Chronic Unpredictable Stress Model Research Articles

Pre-gestational stress alters stress-response of pubertal offspring rat in sexually dimorphic and hemispherically asymmetric manner

BackgroundThere is increasing evidence that maternal stress may have long-term effects on brain development in the offspring. In this study, we examined whether pre-gestational stress might affect offspring rats on the medial prefrontal cortical (mPFC) dopaminergic activity in response to acute stress in puberty and if so, whether such effects exhibited hemispheric asymmetry or sexual dimorphism.ResultsWe used behavioral tests to assess the model of chronic unpredictable stress (CUS). We found that the activity in the open field test and sucrose intake test were lower for maternal rats in the CUS group than those in the control group. Offspring rats in the CUS group floated more and swam or climbed less as compared to the offsprings in the control group in the forced swimming test. The floating time was longer and swimming or climbing time was shorter in the female offspring rats than those in the males. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for CUS maternal rats and their offsprings than the respective controls. The ratio of dihydroxy-phenyl acetic acid (DOPAC) to dopamine (DA), DA transporter (DAT), norepinephrine transporter (NET) were lower in the mPFC of offspring rats in the CUS group than the control group. Levels of catechol-O-methyltransferase (COMT) in the left mPFC of female offspring rats and in the right mPFC of both female and male offspring rats were lower in the CUS group than those in the controls, but there was no difference in the left mPFC of male offspring between the CUS and control groups. DOPAC, the ratio of DOPAC to DA, NET and COMT were lower in the right mPFC than in the left mPFC of offspring rats in the CUS group. The ratio of DOPAC to DA in the right mPFC was lower in the female offspring rats than male offspring rats in the CUS group. The NET and COMT levels in both left and right mPFC were lower in the female offspring rats than those of the male offsprings in the CUS group.ConclusionOur data provide evidence that the effect of pre-gestational stress on the mPFC dopaminergic activity in response to acute stress exhibited hemispheric asymmetry and sexual dimorphism in the pubertal offspring rats.

Rosmarinic Acid Ameliorates Depressive-Like Behaviors in a Rat Model of CUS and Up-Regulates BDNF Levels in the Hippocampus and Hippocampal-Derived Astrocytes

Rosmarinic acid (RA), a primary constituent of a Chinese herbal medicine, has been shown to have some therapeutic effects in an animal model of depression, but its underlying mechanisms are poorly understood. Sprague-Dawley rats were exposed to chronic unpredictable stress (CUS) for 21days, and received RA for 14days from the last week of CUS, then the behavioral changes, hippocampal pERK1/2 and BDNF levels were observed. Rats were further treated with U0126 (an ERK1/2 phosphorylation inhibitor) 30min before RA treatment to assess the effects of RA and ERK1/2 signaling in depressive-like behavior and hippocampal BDNF levels. In addition, brains of newly born Sprague-Dawley rats were used to harvest and expand hippocampal astrocytes. Cells were exposed to different concentrations of RA (sham, 1, 5, 10, 20, and 40μg/mL) or U0126 (2μM as a final concentration)+RA (sham, 1, 5, 10, 20, and 40μg/mL) for 48h, and the pERK1/2 and BDNF levels were assessed by western and ELISA assays. RA administration (10mg/kg daily) reversed depressive-like behaviors in rats exposed to a chronic unpredictable stress paradigm and restored pERK1/2 protein expression and hippocampal brain-derived neurotrophic factor (BDNF). Moreover, in vitro experiments revealed that 20μg/mL RA increased pERK1/2 and BDNF levels in cultured astrocytes. Interestingly, the effects of RA were inhibited by U0126. RA might be a useful treatment for depression and the changes in ERK1/2 signaling and BDNF levels may play a critical role in the pharmacological action of RA.

Chronic Unpredictable Stress (CUS)-Induced Anxiety and Related Mood Disorders in a Zebrafish Model: Altered Brain Proteome Profile Implicates Mitochondrial Dysfunction

Anxiety and depression are major chronic mood disorders, and the etiopathology for each appears to be repeated exposure to diverse unpredictable stress factors. Most of the studies on anxiety and related mood disorders are performed in rodents, and a good model is chronic unpredictable stress (CUS). In this study, we have attempted to understand the molecular basis of the neuroglial and behavioral changes underlying CUS-induced mood disorders in the simplest vertebrate model, the zebrafish, Danio rerio. Zebrafish were subjected to a CUS paradigm in which two different stressors were used daily for 15 days, and thorough behavioral analyses were performed to assess anxiety and related mood disorder phenotypes using the novel tank test, shoal cohesion and scototaxis. Fifteen days of exposure to chronic stressors appears to induce an anxiety and related mood disorder phenotype. Decreased neurogenesis, another hallmark of anxiety and related disorders in rodents, was also observed in this zebrafish model. The common molecular markers of rodent anxiety and related disorders, corticotropin-releasing factor (CRF), calcineurin (ppp3r1a) and phospho cyclic AMP response element binding protein (pCREB), were also replicated in the fish model. Finally, using 2DE FTMS/ITMSMS proteomics analyses, 18 proteins were found to be deregulated in zebrafish anxiety and related disorders. The most affected process was mitochondrial function, 4 of the 18 differentially regulated proteins were mitochondrial proteins: PHB2, SLC25A5, VDAC3 and IDH2, as reported in rodent and clinical samples. Thus, the zebrafish CUS model and proteomics can facilitate not only uncovering new molecular targets of anxiety and related mood disorders but also the routine screening of compounds for drug development.

Influence of zinc supplementation on fluoxetine, moclobemide and tianeptine effects in a chronic unpredictable stress model of depression in rats

Influence of zinc supplementation on fluoxetine, moclobemide and tianeptine effects in a chronic unpredictable stress model of depression in rats

The effects of quetiapine on the improvement of behavior and expression of pERK1/2 in the hippocampus of chronic unpredictable stress model rats

Objective To investigate the effect of quetiapine on the behavior and expression of pERK1/2 in chronic unpredictable stress(CUS) model rats. Methods 32 adult male Sprague Dawley rats were randomly divided into four groups(n=8 for each group): control group, CUS group, CUS+ QUE(5 mg/kg, L)group and CUS+ QUE(10 mg/kg, M)group. The rats in control group were left undisturbed in their home cage for 28 days and the other groups were exposed to 28 consecutive days of CUS, then the rats in control group and CUS group were treated with 1% DMSO in saline(5 ml/kg, intraperitoneal injection), the rats in CUS+ QUE(L)group and CUS+ QUE(M)group respectively treated with quetiapine(5 mg/kg)or quetiapine(10 mg/kg) for consecutive 7 days.The weight data of each group were recorded, and the behavioral changes in these rats were analyzed by open field test and forced swimming test; and the expression of pERK1/2 was measured by Western blot. Results (1) Compared with control group, quetiapine (10 mg/kg) ameliorated the inhibition of body weight gain that induced by chronic unpredictable stress (P 0.05). (3)The expression of pERK1/2 in CUS group showed significant decrease when compared with control group or CUS+ QUE(M)group, but showed no significant difference with CUS+ QUE(L)group(F=6.641, P<0.01). Conclusion Quetiapine can ameliorate depressive-like behaviors induced by chronic unpredictable stress, and this effect may be carried out by up-regulation the expression of pERK1/2 in the hippocampus. Key words: Qutiapine; Chronic unpredictable stress; Phosphorylated extracellular signal-regulated protein kinase; Rat; Hippocampus

Antidepressant-like effects of paeoniflorin on the behavioural, biochemical, and neurochemical patterns of rats exposed to chronic unpredictable stress

We have previously demonstrated that the total glycosides of peony exert antidepressant-like effects in animal models. Paeoniflorin is the main active glycoside of peony. The purpose of this study was to evaluate the antidepressant-like effects of paeoniflorin in a rat model of chronic unpredictable stress (CUS) and its active mechanisms. The results showed that CUS-exposed rats exhibited depressive-like behaviour with reduced weight, low motor activity as well as reduced consumption of sucrose, biochemical changes with increased concentrations of corticosterone and adrenocorticotropic hormone and neurochemical changes with reduced monoamine neurotransmitter levels. Paeoniflorin treatment markedly increased sucrose consumption and decreased serum corticosterone and adrenocorticotropic hormone levels in the CUS-treated rats. Furthermore, paeoniflorin treatment significantly attenuated CUS-induced reductions in noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid as well as CUS-induced increases in the ratio between the latter two factors. These results suggest that the modulation of the hypothalamic–pituitary–adrenal axis and up-regulation of serotonergic and noradrenergic systems are important mechanisms underlying the antidepressant-like effects of paeoniflorin in CUS-treated rats.

Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects

Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.

Antidepressant-like effects of tea polyphenols on mouse model of chronic unpredictable mild stress

Tea polyphenols (TPs), which are the natural compounds extracted from tea leaves, possess a number of beneficial properties, such as reducing the risks of cancer and heart diseases, alleviating cognitive impairments and showing antidepressant-like activity in the forced swim test (FST) and tail suspension test (TST). The present study was designed to investigate the protective effect of TPs on the chronic unpredictable mild stress (CUMS)-induced depression model in mice and to elucidate the related underlying mechanisms. With the daily exposure to stressor for 5 consecutive weeks, TPs were administered in mice at a daily dose of 25mg/kg or 50mg/kg by gavage for 3 consecutive weeks from the 3rd week. Our results showed that CUMS significantly decreased the levels of serum serotonin (5-HT) and norepinephrine (NE) in the hippocampus, the prefrontal cortex and serum, and the activities of superoxide dismutase (SOD) and catalase (CAT), with an increase in lipid peroxidation level as well as a reduction in glutathione (GSH) level and an elevation in the production of malondialdehyde (MDA) in the hippocampus and the prefrontal cortex. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. TPs administration could effectively reverse the alterations in the concentrations of 5-HT and NE, elevate the activities of SOD and CAT as well as the level of GSH, reduce the MDA level and inhibit lipid peroxidation. Moreover, TPs could effectively reverse alterations in immobility duration, sucrose consumption and open-field activity. In conclusion, TPs administration has exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of TPs might be related to the alteration of monoaminergic responses and antioxidant defenses.

Effect of dialkyl- [2-(1-oxa-3,4,9-triaza-fluoren-2-yl-methoxy)ethyl] amines on biogenic amines: new potential antidepressants

A thorough survey of the literature has revealed that indole derivatives have shown various central nervous system activities. This study aims to evaluate the antidepressant activity of the newly synthesized dialkyl- [2-(1-oxa-3,4,9-triaza-fluoren-2-yl-methoxy)ethyl] amines and their effect on biogenic amines. In this study, the synthesized compounds were assessed by in-vivo antidepressant models, by forced swim test and tail suspension test in mice and effect of synthesized compounds on biogenic amines in brain in a chronic unpredictable stress model. The test compounds have demonstrated significant (P< 0.05) reduced immobility duration in mice when compared with the control group animals. The reduced immobility displayed by mice indicates potential antidepressant activity. In this study, chronic unpredictable stress led to decreased monoamine levels in the cortex and hippocampus regions of the brain. With chronic administration of the investigated compounds there is an increased in monoamines in the brain, in the chronic unpredictable stress model. Decreased levels of monoamines induced by the chronic unpredictable stress induced model of depression, were normalized by treatment with the test compounds, which indicates potential antidepressant activity.

Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress

The activity of the mammalian target of rapamycin (mTOR), an ubiquitously expressed serine/threonine kinase, is central to the regulation of translation initiation and, consequently protein synthesis required for long-term potentiation and new synaptic connections. Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-d-aspartate (NMDA) receptor antagonists such as ketamine. Our prior work documented the first evidence of robust deficits in the mTOR signaling pathway in the prefrontal cortex (PFC) from subjects diagnosed with major depressive disorder (MDD). The goal of this study was to determine whether alterations in mTOR signaling can be observed in rats exposed to the chronic unpredictable stress (CUS) model of depression. In the present study, we examined the effect of CUS on the expression of phosphorylated mTOR and its downstream signaling components in the frontal cortex, hippocampus, amygdala, and dorsal raphe. We also examined the effect of CUS on the expression of kinases that phosphorylate mTOR such as extracellular signal-regulated kinase (ERK1/2) and protein kinase B/Akt (Akt1). In addition, we examined the effect of stress on the phosphorylation of GluR1 an, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit. We found that eight-weeks of CUS exposure significantly decreased the phosphorylation levels of mTOR and its downstream signaling components in the amygdala. Reduced level of phospho-mTOR in the amygdala was accompanied by decreased phosphorylation of ERK-1/2, Akt-1, and GluR1. No significant changes were seen in the frontal cortex, hippocampus, or dorsal raphe. Our study demonstrates that long-term stress exposure results in brain region-specific abnormalities in signaling pathways previously linked to novel mechanisms for rapid antidepressant effects. These observations are in line with evidence showing that mTOR and its upstream and downstream signaling partners could be important targets for the development of novel antidepressants.

Effect of long-term caffeine administration on depressive-like behavior in rats exposed to chronic unpredictable stress

Chronic unpredictable stress (CUS) was used to study the effects of a long-term treatment with either caffeine (8 mg/kg, orally) or desipramine (DMI) (10 mg/kg, intraperitoneally) in Wistar rats. The CUS procedure was applied for 6 weeks. Animals underwent a 2-week drug-free CUS procedure. Drugs were administered for 4 weeks alongside the stress and both drug and stress were continued throughout the behavioral testing period. CUS-exposed rats showed depressive-like behavior with reduced weight gain, reduced consumption of sucrose solution, increased immobility in the forced swimming test, and hypolocomotion in an open field. For the open field and elevated plus maze, calculation of an anxiety index confirmed that CUS increased anxiety, which was accompanied by an increase in the core temperature. DMI counteracted these physical and behavioral changes. Caffeine caused similar effects to DMI on weight gain, motor activity, anxiety level, and core temperature. In CUS-exposed rats, caffeine showed antidepressant and anxiolytic activity, accompanied by increased hippocampal dopamine and serotonin levels. However, no significant change in weight gain or core temperature was observed after caffeine treatment in CUS-exposed rats. These results suggest that, similar to the antidepressant DMI, long-term caffeine exposure exerts an antidepressant and anxiolytic effect in the CUS model. The involvement of the dopaminergic and serotonergic systems is discussed.

Region-specific changes in activities of cell death-related proteases and nitric oxide metabolism in rat brain in a chronic unpredictable stress model

Effects of a chronic combined unpredictable stress on activities of two cell death-related proteases, calpain and cathepsin B, were studied along with indices of nitrergic system in rat brain structures. Male Wistar rats were subjected to a 2-week-long combined stress (combination of unpaired flash light and moderate footshock associated with a white noise session). Stress resulted in a significant loss in the body and thymus weight and increased defecation in the open field test, though neither motor and exploratory activity, nor plasma corticosterone differed from the respective control levels. Decreased calpain activity and increased cathepsin B activity were demonstrated in the hippocampus of stressed rats (previously we have shown that caspase-3 activity was significantly suppressed in the brain of rats subjected to same type of stress). A significant reduction in the number of NOS-containing neurons was accompanied by a chronic stressinduced decline in NOS activity in the neocortex. Similar changes were observed in the hippocampus. However, levels of NO metabolites were elevated in both structures. Thus, stress-induced structural modifications in the brain may be mediated by disturbances in the nitrergic system and increased lysosomal proteolysis.

Fibroblast Growth Factor-2: An Endogenous Antidepressant and Anxiolytic Molecule?

Fibroblast Growth Factor-2: An Endogenous Antidepressant and Anxiolytic Molecule?

Novel Ocimumoside A and B as anti-stress agents: Modulation of brain monoamines and antioxidant systems in chronic unpredictable stress model in rats

Therapies targeting central stress mechanisms are fundamental for the development of successful treatment strategies. Ocimum sanctum (OS) is an Indian medicinal plant traditionally used for the treatment of various stress-related conditions. Previously, we have isolated and characterized three OS compounds; Ocimarin, Ocimumoside A and Ocimumoside B. However, their role in modulating chronic stress-induced central changes is unexplored. Thus, in the present study the efficacy of these OS compounds have been evaluated on the chronic unpredictable stress (CUS)-induced alterations in the monoaminergic and antioxidant systems in the frontal cortex, striatum and hippocampus, along with the changes in the plasma corticosterone levels. CUS (two different types of stressors daily for seven days) resulted in a significant elevation of plasma corticosterone level, which was reversed to control levels by pretreatment with Ocimumoside A and B (40mg/kg p.o.), while Ocimarin showed no effect. The levels of NA, DA and 5-HT were significantly decreased in all the three brain regions by CUS, with a selective increase of DA metabolites. A significant decrease in the glutathione (GSH) content, the activities of superoxide dismutase and catalase with a significant increase in the glutathione peroxidase activity and lipid peroxidation was observed in all the three regions of the brain by CUS. The OS compounds alone did not cause any significant change in the baseline values of these parameters. However, Ocimumoside A and B (40mg/kg body p.o.) attenuated these CUS-induced alterations with an efficacy similar to that of standard anti-stress (Panax quinquefolium; 100mg/kg p.o.) and antioxidant (Melatonin; 20mg/kg i.p.) drugs. While, Ocimarin failed to modulate these CUS-induced alterations. Therefore, this is the first report which identified the anti-stress activity of novel Ocimumoside A and B at the level of central monoamines and antioxidant properties, implicating their therapeutic importance in the prevention of stress-related disorders.

Pre-gestational stress reduces the ratio of 5-HIAA to 5-HT and the expression of 5-HT1A receptor and serotonin transporter in the brain of foetal rat

BackgroundMany studies have found that stress before or during pregnancy is linked to an increased incidence of behavioural disorders in offspring. However, few studies have investigated hypothalamic-pituitary-adrenal (HPA) axis activity and the serotonergic system as a consequence of pregestational stress. In the present study, we investigated the effect of pre-gestational stress on HPA axis activity in maternal rats and their foetuses and examined whether changes in HPA axis activity of maternal rats produced functional changes in the serotonergic system in the brain of foetuses.ResultsWe used the behavioural tests to assess the model of chronic unpredictable stress (CUS) in maternal rats. We found the activity in the open field and sucrose consumption was lower for rats with CUS than for the controls. Body weight but not brain weight was higher for control foetuses than those from the CUS group. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for mothers with CUS before pregnancy and their foetuses than for the controls. Levels of 5-hydroxytryptamine (5-HT) were higher in the hippocampus and hypothalamus of foetuses in the CUS group than in the controls, and 5-hydroxyindoleacetic acid (5-HIAA) levels were lower in the hippocampus in foetuses in the CUS group than in the control group. Levels of 5-HIAA in the hypothalamus did not differ between foetuses in the CUS group and in the control group. The ratio of 5-HIAA to 5-HT was significantly lower for foetuses in the CUS group than in the control group. Levels of 5-HT1A receptor were significantly lower in the foetal hippocampus in the CUS group than in the control group, with no significant difference in the hypothalamus. The levels of serotonin transporter (SERT) were lower in both the foetal hippocampus and foetal hypothalamus in the CUS group than in the control group.ConclusionsOur data demonstrate that pre-gestational stress alters HPA axis activity in maternal rats and their foetuses, which is associated with functional changes in 5-HT activity (5-HT, 5-HIAA and ratio of 5-HIAA to 5-HT), as well as the levels of the 5-HT1A receptor and SERT in the hippocampus and hypothalamus of foetuses.

Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS challenge

BackgroundThere is ample evidence that psychological stress adversely affects many diseases. Recent evidence has shown that intense stressors can increase inflammation within the brain, a known mediator of many diseases. However, long-term outcomes of chronic psychological stressors that elicit a neuroinflammatory response remain unknown.MethodsTo address this, we have modified previously described models of rat/mouse predatory stress (PS) to increase the intensity of the interaction. We postulated that these modifications would enhance the predator-prey experience and increase neuroinflammation and behavioral dysfunction in prey animals. In addition, another group of mice were subjected to a modified version of chronic unpredictable stress (CUS), an often-used model of chronic stress that utilizes a combination of stressors that include physical, psychological, chemical, and other. The CUS model has been shown to exacerbate a number of inflammatory-related diseases via an unknown mechanism. Using these two models we sought to determine: 1) whether chronic PS or CUS modulated the inflammatory response as a proposed mechanism by which behavioral deficits might be mediated, and 2) whether chronic exposure to a pure psychological stressor (PS) leads to deficits similar to those produced by a CUS model containing psychological and physical stressors. Finally, to determine whether acute PS has neuroinflammatory consequences, adult mice were examined at various time-points after PS for changes in inflammation.ResultsAdolescent mice subjected to chronic PS had increased basal expression of inflammation within the midbrain. CUS and chronic PS mice also had an impaired inflammatory response to a subsequent lipopolysaccharide challenge and PS mice displayed increased anxiety- and depressive-like behaviors following chronic stress. Finally, adult mice subjected to acute predatory stress had increased gene expression of inflammatory factors.ConclusionOur results demonstrate that predatory stress, an ethologically relevant stressor, can elicit changes in neuroinflammation and behavior. The predatory stress model may be useful in elucidating mechanisms by which psychological stress modulates diseases with an inflammatory component.

Anti-depressant effects of Xiaoyaosan on rat model of chronic unpredictable mild stress: a plasma metabonomics study based on NMR spectroscopy

To investigate the antidepressant effects of Xiaoyaosan (XYS) in a chronic unpredictable mild stress (CUMS) depression model. The changes in behaviour and plasma metabolic profiles were investigated after four-week CUMS exposure and treatment. Drugs were administered during the four-week period of CUMS, with the healthy group serving as negative controls, and the fluoxetine and venlafaxine groups serving as positive controls. Plasma samples were collected at 28th day, and the plasma metabolic profiling was measured using NMR, followed by multivariate analysis. Exposure to CUMS for four weeks caused depression-like behaviour in rats, as indicated by significant decreases in weight gain, sucrose consumption and locomotor activity. Eleven potential biomarkers, including seven in the Carr-Purcell-Meiboom-Gill spectra, five in the diffusion-edited spectra, and one in both were identified. It was found that trimethylamine-N-oxide, alanine, β-hydroxybutyrate, valine, leucine/isoleucine, low-density lipoprotein/very low-density lipoprotein and lipids were lower and phosphatidylcholine, high-density lipoprotein, choline and N-acetyl glycoproteins were higher in CUMS-treated rats, as compared with controls. XYS significantly suppressed behavioural changes and attenuated plasma metabolite changes. XYS produced an obvious antidepressant effect, and the metabonomic approach benefits estimation of the pharmacodynamic action of traditional Chinese medicine prescriptions.

Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease of neurogenesis. Our previous studies have shown leptin, an adipocyte-derived hormone with antidepressant-like properties 1, promotes baseline neurogenesis in the adult hippocampus 2. The present study aimed to determine whether leptin is able to restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited delayed long-lasting antidepressant-like effects in the behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on GSK3β and β-catenin. DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK3β, while leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK3 β and a key regulator in controlling neural progenitor proliferation, and reversed the inhibitory effects of DEX on β-catenin. Together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK3β/β-catenin signaling pathway.

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice

Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5mg/kg) and medium-dose (1mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7wk of stress sessions, daily p.o. diazepam administration during 1wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect, whereas 4wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.

Neuroprotective and anti-stress effect of A68930 in acute and chronic unpredictable stress model in rats

The neurorescuing effect of A68930 (a potent selective D1 agonist) and its role on the regulation of hypothalamus–pituitary–adrenal (HPA)-axis have been investigated. Acute (AS) and chronic unpredictable (CUS) stress models were used to evaluate the effect of A68930 on HPA-axis regulation in relation to the change in the fiber density and number of immunoreactive (ir) neurons of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) in the dopamine (DA) and GR rich brain regions in rats. CUS caused a significant decrease in the number of TH ir neurons in the striatum, medial forebrain bundle, ventral tegmental area and substansia nigra and GR in the cortex, striatum and hippocampus as compared to the non-stress controls (NS). Administration of A68930 (0.25mg/kg i.p.) significantly normalized these CUS-induced alterations. We also examined the role of A68930 on stress-induced brain oxidative status. AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with NS. Increased GSH-Px activity, with reduced glutathione and increased lipid peroxidation was observed in both AS and CUS in selected brain regions as compared to NS. Administration of A68930 normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation. In conclusion, present findings suggest that the stress-induced immunoreactivity of TH and GR in distinct brain regions are modulated by A68930 leading to the normalization of HPA-axis response. Ours results show the therapeutic importance of DA D1 agonist in stress-induced dopaminergic-related neurological disorders. A68930 also influenced the brain antioxidant machinery probably through the restoration of stress-induced changes in the dopaminergic system and its crosstalk with GR.