Social defeat stress is associated with endoplasmic reticulum (ER) stress, inflammation and apoptosis. ER stress is thought to contribute to many lifestyle diseases such as liver injury, ...cardiovascular dysfunction and depression. We investigated the expression of the ER stress markers RNA-dependent protein kinase-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α) and C/EBP homologous protein (CHOP), as well as inflammatory and apoptotic factors, to assess how social defeat stress induces liver injury. Furthermore, we evaluated the effects of the ER stress inhibitor phenylbutyric acid (PBA) and ER stress inducer thapsigargin (TG) on liver injury. Adult mice were divided into the control, social defeat, social defeat + PBA, TG, PBA and TG + PBA groups. The social defeat and social defeat + PBA groups were simultaneously exposed to social defeat stress for 10 days. The social defeat + PBA, TG, PBA and TG + PBA groups were treated with PBA or TG via intraperitoneal injections. PBA was injected 1 h before the TG injection into the TG + PBA group. Liver samples from six groups of mice were analyzed by histological analysis and western blotting. Social defeat stress promoted ER stress, increased the expression of inflammatory factors and induced apoptosis in the liver of socially defeated mice, which was reversed by PBA. Moreover, ER stress induces TG-induced liver injury by initiating ER stress. Social defeat stress initiates ER stress, promotes the expression of inflammatory and apoptotic factors, and induces liver injury. PBA suppresses liver injury caused by social defeat stress and TG treatment.
Parishin C (Par), a prominent bioactive compound in Gastrodia elata Blume with little toxicity and shown neuroprotective effects. However, its impact on depression remains largely unexplored.
This ...study aims to investigate the antidepressant effects of Par using a chronic social defeat stress (CSDS) mouse model and elucidate its molecular mechanisms.
The CSDS-induced depression mouse model was used to evaluate the therapeutic efficacy of Par. The social interaction test (SIT) and sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were conducted to assess the effects of Par on depressive-like behaviours. The levels of corticosterone, neurotransmitters (5-HT, DA and NE) and inflammatory cytokines (IL-1β, TNF-α, and IL-6) were evaluated by enzyme-linked immunosorbent assay (ELISA). Activation of a microglia was assessed by immunofluorescence labeling Iba-1. The protein expressions of NLRP3, ASC, caspase-1, and IL-6 verified by Western blot.
Oral administration of Par (4 and 8 mg/kg) and fluoxetine (10 mg/kg, administration significantly ameliorate depression-like behaviors induced by CSDS, as shown by the increase social interaction in SIT, increase sucrose preference in SPT and the decrease immobility in TST and FST. Par administration decreased serum corticosterone level and increased the 5-HT, DA and NE concentration in the hippocampus and prefrontal cortex. Furthermore, Par treatment suppressed microglial activation (Iba1) as well as reduced levels of IL-1β, TNF-α, and IL-6) with decreased protein expressions of NLRP3, ASC, caspase-1, and IL-6.
our study provides the first evidence that Par exerts antidepressant-like effects in mice with CSDS-induced depression. This effect appears to be mediated by the normalization of neurotransmitter and corticosterone levels, inhibition of NLRP3 inflammasome activation. This newfound antidepressant property of Par offers a novel perspective on its pharmacological effects, providing valuable insights into its potential therapeutic and preventive applications in depression treatment.
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•Parishin C significantly ameliorates depression-like behaviors induced by chronic social defeat stress.•Parishin C normalized neurotransmitters and corticosterone levels.•Parishin C inhibits the activation of the NLRP3 inflammasome.
Perillae Folium, the leaves and twigs of Perilla frutescens (L.) Britton, has been included in many traditional Chinese medicine herbal formulas to treat depression. However, the precise ...antidepressant mechanism of the essential oil from Perillae Folium (PFEO) has not been fully investigated.
To assess the effects and potential mechanisms of PFEO on depression using animal models and network pharmacology analysis.
PFEO was intranasally administered to a mouse model of social defeat stress (SDS). The antidepressant effects of PFEO on SDS-induced mice were evaluated using behavioral tests. Enzyme-linked immunosorbent assay (ELISA) and western blot were performed to measure the levels of depression-related biomarkers in the hippocampus and serum of the mice. The chemical compounds of PFEO were determined using gas chromatography-mass spectrometry (GC-MS). Network pharmacology and molecular docking analyses were conducted to investigate the potential bioactive components of PFEO and the mechanisms underlying the antidepressant effects. To validate the mechanisms of the bioactive compounds, in vitro models using PC12 and BV2 cells were established and the blood-brain barrier (BBB) permeability was evaluated.
The intranasal administration of PFEO suppressed SDS-induced depression in mice by increasing the time spent in the social zone and the social interactions in the social interaction test and by decreasing the immobility time in the tail suspension and forced swimming tests. Moreover, the PFEO treatment reduced the SDS-induced anxiety-like behavior, as inferred from the increased activity in the central zone observed in the open field test and in the open arms observed in the elevated plus maze test. PFEO administration recovered the SDS-induced decrease in the levels of 5-HT, NE, gamma-aminobutyric acid (GABA), and p-ERK in the hippocampus of mice. Furthermore, the increased serum corticosterone level was also attenuated by the PFEO treatment. A total of 21 volatile compounds were detected in PFEO using GC-MS, among which elemicin (15.52%), apiol (15.16%), and perillaldehyde (12.79%) were the most abundant ones. The PFEO compounds targeted 32 depression-associated genes, which were mainly related to neural cells and neurotransmission pathways. Molecular docking indicated good binding affinities between the bioactive components of PFEO (apiol, β-caryophyllene, elemicin, and myristicin) and the key targets, including ACHE, IL1B, IL6, MAOB, SLC6A2, SLC6A3, SLC6A4, and tumor necrosis factor. Among the four compounds, β-caryophyllene, elemicin, and myristicin were more effective in reducing neurotoxicity and neuroinflammation. Elemicin showed the highest BBB permeability rate.
This study shows the antidepressant activities of PFEO in an SDS-induced mouse model and suggests its potential mechanisms of action: regulation of the corticosterone levels, hippocampal neurotransmitters, and ERK signaling. Apiol, β-caryophyllene, elemicin, and myristicin may be the main contributors to the observed effects induced by PFEO. Further studies are needed to fully elucidate the underlying mechanisms and the main PFEO bioactive components.
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Exposure to stress induced by intermittent repeated social defeat (IRSD) increases vulnerability to the development of cocaine-induced conditioned place preference (CPP) among male mice; however, ...some defeated mice are resilient to these effects of stress. In the present study we evaluated the effects of vicarious IRSD (VIRSD) in female mice and explored behavioural traits that are potentially predictive of resilience. C57BL/6 female mice (n = 28) were exposed to VIRSD, which consisted of the animals witnessing a short experience of social defeat by a male mouse on postnatal day (PND) 47, 50, 53 and 56. The control group (n = 10) was not exposed to stress. Blood samples were collected on PND 47 and 56 for corticosterone and interleukin-6 determinations. On PND 57-58, female mice performed several behavioural tests (elevated plus maze, hole-board, object recognition, social interaction, TST and splash tests). Three weeks later, the effects of cocaine (1.5 mg/kg) on the CPP paradigm were assessed. VIRSD decreased corticosterone levels (on PND 56), increased interleukin-6 levels, enhanced novelty-seeking, improved recognition memory and induced anxiety- and depression-like symptoms. Control and VIRSD female mice did not acquire CPP, although some stressed individuals with certain behavioural traits - including a high novelty-seeking profile or the development of depression-like behaviour in the splash test shortly after VIRSD - acquired cocaine CPP. Our results confirm that some behavioural traits of female mice are associated with vulnerability or resilience to the long-term effects of social stress on cocaine reward, as previously observed in males.
Major depressive disorder is a complex psychiatric disorder with a high prevalence rate worldwide. Previous studies have demonstrated the involvement of the prelimbic cortex (PL) in mediating ...depressive-like behavior, however, the exact molecular mechanism taking place in the PL remains unclear. In the present study, we conducted high-throughput sequencing of mRNAs and miRNAs in PL tissue harvested from chronic social defeat stress (CSDS) susceptible male mice. We identified 59 differentially expressed mRNAs and 6 differentially expressed miRNAs, in which 40 mRNAs and 3 miRNAs were up-regulated, while 19 mRNAs and 3 miRNAs were down-regulated. Integrated analysis of miRNA-mRNA networks suggested that GPR35 signaling might be involved in CSDS-induced depressive-like behaviors. RT-PCR and western blot assays validated that Abra, Sell and GPR35 were up-regulated. Functionally, inhibition of GPR35 in the PL ameliorated CSDS-induced depressive-like behaviors. Thus, the present study provided a global view of mRNA and miRNA profiles in the PL of male stress susceptible mice, and suggested that GPR35 signaling was associated with CSDS-induced depressive-like behaviors. These results may be valuable for further investigations of the molecular regulatory mechanisms in stress-induced depression.
•CSDS induces depressive-like behavior.•CSDS activates the prelimbic cortex.•59 mRNAs and 6 miRNAs were changed in the prelimbic cortex after CSDS.•GPR35 signaling may be involved in depressive-like behavior.
•GLP treatment led to a rapid and robust antidepressant effect in the CSDS mice.•GLP attenuated IL-1β and TNF-α, enhanced IL-10 and BDNF expression.•GLP inhibited the activation of microglia and the ...proliferation of astrocytes.•GLP significantly enhanced GluA1 S845 phosphorylation, GluA1, and GluA2 expression.•GLP exerted antidepressant effects on CSDS mice via modulation of Dectin-1.
Major depressive disorder (MDD) is a prevalent, chronic, and recurrent disease. At least one-third of patients have treatment-resistant depression; therefore, there is an urgent need for novel drug development. Cumulative studies have suggested an inflammatory mechanism for the pathophysiology of MDD. Ganoderma lucidum polysaccharides (GLP) is an anti-inflammatory and immunomodulatory agent. Here, we found that an injection of GLP led to a rapid and robust antidepressant effect after 60 min in the tail suspension test. This antidepressant effect remained after 5 days of treatment with GLP in the forced swim test. Unlike psychostimulants, GLP did not show a hyperactive effect in the open field test. After 60 min or 5 days of treatment, GLP exhibited an antidepressant effect in a chronic social defeat stress (CSDS) depression animal model. Moreover, after 5 days of treatment, GLP attenuated the expression of the proinflammatory cytokines IL-1β and TNF-α, enhanced the expression of the anti-inflammatory cytokine IL-10 and the neurotrophic factor BDNF, and inhibited the activation of microglia and proliferation of astrocytes in the hippocampus of CSDS mice. In addition, after 5 days of treatment, GLP significantly enhanced GluA1 S845 phosphorylation as well as GluA1 and GluA2 expression levels in the hippocampus of CSDS mice. To determine whether the antidepressant effect was mediated by Dectin-1, we found that GLP treatment enhanced Dectin-1 expression in the hippocampus in CSDS mice, and the Dectin-1-specific inhibitor laminarin almost completely blocked the antidepressant effect of GLP. This study identified GLP, an agonist of Dectin-1, as a novel and rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the neuroimmune system and, subsequently, AMPA receptor function.
•Social conflict of adult zebrafish gives rise to winners and losers.•Continuously-defeated losers were demotivated to fight and to win against opponents.•Continuous losing induces neural activities ...in the zebrafish ventral habenula.•The effect of chronic social defeat could be evolutionarily conserved.
Social subordination, which causes severe stress in animals, can affect animal’s behaviors, homeostasis, and mental health. In rodents, experiences of repeated social defeats, but not a single defeat, induce a depression-like state. However, it is unclear whether such experiences similarly affect behaviors of other model animals than rodents. Here, we established a behavioral paradigm for repeated social defeats with zebrafish, an emerging model for behavioral neuroscience and pharmacological analysis. We put fish into repeated social subordination for 6 consecutive days. Using behaviors during fighting as indicators, we observed that experiencing repeated social defeats led to a reduction in fight frequency and duration. The continuously-defeated zebrafish failed to win even against the transgenic fish with an impaired winning-associated neural pathway. These results suggest that repeated social defeats led to demotivation to fight and to win against opponents. Moreover, they showed strong activity in the ventral habenula, an evolutionary homolog of the mammalian lateral habenula. However, unlike the mice model, the continuously-defeated zebrafish showed no change in anxiety level and sociability. Our established behavioral paradigm will be a new tool to investigate neural mechanisms underlying social defeats.
Over the years, it has become increasingly clear that males and females respond differently towards environmental stressors, highlighting the importance of including both sexes when studying the ...effects of stress. This study aims to provide further insight into the detailed consequences of exposing female mice to 21 days of chronic social defeat stress (CSDS). We used a protocol that relies on the ability of odorants and pheromones in male urine to trigger male mouse aggressive behavior. Collected male C57Bl/6n urine was applied to female C57Bl/6n mice who were then attacked by a novel male CD1 mouse each day according to the CDSD protocol. Control females were pair-housed and handled daily. Physiological, neuroendocrine and behavioral changes were evaluated during the experiment. CSDS exposure resulted in number of physiological changes, such as body weight gain, enlarged adrenals and reduced thymus weight, exaggerated HPA-axis negative feedback and increased anxiety-like behavior. However, no generalized social avoidance behavior was observed. This study provides important insights in the physiological, neuroendocrine and behavioral responses of female mice to CSDS, which are partially dependent on estrous cycle stage. This protocol will allow direct comparison of male and female responses to CSDS and enable sex-specific study of mechanisms underlying individual stress resilience.
Lay summary
In this study we found that there are differences in the way that female and male mice respond towards chronic social stress conditions when it comes to behavior and hormonal changes.
While stress does not affect the phase or period of the central pacemaker in the suprachiasmatic nucleus, it can shift clocks in peripheral tissues. Our previous studies showed significant delays of ...the PER2 rhythms in lung and kidney following social defeat stress. The mechanism underlying these effects is not fully understood, but might involve glucocorticoids (GC) released during the stressor. In the present study, we performed social defeat stress in adrenalectomized (ADX) mice to see if the induction of endogenous GC is necessary for the stress-induced phase shifts of peripheral clocks. We used mice that carry a luciferase reporter gene fused to the circadian clock gene Period2 (PER2::LUC) to examine daily rhythms of PER2 expression in various peripheral tissues. Mice were exposed to 5 consecutive daily social defeat stress in the late dark phase (ZT21–22). Running wheel rotations were recorded during 7 baseline and 5 social defeat days, which showed that social defeat stress suppressed locomotor activity without affecting the phase of the rhythm. This suppression of activity was not prevented by ADX. One hour after the last stressor, tissue samples from the liver, kidney and lung were collected and cultured for ex vivo bioluminescence recordings. In the liver, PER2 rhythms were not affected by social defeat stress or ADX. In the kidney, social defeat stress caused a > 4 h phase delay of the PER2 rhythm, which was prevented by ADX, supporting the hypothesis of a crucial role of GC in this stress effect. In the lung, social defeat stress caused an 8 h phase delay, but, surprisingly, a similar phase delay was seen in ADX animals independent of defeat. The latter indicates complex effects of stress and stress hormones on the lung clock. In conclusion, the findings show that repeated social defeat stress in the dark phase can shift PER2 rhythms in some tissues (lung, kidney) and not others (liver). Moreover, the social defeat stress effect in some tissues appears to be mediated by glucocorticoids (kidney) whereas the mechanism in other tissues is more complex (lung).
•Social stress shifts peripheral circadian clocks in a tissue dependent manner.•Social stress can phase delay circadian rhythms in the lung by over 8 h.•Adrenalectomy can prevent the stress-induced shifts of peripheral clocks.
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