisms. Behavioral research and metabonomics method based on UPLC-MS were used to assess the efficacy of different fractions of BHD on chronic unpredictable mild stress (CUMS) model of depression. There was a significant difference between the BHD group and the model group. Eight endogenous metabolites, which are contributing to the separation of the model group and control group, were detected, while BHD group regulated the perturbed metabolites showing that there is a tendency of recovery compared to control group. Therefore, we think that those potential metabolite biomarkers have some relationship with BHD’s antidepression effect. This work appraised the antidepressant effect of Banxia Houpu decoction as well as revealing a metabonomics method, a valuable parameter in the TCM research.

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For better or worse: reduced adult lifespan following early-life stress is transmitted to breeding partners

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2011.1291 ◽

2011 ◽

Vol 279 (1729) ◽

pp. 709-714 ◽

Cited By ~ 44

Author(s):

Pat Monaghan ◽

Britt J. Heidinger ◽

Liliana D'Alba ◽

Neil P. Evans ◽

Karen A. Spencer

Keyword(s):

Stress Responses ◽

Life Stress ◽

Disease Risk ◽

Stress Hormones ◽

Adult Life ◽

Early Life Stress ◽

Stress Sensitivity ◽

Adult Lifespan ◽

Early Stress ◽

Negative Effect

Stressful conditions early in life can give rise to exaggerated stress responses, which, while beneficial in the short term, chronically increase lifetime exposure to stress hormones and elevate disease risk later in life. Using zebra finches Taeniopygia guttata , we show here that individuals whose glucocorticoid stress hormones were experimentally increased for only a brief period in early post-natal life, inducing increased stress sensitivity, had reduced adult lifespans. Remarkably, the breeding partners of such exposed individuals also died at a younger age. This negative effect on partner longevity was the same for both sexes; it occurred irrespective of the partner's own early stress exposure and was in addition to any longevity reduction arising from this. Furthermore, this partner effect continued even after the breeding partnership was terminated. Only 5 per cent of control birds with control partners had died after 3 years, compared with over 40 per cent in early stress–early stress pairs. In contrast, reproductive capability appeared unaffected by the early stress treatment, even when breeding in stressful environmental circumstances. Our results clearly show that increased exposure to glucocorticoids early in life can markedly reduce adult life expectancy, and that pairing with such exposed partners carries an additional and substantial lifespan penalty.

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ANTIDEPRESSANT-LIKE ACTIVITY OF FLOWERS OF TECOMELLA UNDULATA IN MICE SUBJECTED TO CHRONIC UNPREDICTABLE MILD STRESS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v12i1.28981 ◽

2019 ◽

Vol 12 (1) ◽

pp. 130

Author(s):

Dinesh Dhingra ◽

Deepak Deepak

Keyword(s):

Young Male ◽

Ethanol Extract ◽

Preference Test ◽

Tail Suspension Test ◽

Plasma Corticosterone ◽

Sucrose Preference ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Tecomella Undulata ◽

Plasma Nitrite

Objective: Flowers of Tecomella undulata have been reported to be a rich source of flavonoids such as rutin and quercetin. The present study was designed to evaluate the effect of ethanol extract of flowers of T. undulata on chronic unpredictable mild stress (CUMS)-induced depression in Swiss young male albino mice.Methods: The mice were subjected to CUMS for 21 successive days. Ethanol extract of the flowers (50, 100, and 200 mg/kg, p.o.) and fluoxetine (20 mg/kg, p.o.) per se was administered for 21 successive days to separate groups of unstressed and stressed mice. Tail suspension test (TST) and sucrose preference test were used to evaluate the effect of the extract on depression-like behavior in mice.Results: Extract of flowers of T. undulata (100 and 200 mg/kg) significantly decreased immobility period of stressed mice in TST, indicating significant antidepressant-like activity of the extract. Stress-induced reduced sucrose preference was significantly restored by the extract. There was no significant effect on locomotor activity of mice by the extract and fluoxetine. The extract significantly reversed stress-induced increase in brain malondialdehyde levels; plasma nitrite and corticosterone levels; and also significantly reversed the stress-induced decrease in reduced glutathione and catalase levels. There was no significant effect of the extract on brain MAO-A activity in both unstressed and stressed mice.Conclusion: These results indicated that ethanol extract of flowers of T. undulata showed significant antidepressant-like activity in mice subjected to CUMS, probably through alleviation of oxidative stress and decrease in plasma corticosterone levels.

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Antidepressant Like Effect of Sodium Orthovanadate in A Mouse Model of Chronic Unpredictable Mild Stress.

10.21203/rs.3.rs-643262/v1 ◽

2021 ◽

Author(s):

Angel Joshi ◽

Ansab Akhtar ◽

Priyanka Saroj ◽

Anurag Kuhad ◽

Sangeeta Pilkhwal Sah

Keyword(s):

Molecular Mechanisms ◽

Nitrosative Stress ◽

Tyrosine Phosphatase ◽

Preference Test ◽

Tail Suspension Test ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Sodium Orthovanadate ◽

Behavioral Tests ◽

Oxidative And Nitrosative Stress

Abstract Depression is a psychiatric disorder characterized by low esteem, anhedonia, social deficit, and lack of interest. Decreased BDNF and impaired TrKB signaling be associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), and sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and ELISA for BDNF were performed. Body weight was measured every week. Depressive-like behavior was associated with increased oxidative stress in the brain and subsequent reduction of BDNF. Further, sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor was used as a test drug as it is reported to stimulate BDNF levels. Sodium orthovanadate (SOV-5 mg/kg, 10 mg/kg) and fluoxetine (10 mg/kg) was given to mice orally for 21 days before 30 minutes of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg has demonstrated significant results in our study by decreasing malondialdehyde levels (MDA/LPO), NO levels, and increasing GSH and SOD in both the cortex and hippocampus. Besides, ELISA revealed the elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg, and FLX-10 mg/kg) as compared with the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels (SOV-5 mg/kg, 10 mg/kg); FLX (10 mg/kg) + SOV (5 mg/kg); FLX-10 mg/kg and per-se) and elevated BDNF level (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effect or prevention of stress-induced anhedonia and so further molecular mechanisms will be warranted for clinical translation.

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FGF21 restores hippocampual mitochondrial dysfunction via enhancing Nrf2/HO-1 and AMPK/SirT1/PGC-1α signaling pathways to alleviate chronic unpredictable mild stress induced depressive like behaviors in mice

10.21203/rs.3.rs-1003374/v1 ◽

2021 ◽

Author(s):

Yun-Tao Zhao ◽

Ling Shen ◽

Yong-Ping Zhang ◽

Lulu Zhang ◽

Leigang Jin ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Signaling Pathways ◽

Forced Swim Test ◽

Preference Test ◽

Tail Suspension Test ◽

Expression Level ◽

Fibroblast Growth Factor 21 ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Immobility Time

Abstract Mitochondrial dysfunction plays a key role in the pathogenesis of depression. Ample research proves mitochondria are a promising target for depression. Fibroblast growth factor 21 (FGF21) exerts roles in neuroprotection and could enhance mitochondria function. Here, the anti-depressive effect of FGF21 was evaluated on a chronic unpredictable mild stress (CUMS)- induced model of depression. The depressive-like behaviors were assessed using sucrose preference test (SPT), forced swim test (FST) and tail suspension test (TST). The results showed that treatment of FGF21 significantly attenuated the decrease in SPT, and dramatically reduced the immobility time in the TST and FST. These effects were associated with enhanced hippocampal mitochondrial function, reflected by FGF21-induced increases in mitochondrial ATP concentration, mitochondrial membrane potential (MMP), and decrease of reactive oxygen species (ROS) levels. At the same time, FGF21 ameliorated oxidative stress in CUMS-exposed mice by enhancing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase activities, and reducing malondialdehyde (MDA) level in the hippocampus. Mechanistically, we found that CUMS treatment decreased expression level of mitochondrial fusion protein 1 (MFN1), and increased expression level of mitochondrial dynamin-related protein 1 (DRP1). FGF21 administration increased expression of MFN1, and reduced expression of DRP1. Meanwhile, FGF21 treatment promoted the expression levels of Nrf2, HO-1, phosphorylated AMPK, SirT1, PGC-1a in the hippocampus. This study revealed that FGF21 alleviates CUMS induced depressive like behaviors by restoring mitochondria function via enhancing Nrf2/HO-1 and AMPK/SirT1/PGC-1α signaling pathways. It suggested that FGF21 would be a potential therapeutic agent in the management of depression.

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Albiflorin Ameliorates Depressive-like Behaviors in Mice Induced by Chronic Unpredictable Mild Stress

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:102-107 ◽

2019 ◽

Vol 18 (1) ◽

pp. 102-107

Author(s):

Wang Jun ◽

Wan Yanfang ◽

Zheng Nan

Keyword(s):

Forced Swim Test ◽

Tail Suspension Test ◽

Underlying Mechanism ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Tail Suspension ◽

Sucrose Consumption ◽

Swim Test ◽

Forced Swim ◽

Suspension Test

Depression is a common psychiatric disorder with a high recurrence rate leading to suicidal thoughts in some cases. Albiflorin is a monoterpene glycoside that is commonly used in the treatment of psychiatric disorders. However, the underlying mechanism of albiflorin on depression is unclear and remains to be investigated. To this end, a mouse model of depression was established via chronic unpredictable mild stress treatment. Next, the effects of albiflorin on depression in these mice were evaluated using the sucrose preference test, forced swim test, tail suspension test, and open field test. The results showed that chronic unpredictable mild stress decreased sucrose consumption, while albiflorin (10 mg/kg) treatment significantly increased sucrose consumption just as fluoxetine (10 mg/kg), a drug commonly used to treat depression. Moreover, both albiflorin and fluoxetine demonstrated significant decrease in immobility time in the forced swim test and tail suspension test with no change in spontaneous locomotor activities. Finally, the underlying mechanism of albiflorin was evaluated using western blot. Results showed an up-regulation of phospho-Akt without changing total-Akt, indicating that albiflorin improved the depression symptoms via inactivation of the Akt signaling pathway. Therefore, albiflorin might be a potential therapeutic treatment for depression.

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Gastrodiae Rhizoma Water Extract Ameliorates Hypothalamic–Pituitary–Adrenal Axis Hyperactivity and Inflammation Induced by Chronic Unpredictable Mild Stress in Rats

BioMed Research International ◽

10.1155/2020/8374614 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Min Wang ◽

Wanrui Dong ◽

Ruiying Wang ◽

Xudong Xu ◽

Ying Wu ◽

...

Keyword(s):

Interleukin 1 ◽

Plasma Concentrations ◽

Water Extract ◽

Preference Test ◽

Tail Suspension Test ◽

Plasma Corticosterone ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Hypothalamic Pituitary Adrenal ◽

Gastrodiae Rhizoma

Gastrodiae Rhizoma is a highly valuable traditional herbal medicine commonly used to treat neurological disorders. The present study is designed to determine the antidepressant-like effect of the Gastrodiae Rhizoma water extract (GRWE) on a depression model and the potential mechanisms. The chronic unpredictable mild stress (CUMS) rat model was used to induce depression. The sucrose preference test, open field test, forced swimming test, and tail suspension test were performed to assess the depressive-like behaviors, respectively. Hypothalamic–pituitary–adrenal (HPA) function was measured via plasma corticosterone (CORT), adrenocorticotrophic hormone (ACTH), hypothalamic corticotropin-releasing factor (CRF), and glucocorticoid receptor (GR) concentrations. Plasma concentrations of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were also evaluated. The results showed that GRWE significantly attenuates the behavioral abnormalities in CUMS rats, as shown by elevated sucrose consumption, raised locomotor activity, and reduced immobility duration. Moreover, GRWE treatment reduced CORT, ACTH, CRF, and GR levels and decreased the plasma IL-1β, IL-6, and TNF-α concentrations. These findings indicate that GRWE improves depressive behaviors in a chronic stress model of rats; its effect may be ascribed to the modulation of the HPA axis activity and inflammatory response.

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