Stress Rat Model Of Depression Research Articles

Changes in neurotrophic signaling pathways in brain areas of the chronic mild stress rat model of depression as a signature of ketamine fast antidepressant response/non-response

Major Depressive Disorder (MDD) is a highly debilitating disorder characterized by a persistent feeling of sadness and anhedonia. Traditional antidepressants have a delayed onset of action and lack of efficacy in up to one third of patients, leading to treatment resistant depression (TRD). Recent years have witnessed a revolutionary treatment of TRD with the introduction of the fast-acting antidepressant ketamine. However, ketamine's mechanisms of action are still poorly understood. Here, we used the chronic mild stress animal model of depression on male rats to investigate the involvement of neurotrophic signaling pathways in stress vulnerability/resilience and fast antidepressant response/non-response to acute subanesthetic ketamine. We performed our analysis on both the hippocampus and the prefrontal cortex, two brain areas implicated in stress-related disorders, considering different subcellular fractions. We measured the activation by phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), glycogen synthase kinase-3 beta (GSK3 β), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2), key effectors in the regulation of neuroplasticity and glutamatergic transmission which were previously associated to ketamine's fast antidepressant effect. We showed here for the first time that both stress and ketamine induced brain area and subcellular fraction specific changes in these pathways. Our study represents the first attempt to identify molecular mechanisms underlying the response/non-response to ketamine in an animal model of depression. This approach could give a crucial contribution to the study of etiopathogenetic mechanisms as well as to the identification of novel targets for the development of innovative therapeutic strategies.

Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine

Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress.

Acupuncture inhibits NLRP3 inflammasome activation in the prefrontal cortex of a chronic stress rat model of depression.

The Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-driven inflammatory response plays a key role in the pathophysiology of depression. Mounting evidence suggests that acupuncture is an effective treatment for depression. In this study, we investigated the effects of acupuncture treatment at the acupoints Baihui (GV20) and Yintang (GV29) on NLRP3 inflammasome in the prefrontal cortex (PFC) of an animal model of depression. Rats that underwent chronic unpredictable mild stress (CUMS) for 6 weeks showed depressive-like behaviors, which were confirmed by sucrose preference and locomotor activity in the open field test. The protein levels of NLRP3, apoptotic speck-containing protein with a card (ASC), and cysteinyl aspartate specific proteinase-1 (Caspase-1) in the PFC were detected by Western blot analysis. The mRNA and protein expressions of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in the PFC were measured by the real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Our results showed that the depressive-like behaviors in stressed rats were reversed by acupuncture treatment. Compared with control rats, the protein expression of NLRP3, ASC, and Caspase-1 and the mRNA and protein expressions of IL-1β and IL-18 in the PFC were markedly increased in CUMS rats. Acupuncture treatment significantly decreased the levels of NLRP3 inflammasome components and inflammatory cytokines in the PFC. Acupuncture treatment also reduced the number of TUNEL-positive cells in the PFC. These results suggested that acupuncture has antidepressant-like effects, and its mechanism appears to be involved in the inhibition of NLRP3 inflammasome activation and apoptosis in the PFC.

Cognitive effects of the GSK-3 inhibitor “lithium” in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. MethodsThis study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3β (GSK-3β) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. ResultsLPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3β expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3β over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. ConclusionThis study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3β inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.

Ginsenoside Rg1 attenuates chronic unpredictable mild stress-induced depressive-like effect via regulating NF-κB/NLRP3 pathway in rats.

Ginsenoside (GS Rg1), which has neuroprotection and anti-inflammation activities, is the main active ingredient of Radix Ginseng. However, its antidepressant-like effect in rats remains unclear. Our study was conducted to investigate whether GS Rg1 confers an antidepressant effect in rats exposed to a chronic unpredictable mild stress model of depression and to explore its possible mechanisms. Our results revealed that GS Rg1 treatments for 3 weeks alleviated the depression-related behaviors of chronic unpredictable mild stress-exposed rats, as indicated by increasing sucrose preference, improving locomotor activity and shortening immobile time in both the forced swimming tests and tail suspension tests. And these ameliorative effects of GS Rg1 treatment were involved with regulating chronic unpredictable mild stress-induced pro-inflammatory cytokine interleukin beta (IL-1β) related neuro-inflammation. In addition, we further found that GS Rg1 reversed chronic unpredictable mild stress-induced IL-1β elevation, possibly by inhibiting nuclear factor kappa B pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome expression. In short, our results suggested that GS Rg1 exerted a potential antidepressant-like effect in chronic unpredictable mild stress rat model of depression, which may provide an insight into the potential of GS Rg1 in therapeutic implications for depression.

6 Effect of fresh lily and rhubarb powder on chronic stress depression in rats

Objectives To examine the effect of fresh lily and rhubarb powder on chronic stress depression on rats. Methods A chronic unpredictable mild stress rat model of depression was established. Body mass, sugar consumption and open-field behavior were measured to assess the effect of fresh lily and rhubarb powder on rat behavior. Plasma MDA levels and erythrocyte SOD activity were measured using a kit, the fluorescence of brain tissue homogenates was measured to determine the 5-HT, NE and DA content of amine neurotransmitters, and the thymus and spleen were also examined for any changes. Results In the rat chronic stress depression model, rats administered large and small doses of fresh lily and rhubarb powder over 3 weeks significantly increased their body weight (p < 0.05), while rats administered large, medium and small doses of fresh lily and rhubarb powder significantly increased their consumption of sucrose (p < 0.05). There was also a trend towards reduced plasma levels of MDA (p < 0.01) and the 3 min vertical motion score was significantly increased ( p Conclusions Fresh lily and rhubarb powder exhibited a therapeutic effect on rats with depression.

Acupuncture ameliorates inflammatory response in a chronic unpredictable stress rat model of depression.

Depression is one of the most common psychiatric disorders. Chronic inflammatory response has been viewed as a key factor in depression. Acupuncture in Chinese medicine has been shown to be an effective treatment for depression. In the present study, we investigated the mechanism underlying antidepressant effect of acupuncture. The rats were subjected to chronic unpredictable mild stress (CUMS) for 28days to induce depressive-like behaviors. Acupuncture treatment was applied once every other day during the 28-day stress period. The behavioral tests (body weight, sucrose consumption and locomotor activity) were performed. The expressions of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) were determined in the rat hippocampus and prefrontal cortex. CUMS induced depressive-like behavior in rats, which was alleviated by acupuncture treatment. The increased levels of NO, PGE2, iNOS and COX-2 induced by CUMS, were all significantly decreased in the hippocampus and prefrontal cortex by acupuncture. Moreover, acupuncture markedly inhibited the activation of NF-κB in rats. These findings showed that the antidepressant-like effect of acupuncture might be mediated by inhibition of inflammatory mediators via modulation of NF-κB in the brain regions.

Disturbed diurnal rhythm of three classical phase markers in the chronic mild stress rat model of depression

Disturbances of circadian rhythms have been suggested to be a causal factor in the development of major depressive disorder. However, the mechanisms underlying the association between circadian rhythm abnormalities and mood disorders are still unknown. In the current study the association between diurnal pattern of key phase markers (melatonin, corticosterone, and core body temperature) and anhedonic-like behavior was investigated using the highly validated rat chronic mild stress (CMS) model of depression. Phase marker measurements were done after 3.5 weeks of CMS in 48 control rats and 48 anhedonic-like rats at 6 time points within 24h. The results showed that anhedonic-like behavior associates with changes in all three phase markers: an increased dark phase melatonin secretion, an additional peak in corticosterone level in the beginning of the light phase, and hypothermia in the dark phase. The result adds to the validity of the CMS model in general and in particular to be adequate as a model for studying the chronobiology of depressive disorder.

The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression

Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography–mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression.

TNF-alpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression

Previous findings have shown that patients with depression express higher levels of proinflammatory cytokines such as TNF-α and IL-6. We have recently found that Infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress (UCMS) model of depression suggesting that inflammation might play an important role in depression. An increasing number of studies suggest that inflammation is also associated with cognitive impairments. The current study aimed to investigate the effect of UCMS on the cognitive performance of rats and their hippocampal BDNF levels and the effect of chronic Infliximab (5mg/kg/weekly, i.p.) treatment on these measures. Rats were subjected to different types of stressors daily for a period of 56 days to induce depression-like state. The UCMS resulted in impairments in spatial and emotional memory acquisition and retention with no effect on the level of locomotor activity. These behavioral effects of UCMS were accompanied by reduction in the level of BDNF in the CA1 and CA3 regions of the hippocampus. Chronic Infliximab treatment prevented the UCMS-induced cognitive impairments as well as the reduction in the levels of hippocampal brain-derived neurotrophic factor (BDNF). These results suggest that Infliximab improves the spatial and emotional memory impairments induced by chronic stress in rats likely through its effects on hippocampal function by modulating inflammation.

Prolactin and its receptors in the chronic mild stress rat model of depression

Prolactin (PRL) exhibits many physiological functions with wide effects on the central nervous system including stress responses. Our study aimed to investigate the effect of chronic unpredictable mild stress (CMS) – which is a good animal model of depression – on PRL receptor (PRLR) expression in the rat brain. Rats were exposed to CMS for two weeks and subsequently to CMS in combination with imipramine (IMI) treatment for five consecutive weeks. Behavioral deficit measured in anhedonic animals is a reduced intake of sucrose solution. Two weeks of CMS procedure allowed the selection of animals reactive to stress and displaying anhedonia, and the group which is considered as stress-non-reactive as far as behavioral measures are concerned. In this group the elevated level of PRL in plasma was observed, decrease in dopamine release in the hypothalamus, increase in [125I]PRL binding to PRLR in the choroid plexus, increase of mRNA encoding the long form of PRLR in the arcuate nucleus and the decrease of mRNA encoding its short form, and decrease in the mRNA encoding dopamine D2 receptor. All these alterations indicate these parameters as involved in the phenomenon of stress-resilience. The prolongation of the CMS procedure for additional five weeks shows the form of habituation to the stressful conditions. The most interesting result, however, was the up-regulation of PRLR in the choroid plexus of rats subjected to full CMS procedure combined with treatment with IMI, which may speak in favor of the role of this receptor in the mechanisms of antidepressant action.

Peripheral blood mononuclear cell-based metabolomic profiling of a chronic unpredictable mild stress rat model of depression.

Major depressive disorder (MDD) is a debilitating mood disorder with various etiopathological hypotheses. However the pathogenesis and diagnosis are still unclear. Peripheral blood mononuclear cells (PBMCs) have been shown to be well-suited to biomarker investigation in major depressive disorder (MDD), as well as to unveil the underlying pathogenesis of MDD. In this study, PBMCs were obtained from a chronic unpredictable mild stress (CUMS) rodent model of depression. A gas chromatography-mass spectrometry (GC/MS) metabolomic approach coupled with principal component analysis (PCA) and open partial least-squares discriminant analysis (OPLS-DA) statistical analysis was used to detect differential metabolites in PBMCs of depressed rats. A total number of 18 differential metabolites were screened out. Seven metabolites showed lower levels in CUMS relative to healthy control rats, including aspartic acid, glutamic acid, dehydroascorbic acid, aminomalonic acid, glycine, β-alanine, and ethanolamine, while eleven metabolites showed an increase in CUMS relative to healthy control rats, namely erythronic acid, fructose, β-tocopherol, adenosine-5-monophosphate, 5-hydroxytryptamine, 5-hydroxytryptamine, glycolic acid, α-tocopherol, tetradecanoic acid, creatinine, 4,5-dimethyl-2,6-dihydroxypyrimidine, and myo-inositol. These molecular changes were closely related to perturbations in neurotransmitter metabolism, energy metabolism and oxidative stress metabolism. Biochemical function analysis of these differential metabolites suggested that altered neurotransmitter, energy and oxidative metabolism disorder might be evolved in the pathogenesis of MDD, which could be of valuable assistance in the clinical diagnosis of MDD.

Depresyonun Kronik Hafif Stres Sıçan Modelinde Serum Hormonal Parametrelerin (Ghrelin, Kortikosteron, İnsülin, T3 ve T4) Araştırılması

Depresyonun Kronik Hafif Stres Sıçan Modelinde Serum Hormonal Parametrelerin (Ghrelin, Kortikosteron, İnsülin, T3 ve T4) Araştırılması

P.2.e.005 Expression profiling of the lateral habenula in the chronic mild stress rat model of depression

Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems. Acute and chronic administration of vortioxetine resulted in changes in histamine concentrations in microdialysates collected from the rat prefrontal cortex and ventral hippocampus. Based on these results and a literature review of the current understanding of the interaction between the histaminergic and serotonergic systems and the role of histamine on cognitive function, we hypothesize that vortioxetine through an activation of the orexinergic system stimulates the tuberomammilary nucleus and enhances histaminergic neurotransmission, which contributes to vortioxetine's positive effects on cognitive function.

Low maternal care exacerbates adult stress susceptibility in the chronic mild stress rat model of depression

In the present study we report the finding that the quality of maternal care, in early life, increased the susceptibility to stress exposure in adulthood, when rats were exposed to the chronic mild stress paradigm. Our results indicate that high, as opposed to low maternal care, predisposed rats to a differential stress-coping ability. Thus rats fostered by low maternal care dams became more prone to adopt a stress-susceptible phenotype developing an anhedonic-like condition. Moreover, low maternal care offspring had lower weight gain and lower locomotion, with no additive effect of stress. Subchronic exposure to chronic mild stress induced an increase in faecal corticosterone metabolites, which was only significant in rats from low maternal care dams. Examination of glucocorticoid receptor exon 17 promoter methylation in unchallenged adult, maternally characterized rats, showed an insignificant tendency towards higher total cytosine methylation in rats from low maternal care dams. Assessment of methylation in the resilient versus anhedonic-like rat phenotypes, revealed only minor differences. Thus, maternal care status seems to be a strong predictor or trait marker for the behavioural phenotype.

Metabolomic identification of molecular changes associated with stress resilience in the chronic mild stress rat model of depression

Chronic stressful events are key risk factors for major depressive disorder (MDD), yet some individuals exposed to stressful events do not develop MDD. This disparity suggests the significance of resilience to deleterious stress effects. However, the underlying molecular mechanisms of stress resilience are poorly understood. In the present study, the chronic mild stress (CMS) rat model of depression was used to reveal the individual differences in stress response. Employing a gas chromatography/mass spectrometry metabolomic approach, the molecular changes associated with stress resilience in rat cerebellum were characterized by comparing anhedonic, CMS resilient and control groups. The results showed that four cerebellar metabolites—proline, lysine, glutamine, and dihydroxyacetone phosphate—were identified as the key differential metabolites associated with stress resilience. These metabolites may play a potential role in rendering individuals less vulnerable to CMS exposure. These findings provide insight into the molecular mechanisms underlying stress resilience and shed light on novel therapeutic opportunities to augment stress resiliency.

Candidate Hippocampal Biomarkers of Susceptibility and Resilience to Stress in a Rat Model of Depression

Susceptibility to stress plays a crucial role in the development of psychiatric disorders such as unipolar depression and post-traumatic stress disorder. In the present study the chronic mild stress rat model of depression was used to reveal stress-susceptible and stress-resilient rats. Large-scale proteomics was used to map hippocampal protein alterations in different stress states. Membrane proteins were successfully captured by two-phase separation and peptide based proteomics. Using iTRAQ labeling coupled with mass spectrometry, more than 2000 proteins were quantified and 73 proteins were found to be differentially expressed. Stress susceptibility was associated with increased expression of a sodium-channel protein (SCN9A) currently investigated as a potential antidepressant target. Differential protein profiling also indicated stress susceptibility to be associated with deficits in synaptic vesicle release involving SNCA, SYN-1, and AP-3. Our results indicate that increased oxidative phosphorylation (COX5A, NDUFB7, NDUFS8, COX5B, and UQCRB) within the hippocampal CA regions is part of a stress-protection mechanism.

Escitalopram Increased Gray Matter and White Matter in a First-Episode Drug-Naïve Panic Disorder Patient Within 6 Weeks

Escitalopram Increased Gray Matter and White Matter in a First-Episode Drug-Naïve Panic Disorder Patient Within 6 Weeks

A GABAergic fingerprint identifies stress-susceptibility versus resilience in a chronic mild stress rat model of depression

Event Abstract Back to Event A GABAergic fingerprint identifies stress-susceptibility versus resilience in a chronic mild stress rat model of depression M. Holm1*, K. Jensen1, 2, J. Nieto-Gonzalez1, I. Vardya1 and O. Wiborg2 1 Aarhus University, Synaptic Physiology Laboratory, Department of Physiology and Biophysics, Denmark 2 Aarhus University Hospital, Centre for Psychiatric Research, Denmark It is known that GABAergic hippocampal synapses display short-term synaptic plasticity, i.e. an activity-dependent change in neurotransmitter release during repeated activation. Here we tested whether such synaptic plasticity could be correlated with the behavioral readouts in the chronic mild stress model of depression. Adult male rats were exposed to an eight week long chronic mild stress protocol leading to an anhedonic-like behavior. 350 µm thick ventral horizontal brain slices were prepared for electrophysiological recordings. Spontaneous and evoked inhibitory postsynaptic currents (IPSCs) were recorded in dentate gyrus granule cells. In controls, evoked GABAergic IPSCs showed a paired-pulse ratio (PPR) of 0.81 ± 0.05 (n = 24 cells / 6 rats). In contrast, in stress-susceptible rats the evoked GABAergic IPSCs showed a PPR of 1.26 ± 0.1 (n = 22 cells / 6 rats). Stress-resilient rats showed a paired-pulse ratio which was not significantly different from control rats (PPR of 0.78 ± 0.03 (n = 19 cells / 6 rats)). The GABAB receptor antagonist CGP55845 (5 µM) had no effect on the paired-pulse ratio in any of the groups. Postsynaptically, there were no changes in the frequency and decay kinetics of miniature IPSCs. We propose that stress-susceptibility in rats is associated with presynaptic changes, which may be due to alterations in the presynaptic release machinery, including its complex protein and vesicle composition. Notably, this is the first demonstration of an electrophysiological fingerprint clearly distinguishing stress-susceptible from stress-resilient rats in this model, which indicates that stress-susceptibility is linked to a distinct hippocampal synaptopathy. Conference: EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010. Presentation Type: Poster Presentation Topic: Posters Citation: Holm M, Jensen K, Nieto-Gonzalez J, Vardya I and Wiborg O (2010). A GABAergic fingerprint identifies stress-susceptibility versus resilience in a chronic mild stress rat model of depression. Conference Abstract: EMBO workshop: Gaba Signalling and Brain Networks . doi: 10.3389/conf.fnins.2010.15.00010 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 23 Jun 2010; Published Online: 23 Jun 2010. * Correspondence: M. Holm, Aarhus University, Synaptic Physiology Laboratory, Department of Physiology and Biophysics, Aarhus, Denmark, mmh@biomed.au.dk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers M. Holm K. Jensen J. Nieto-Gonzalez I. Vardya O. Wiborg Google M. Holm K. Jensen J. Nieto-Gonzalez I. Vardya O. Wiborg Google Scholar M. Holm K. Jensen J. Nieto-Gonzalez I. Vardya O. Wiborg PubMed M. Holm K. Jensen J. Nieto-Gonzalez I. Vardya O. Wiborg Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Stress sensitivity and resilience in the chronic mild stress rat model of depression; an in situ hybridization study

We used the validated chronic mild stress (CMS) paradigm to induce anhedonia, a core symptom of major depression, in rats. Thirty percent of animals exposed to CMS are resistant to the development of anhedonia, whereas the remaining are responsive, CMS resilient and CMS sensitive, respectively. We used in situ hybridization to elucidate the molecular mechanisms, which may be involved in the development of anhedonia during CMS. In the CA3 of the ventral hippocampus, we found upregulation of brain-derived neurotrophic factor (BDNF) mRNA in the CMS resilient group indicating protective role of BDNF in stress. Moreover, in the CA3 we found downregulation of vascular endothelial growth factor (VEGF) mRNA in the CMS sensitive group. Downregulation of VEGF suggests impaired hippocampal function, caused by loss of trophic factor neuroprotective support, as part of a previously uncharacterized mechanism for development of anhedonia. CMS induced anhedonia was not related to mRNA expression differences of the dopamine receptors D 1 and D 2, enkephalin, dynorphin, the NMDA receptor subtype NR2B in the ventral striatum, BDNF expression in the dentate gyrus, nor corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) in the paraventricular nucleus of the hypothalamus. In particular, HPA axis seems to be activated in the CMS resilient group suggesting other pathways protecting against stress sensitivity. We applied the restraint stress procedure to compare effects of a faster and simpler form of stress to CMS and found the latter to be more valid as rats probably easier adapt to restraint stress. Finally, we used the conditioned place preference model to demonstrate a clear tendency towards a distinct morphine induced behavioral difference between CMS resilient and CMS sensitive animals.