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Models of Depression: Unpredictable Chronic Mild Stress in Mice
Abstract
Major depression is a complex psychiatric disorder characterized by affective, cognitive, and physiological impairments that lead to maladaptive behavior. The high lifetime prevalence of this disabling condition, coupled with limitations in existing medications, make necessary the development of improved therapeutics. This requires animal models that allow investigation of key biological correlates of the disorder. Described in this unit is the unpredictable chronic mild stress mouse model that is used to screen for antidepressant drug candidates. Originally designed for rats, this model has been adapted for mice to capitalize on the advantages of this species as an experimental model, including inter-strain variability, which permits an exploration of the contribution of genetic background, the ability to create transgenic animals, and lower cost. Thus, by combining genetic features and socio-environmental chronic stressful events, the unpredictable, chronic mild stress model in mice can be used to study the etiological and developmental components of major depression, and to identify novel treatments for this condition. Curr. Protoc. Pharmacol. 61:5.65.1-5.65.17 © 2013 by John Wiley & Sons, Inc.
... Depression in humans may be accompanied by either weight gain or weight loss 28 . Thus, we assessed the impact of the three extracts on possible weight variation during the experiment. ...
... This finding corroborates earlier reports where the antidepressant-like effect of the hydroethanolic extract of M. oppositifolius was devoid of significant weight changes in mice 29. Animals typically display neurobiological abnormalities, including reduced hippocampal dendritic branching, decreasing levels of monoamines, and reduced hippocampal neurogenesis in chronic depression models 28 . It is known that classical antidepressants reverse these anomalies. ...
... The use of fur appearance to evaluate depressive-like behavior is based on the autogrooming behavior of rodents, which is carried out to maintain physical hygiene [13,43]. In a depressive-like state, this behavior tends to decrease and may be reflected in the fur's appearance as a deteriorated coat state. ...
... The sucrose preference test assesses for anhedonia, a symptom of depression. The decreased sucrose preference observed in the stress group, which is indicative of anhedonia, agrees with previous studies [2,5,43,44] as UCMS is known to induce a depressive-like state. Caffeine administration reversed this effect as the caffeine-treated groups had increased sucrose preference compared to the stress group. ...
Prolonged exposure to stress has detrimental effects on health, and the consumption of caffeine, mostly contained in energy drinks, has become a widely adopted stress coping strategy. Currently, there is limited information regarding the effects of caffeine intake on chronic stress exposure. Thus, this study investigated the effects of caffeine administration on chronic stress-induced behavioral deficits, neurochemical alterations, and glial disruptions in experimental rats. Thirty male Wistar rats were randomly assigned to five groups (n = 6): non-stress control, stress control, and caffeine groups of doses 12.5, 25, and 50 mg/kg. The stress control and caffeine groups were subjected to an unpredictable chronic mild stress (UCMS) protocol daily for 14 days. The rats were evaluated for phenotypic and neurobehavioral assessments. Thereafter, the rat brains were processed for biochemical and immunohistochemical assays. Caffeine administration was found to ameliorate behavioral dysfunctions in rats exposed to UCMS. The UCMS-induced changes in brain levels of monoamines, cholinesterases, and some oxidative stress biomarkers were reversed by caffeine. Caffeine administration also produced mild protective effects against UCMS-induced changes in GFAP and Iba-1 expression in stress-specific brain regions. These results showed that low and moderate doses of caffeine reversed most of the stress-induced changes, suggesting its ameliorative potential against chronic stress-induced alterations.
... Stress is, arguably, the most common factor associated with depression, and both clinical and preclinical research have demonstrated robust causal links [31][32][33][34][35][36][37]. While our understanding of stress-induced depressive symptoms is still developing, reduced synaptic plasticity and inhibited neurogenesis have been strongly implicated [33,35,[38][39][40]. ...
... We also evaluated commonly reported inflammatory targets (e.g., Il1b, Il6, Tnf), synaptic health-related targets (e.g., Bdnf, Snap25), and a critical glucose transporter (i.e., Slc2a1) within the hippocampus and frontal cortex, as these brain areas have been linked to depression [28,38,42,43]. Both UCMS and STZ have been shown to independently induce depressive-and anxiety-like behavior in murine models [24,28,34,[44][45][46][47][48][49][50], however, there is limited research directly comparing these models. ...
Introduction:
Among chronically ill populations, affective disorders remain underdiagnosed and undertreated. A high degree of comorbidity exists between diabetes and affective disorders, particularly depression and anxiety. The mechanisms underlying stress-induced affective dysregulation are likely distinct from that induced by diabetes. A direct comparison between stress- and hyperglycemia-induced affective dysregulation could provide insight into distinct mechanistic targets for depression/anxiety associated with these different conditions.
Methods:
To this end, the present study used male C57BL/6J mice to compare the independent and combined behavioral and neuroinflammatory effects of two models: (1) unpredictable chronic mild stress and (2) pharmacologically induced hyperglycemia.
Results:
Streptozotocin-induced hyperglycemia was associated with a set of behavioral changes reflective of the neurovegetative symptoms of depression (i.e., reduced open field activity, reduced grooming, increase immobility in the forced swim task, and decreased marble burying), increased hippocampal Bdnf and Tnf expression, and elevations in frontal cortex Il1b expression. Our chronic stress protocol produced alterations in anxiety-like behavior and decreased frontal cortex Il1b expression.
Discussion:
While the combination of chronic stress and hyperglycemia produced limited additive effects, their combination exacerbated total symptom burden. Overall, the data indicate that stress and hyperglycemia induce different symptom profiles via distinct mechanisms.
... The deterioration of the coat state can be related to a decrease in grooming and, in consequence, to a disturbance of self-directed behavior. The protocol used was based on those performed by Nollet et al. (2013b), wherein the coat state score results from a qualitative scoring of 4 different parts of the body wherein the deteriorations are mainly observed: on the head, the neck, and the back of mice. Each zone is scored: 0, if in a good state (the fur is smooth and shiny, with no tousled, spiky patches), 0.5, if in a moderately bad state (the fur is slightly fluffy with some spiky patches), and 1, in a bad state (the fur is dirty and fluffy on most of the body with slight staining). ...
... It is noteworthy that the NAI group exhibited a decrease in body weight gain during social isolation, indicating that this housing condition only affects weight gain in animals that were not subjected to SDS. Moreover, corroborating previous reports (Nollet et al., 2013b;Nazir et al., 2022), SDS mice displayed a worsening coat state compared to NAI animals, a result that emphasizes that a 10-day SDS exposure and a 10-day social isolation induces some apathy degree. ...
Introduction
Chronic exposure to social defeat stress (SDS) has been used to investigate the neurobiology of depressive- and anxiety-like responses and mnemonic processes. We hypothesized that these affective, emotional, and cognitive consequences induced by SDS are regulated via glutamatergic neurons located in the bed nucleus of the stria terminalis (BNST), amygdaloid complex, and hippocampus in mice.
Methods
Here, we investigated the influence of chronic SDS on (i) the avoidance behavior assessed in the social interaction test, (ii) the anxiety-like behavior (e.g., elevated plus-maze, and open field tests) (iii) depressive-like behaviors (e.g., coat state, sucrose splash, nesting building, and novel object exploration tests), (iv) the short-term memory (object recognition test), (v) ΔFosB, CaMKII as well as ΔFosB + CaMKII labeling in neurons located in the BNST, amygdaloid complex, dorsal (dHPC) and the ventral (vHPC) hippocampus.
Results
The main results showed that the exposure of mice to SDS (a) increased defensive and anxiety-like behaviors and led to memory impairment without eliciting clear depressive-like or anhedonic effects; (b) increased ΔFosB + CaMKII labeling in BNST and amygdala, suggesting that both areas are strongly involved in the modulation of this type of stress; and produced opposite effects on neuronal activation in the vHPC and dHPC, i.e., increasing and decreasing, respectively, ΔFosB labeling. The effects of SDS on the hippocampus suggest that the vHPC is likely related to the increase of defensive- and anxiety-related behaviors, whereas the dHPC seems to modulate the memory impairment.
Discussion
Present findings add to a growing body of evidence indicating the involvement of glutamatergic neurotransmission in the circuits that modulate emotional and cognitive consequences induced by social defeat stress.
... Behavioral tests are performed in the last 2 h before lights off (ZT10-ZT12) and are separated for 1 week Among animal models that lead in depressive-like behavior, the chronic mild stress (CMS) model is often used. In this model, animals are exposed to unpredictable stressor cues (e.g., physical immobility, food deprivation, LD cycle changes) twice per day for several days or weeks [31]. To note, when studying circadian rhythms, it is important to take into account certain considerations and to adapt the protocol accordingly, for example, to not include LD cycle changes as a stress stimulus and to expose animals to stressors at different times of day to avoid synchronizing effects [32]. ...
... CMS leads in behavioral and physiological alterations such as anxiety, depressive-like behavior, and hormonal changes (corticosterone levels increase). Additionally, antidepressant drugs (e.g., fluoxetine) reverse depressive-like behaviors induced by CMS indicating the good predictive validity of the model [31]. ...
Mood disorders, such as depression and anxiety, are characterized by behavioral, physiological, and psychological alterations caused by a combination of genetic predispositions and environmental factors. Among the behavioral and physiological disturbances, changes in daily biological processes such as the sleep-wake cycle or hormonal rhythmic release are the most affected. People suffering of mood disorders (e.g., depression) show delays in the onset of sleep, awakenings during sleep, or sleepiness at daytime. Inversely, people experiencing circadian misalignment (e.g., jet lag, shift work) exhibit mood-related symptoms, emphasizing the reciprocal connection between affective and circadian disorders. Moreover, pharmacological and non-pharmacological treatments that improve daily rhythms have important benefit effects in emotional states, indicating that the circadian system is a good entrance for the successful treatment of mood disorders. Thereby, to understand the physiological mechanisms underlying mood alterations induced by disruptions of daily physiology, it is important to develop and use valid animal models that simulate human circadian activity.
... These findings underpinned a possible molecular mechanism that underlies the beneficial effects of SLDS in relieving the behavioral and cognitional disorders in a depressive mouse Salidroside Improves Depressive Symptoms model, and therefore lying a foundation for the therapeutic opportunity of SLDS in treating depression. Unpredictable chronic stresses have been reported as a promising method to cause a series of depressive behaviors in rodents (Farooq et al., 2012;Nollet et al., 2013;Willner 2017). In the present study, the depressive mouse model was generated using this method and depressive symptoms were assessed by using FST, MWM and OFT. ...
... Nollet et al., 2013;Willner ...
... Previous studies suggest that the LHb acts as a relay center for forebrain limbic regions and midbrain monoaminergic centers; playing a central role in reward or aversion related learning and memory associated to stressful and aversive stimuli [31][32][33] . Thus, we investigated the expression of our candidate snoRNAs in an unpredictable chronic mild stress (UCMS) mice model, a common model of depression 23,34,35 . Given that SNORD54 (Accession No. XR_004934678.1) ...
Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69’s role in MDD pathology is warranted.
... We used three widely used tests of hippocampus-dependent stress behavior and social memory [48,49] throughout this study: the social interaction (SIT), social novelty (SNT), and tail suspension (TST) tests [44,[47][48][49][50][51]. All experimental mice in this study underwent unpredictable chronic mild stress (UCMS) to induce robust stress-and anxiety-induced behavioral phenotype [44,[52][53][54][55][56][57][58][59].Please confirm the section headings are correctly identified.correct ...
Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine’s rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine’s rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained – but not the rapid – behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine’s sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine’s sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine’s dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00018-024-05121-6.
... Studies have also reported that chronic stress increases the risk of developing strokes, diabetes, heart failure, and neurodegenerative diseases, among others (Cohen et al. 2007). Modelling chronic stress towards understanding the mechanism has led to the development of different paradigms in rodents, including the chronic mild stress (CMS) model (Nollet et al. 2013;Willner 2016;Scheggi et al. 2018;Markov 2022). Kim and Diamond (2002) reported that specific brain regions, including the hippocampus, olfactory bulb, amygdala, and prefrontal cortex, are susceptible to stress and antidepressant drugs. ...
Depression is a mental health condition arising from neurochemical alterations that can result from chronic stress. Its management is complex, requiring targeted pathways for intervention, however, the role of antioxidants is essential. Solanum aethiopicum (SA) is one of such antioxidant sources that may abate stress. This study, therefore, investigated the effect of SA leaves ethanol extract on the hippocampus and cerebellum in rats following chronic mild stress (CMS). Twenty-five male adult Wistar rats weighing 180-250g were assigned into five groups (n=5): Control (10mL/kg distilled water); CMS group (CMS-only for 28 days), CMS-SA200 and CMS-SA400 [CMS and SA leaf extract (at 200 and 400mg/kg respectively, from day 15-28)] and 400 mg/kg SA group for 14 days. All the treatments were oral, and the rats were tested for sucrose preference, learning and anxiety, and subsequently sacrificed. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were analysed, and the hippocampus and cerebellum were processed for haematoxylin and eosin staining. Results showed significantly (p<0.05) decreased sucrose preference, spontaneous alternation, open arm entry/duration and SOD, as well as increased (p<0.05) MDA and slightly enlarged hippocampal pyramidal and cerebellar Purkinje cells nuclei in the CMS-only group. Treatment with SA in the CMS-SA200, CMS-SA400 and SA400 groups significantly (p<0.05) reversed the anhedonia, spontaneous alternation and anxiety-like activities, while there was no significant (p<0.05) change to SOD and MDA levels compared with the CMS-only group. However, the enlarged hippocampal and cerebellar cells nuclei persisted, which may be physiological. In conclusion, SA reversed chronic mild-stressed-impaired cognition, anhedonia, and anxiety-like effects, whose action was better at the higher dose
... Construct, face and predictive validities of this model are supported by many studies, showing that rodents exposed to the UCS protocol develop anhedonia-like behavior, cognitive deficits, hormonal and neurochemical imbalances, weight loss and other changes that can be reversed by using antidepressant treatments 5 . Given its translational potential, there has been an exponential growth in the implementation of this protocol across laboratories as it has become an important tool for the study of the neurobiological basis of depression and antidepressant action 6,7 . ...
The zebrafish (Danio rerio) is a model animal that is being increasingly used in neuroscience research. A decade ago, the first study on unpredictable chronic stress (UCS) in zebrafish was published, inspired by protocols established for rodents in the early 1980s. Since then, several studies have been published by different groups, in some cases with conflicting results. Here we conducted a systematic review to identify studies evaluating the effects of UCS in zebrafish and meta-analytically synthetized the data of neurobehavioral outcomes and relevant biomarkers. Literature searches were performed in three databases (PubMed, Scopus and Web of Science) with a two-step screening process based on inclusion/exclusion criteria. The included studies underwent extraction of qualitative and quantitative data, as well as risk-of-bias assessment. Outcomes of included studies (n = 38) were grouped into anxiety/fear-related behavior, locomotor function, social behavior or cortisol level domains. UCS increased anxiety/fear-related behavior and cortisol levels while decreasing locomotor function, but a significant summary effect was not observed for social behavior. Despite including a substantial number of studies, the high heterogeneity and the methodological and reporting problems evidenced in the risk-of-bias analysis made it difficult to assess the internal validity of most studies and the overall validity of the model. Our review thus evidences the need to conduct well-designed experiments to better evaluate the effects of UCS on diverse behavioral patterns displayed by zebrafish.
... In our experimental design, the single prolonged footshock-induced stress served as a distinct experience. This design paralleled other stress protocols using restraint (Kovács et al., 2018;Sousa et al., 2018) or chronic unpredictable mild stress (Nollet et al., 2013;Wiborg, 2013;Chang and Grace, 2014) that the control animals usually were left in their home cages, undisturbed. However, we acknowledged that placing the "Ctrl" animals into fearconditioning cubicles without footshocks could have ruled out the environmental variables. ...
In the face of threats, animals adapt their behaviors to cope with the situation. Under such circumstances, irrelevant behaviors are usually suppressed. In this study, we examined whether food-seeking motivation would decrease under activation of the amygdala, an important nucleus in the regulation of stress response in the central nervous system, or after a physical acute stress session. In Experiment 1, we pharmacologically activated the basolateral nucleus (BLA) or the central nucleus of the amygdala (CeA) before a cue-induced reinstatement test in rats. Our results showed that activation of the BLA or the CeA abolished cue-induced motivation toward food rewards, while locomotor activity and free food intake were not affected. In Experiments 2 and 3, we further assessed anxiety and despair levels, as well as cue-induced reinstatement, after a single prolonged footshock-induced acute stress in rats. Behaviorally, acute stress did not affect anxiety level, despair level, or cue-induced motivation toward food rewards. Physiologically, there was no difference in cellular activities of the amygdala immediately after acute stress. To conclude, our results suggested that pharmacological activation of the amygdala decreased cue-induced motivation toward food reward. However, physiological acute stress did not immediately interfere with the negative emotions, motivation, or amygdala activities of the animals.
... Depression is a neuropsychiatric disorder that has been strongly associated with stress since many depressive episodes occur due to different stressors [54]. The CUMS protocol is one of the paradigms that has been most used in the modeling of depressive-like behaviors, as it reproduces the neurochemical, morphological, and neuroplastic alterations that have been reported in patients with depression [55]. ...
... Depression is a neuropsychiatric disorder that has been strongly associated with stress since many depressive episodes occur due to different stressors [54]. The CUMS protocol is one of the paradigms that has been most used in the modeling of depressive-like behaviors, as it reproduces the neurochemical, morphological, and neuroplastic alterations that have been reported in patients with depression [55]. ...
Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS.
... The CUS model has been used in thousands of studies and the stressor and duration vary among labs [52,61]. In the present study, we chose 15-day CUS, which was based on our previous work [54,62], preliminary data, and our purpose for investigating the behavioral sensitivity to CUS in female mice at different ages. ...
Depression and anxiety are the most common mental health disorders. Though they affect people at any age and occur more often in females, the pathophysiological changes under these conditions are less investigated. In the present study, we examined the effects of age and stress on depression- and anxiety-related behaviors in female mice. Saccharin preference and the open field test were carried out before and after chronic unpredictable stress in 4-, 14- and 25-month-old female mice. After behavioral tests, mRNA levels of monoamine receptors in the hippocampus were measured by real-time RT-PCR. Chronic unpredictable stress decreased saccharin preference in 4-, 14- and 25-month-old mice and the time spent in the center in the open field test in 25-month-old mice. For monoamine receptors, analysis of variance revealed significant effects of age on mRNA levels of Htr1a, Htr2a, Htr6, Adra1a, Adrb2, and Adrb3, significant effects of stress on mRNA levels of Htr4, Adra2c, Adrb1, and Adrb2, and interactions of age × stress on mRNA levels of Htr1a, Htr5b, Adra1d, Adra2a, Adra2c, and Adrb1. Chronic unpredictable stress decreased mRNA levels of Htr4, Htr5b, Adra2c, and Adrb1 in 4-month-old female mice. Correlations were observed between saccharin preference and mRNA levels of Htr4, Htr5b, Htr6, Adra1d, Adra2a, and Adra2c in 4-month-old mice and between the time spent in the center in the open field test and mRNA levels of Htr1b in 4-month-old mice, Htr3a, Htr7, and Adrb2 in 14-month-old mice, and Drd2 in 4- and 14-month-old mice. Our findings support that stress induces depression- and anxiety-related behaviors and the expression of hippocampal monoamine receptors in an age-dependent manner in female mice.
... There were four kinds of UCMS applied in this experiment, such as sound stress for 30 min, no sawdust for 24 h, dampened sawdust for 24 h, tilt cages at 45° against the wall for 30 min [20][21][22] (Table 1). ...
Background
Acute myocardial infarction (AMI) is a main cause of death all around the world. There is a close relationship between myocardial infarction (MI) and depression. MI patients with untreated depression had higher mortality than those without depression. Therefore, this study aimed to explore the effect of escitalopram in treating a model under MI and unpredictable chronic mild stress (UCMS).
Methods
Male C57BL/6J mice were treated with sham surgery, or MI surgery, or UCMS, or escitalopram (ES) for a consecutive two weeks. And the mice were divided into Sham group, MI group, MI + UCMS group, MI + UCMS + ES group (n = 8 in each group). After treatment, the mice went through open field test for anxiety behavior, sucrose preference test for depressive behavior. After sacrificed, the blood, heart, hippocampus, and cortex were collected.
Results
The escitalopram badly increased the area of cardiac fibrosis size. The sucrose preference test demonstrated that escitalopram treatment showed significant effect in improving depressive behaviors of mice under MI + UCMS. The potential mechanism involved the interrelation between 5-HT system and inflammation. MI significantly affected the level of cardiac SERT. Both UCMS and ES significantly affected the level of cortex TNF-α. UCMS significantly affected the level of cardiac IL-33. In the hippocampus tissue, TNF-α was positively correlated with SERT, and IL-10 was positively correlated with SERT. In the cortex tissue, IL-33 was positively correlated with 5-HT4R, and sST2 was positively correlated with 5-HT.
Conclusions
Two-week escitalopram treatment might worsen myocardial infarction. But escitalopram could benefit depressive behaviors, which may be related with the interrelationship between the 5-HT system and inflammatory factors in the brain.
... Unpredictable chronic mild stress (UCMS) is extensively used as a well-validated animal model to induce depressivelike behavior (Nollet et al. 2013;Şahin et al. 2015). The following steps were used for the UCMS procedure: the groups experienced different stressors throughout the seven consecutive steps including exposure to a wet bed for 24 h, deprivation of food and water separately for 24 h, swimming for 5 min in cold and hot water (4 °C, 45 °C, respectively), bending the cage at 45 °C for 24 h, and pairing with another stress-induced animal for 24 h. ...
Introduction
The aim of the current study was to investigate the probable mechanism and effect of crocin on brain oxidative damage and memory deficits induced by unpredictable chronic mild stress (UCMS).
Materials and methods
Male Wistar rats were randomly divided into six groups consisting of one vehicle group (received normal saline), four groups included rats who received UCMS 4 weeks out of which three groups were pretreated with different doses of crocin (10, 20, and 30 mg/kg/day) concomitantly. To assess the pure effect of crocin, the last experimental group received a high dose of crocin (30 mg/kg/day) without exposure to the UCMS procedure. The behavioral tests including Morris water maze (MWM) and passive avoidance (PA) were performed and eventually they were sacrificed for the estimation of biochemical parameters.
Results
The increase in Malondialdehyde (MDA) as an oxidative stress indicator and nitrite levels in the hippocampus were observed in UCMS rats, along with memory deficits in behavioral tests including passive avoidance and Morris water maze (MWM) test. Moreover, treatment with crocin decreased MDA, nitrite, pro-inflammatory cytokine such as TNF-α, and pathological hallmark of Alzheimer’s disease including amyloid-β (Aβ), and glial fibrillary acidic protein (GFAP) in the hippocampus, whereas antioxidant agents including total thiol content, SOD, and catalase activity were increased. Also behavioral test demonstrated a positive effect of crocin on memory deficit induced by UCMS. Interlukin-10 as an important anti-inflammatory agent was increased as well. Interestingly, in some behavioral and biochemical findings, treatment with 30 mg/kg of crocin has given better results compared to vehicle group, which means the administration of crocin could have preventive effects on learning and memory impairment.
Conclusion
The present study strongly confirmed the positive effect of crocin and has the potential as an antioxidant and anti-inflammatory agent that could improve memory impairment induced by UCMS.
... In a typical "chronic mild stress" model, for example, in which animals are subjected to a sequence of stressors that lead to unpredictable stress, female and male mice exhibited different stress-induced behavioral alterations in the open field test (measuring exploratory activity or anxiety-like behavior), the sucrose preference test (measuring anhedonia) and the forced swim test (measuring depression-like behavior). 22 In this last test, females displayed higher levels of depressive-like symptoms (i.e., immobility) and were more responsive than males to a low dose of the selective serotonin reuptake inhibitor (SSRI) sertraline, 23 but contradicting results 24,25 or no sex differences 26,27 were also reported using the same test. Another frequently used animal model of depression is based on the "learned helplessness," a mental condition observed in both animals and humans that experience aversive stimuli repeatedly and stop trying to avoid or escape, i.e., have learned to develop helplessness in a particular situation. ...
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
... Chronic stress is a major risk factor for the development of depression. It induces gut microbiota changes and HPC impairments in both mice and humans, which are due to some extent to deficits in adult HPC neurogenesis [3,4,[17][18][19][20][21][22]. We have recently provided proof that chronic stress-related GM disturbances constitute a causal factor in the development of depressive states and adult HPC neurogenesis deficits in mice, by hijacking tryptophan metabolism and brain serotonin bioavailability [3]. ...
Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown that GM imbalance affects adult hippocampal (HPC) neurogenesis and induces depression-like behaviors, with the exact mechanisms being under active investigation. Here we hypothesized that the vagus nerve (VN), a key bidirectional route of communication between the gut and the brain, could relay the effects of stress-induced GM changes on HPC plasticity and behavior. We used fecal samples derived from mice that sustained unpredictable chronic mild stress (UCMS) to inoculate healthy mice and assess standard behavioral readouts for anxiety-and depressive-like behavior, conduct histological and molecular analyses for adult HPC neurogenesis and evaluate neurotransmission pathways and neuroinflammation. To study the potential role of the VN in mediating the effects of GM changes on brain functions and behavior, we used mice that sustained subdiaphragmatic vagotomy (Vx) prior the GM transfer. We found that inoculation of healthy mice with GM from UCMS mice activates the VN and induces early and sustained changes in both serotonin and dopamine neurotransmission pathways in the brainstem and HPC. These changes are associated with prompt and persistent deficits in adult HPC neurogenesis and induce early and sustained neuroinflammatory responses in the HPC. Remarkably, Vx abrogates adult HPC neurogenesis deficits, neuroinflammation and depressive-like behavior, suggesting that vagal afferent pathways are necessary to drive GM-mediated effects on the brain. Molecular Psychiatry; https://doi.
... In a typical "chronic mild stress" model, for example, in which animals are subjected to a sequence of stressors that lead to unpredictable stress, female and male mice exhibited different stress-induced behavioral alterations in the open field test (measuring exploratory activity or anxiety-like behavior), the sucrose preference test (measuring anhedonia) and the forced swim test (measuring depression-like behavior). 22 In this last test, females displayed higher levels of depressive-like symptoms (i.e., immobility) and were more responsive than males to a low dose of the selective serotonin reuptake inhibitor (SSRI) sertraline, 23 but contradicting results 24,25 or no sex differences 26,27 were also reported using the same test. Another frequently used animal model of depression is based on the "learned helplessness," a mental condition observed in both animals and humans that experience aversive stimuli repeatedly and stop trying to avoid or escape, i.e., have learned to develop helplessness in a particular situation. ...
... Coat state score (CSS) was also evaluated as a pharmacologically validated measure of well-being and depression-like behavior. 28 All animals' CSS worsened during the experiment ( Figure 3L), which was likely caused by the repeated use of the tube test; after a 14-day rest, control CSS improved while SIS CSS remained elevated ( Figure 3L). These data suggest a lasting, rank-independent stress effect ( Figure S2N). ...
Social species form dominance hierarchies to ensure survival and promote reproductive success. Traditionally studied in males, rodent hierarchies are considered despotic, and dominant social rank results from a history of winning agonistic encounters. By contrast, female hierarchies are thought to be less despotic, and rank is conferred by intrinsic traits. Both social buffering and elevated social status confer resilience to depression, anxiety, and other consequences of chronic stress. Here, we investigate whether female social hierarchies and individual traits related to social rank likewise influence stress resilience. We observe the formation of dyadic female hierarchies under varying conditions of ambient light and circadian phase and subject mice to two forms of chronic psychosocial stress: social isolation or social instability. We find that stable female hierarchies emerge rapidly in dyads. Individual behavioral and endocrinological traits are characteristic of rank, some of which are circadian phase dependent. Further, female social rank is predicted by behavior and stress status prior to social introduction. Other behavioral characteristics suggest that rank is motivation-based, indicating that female rank identity serves an evolutionarily relevant purpose. Rank is associated with alterations in behavior in response to social instability stress and prolonged social isolation, but the different forms of stress produce disparate rank responses in endocrine status. Histological examination of c-Fos protein expression identified brain regions that respond to social novelty or social reunion following chronic isolation in a rank-specific manner. Collectively, female rank is linked to neurobiology, and hierarchies exert context-specific influence upon stress outcomes.
... CUMS protocol was involved a variety of mild stressors, including 2 h of habitation alone or crowded, 2 h of physical restraint, 2 h of exposure to a foreign object (e.g., a piece of plastic), 5 min of forced swimming at 8 °C, and 10 min of cage shaking during the daytime, as well as food or water deprivation, illumination or flash of light, cage tilt (30°), and habitation in a soiled cage (200 ml of water in 100 g of sawdust bedding) overnight [20]. Mice in CUMS group were daily received 1 of inconsecutive day and night stressors combination that were prior randomly scheduled for a 6-w period. ...
Background
The “missing” link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice.
Methods
Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed.
Results
Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS–IFI16–STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors.
Conclusions
Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.
... Mice were randomly divided into CUMS treatment and CUMSabsent groups. Then CUMS treatment was used to induce behavioral changes in CUMS groups (bc004004 þ/þ þCUMS and bc004004 À /À þCUMS), as described in previous studies (Biala et al., 2017;Nollet et al., 2013). CUMS treatment was absent for NO CUMS groups (bc004004 þ/þ À CUMS and bc004004 À /À À CUMS). ...
Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004-/- and bc004004+/+ mice exhibited behavioural changes and there was no significant difference between bc004004+/+ and bc004004-/-. However, behavioural changes were observed only in bc004004-/- mice after being exposed to CUMS for 21 days, but not in bc004004+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.
... So far, only a few studies showed that even brief tail handling (2s) can affect behaviour 12,23 . Some of the reported effects of tail handling are strikingly similar to those induced by unpredictable chronic mild stress (UCMS), a paradigm commonly used with laboratory mice to induce and study chronic mild stress [24][25][26] . The paradigm involves exposing the animals to mild unpredictable stressors over several weeks, which results in behavioural, neuroendocrine and morphological changes (e.g. ...
Studies in mice have shown that less aversive handling methods (e.g. tunnel or cup handling) can reduce behavioural measures of anxiety in comparison to picking mice up by their tail. Despite such evidence, tail handling continues to be used routinely. Besides resistance to change accustomed procedures, this may also be due to the fact that current evidence in support of less aversive handling is mostly restricted to effects of extensive daily handling, which may not apply to routine husbandry practices. The aim of our study was to assess whether, and to what extent, different handling methods during routine husbandry induce differences in behavioural and physiological measures of stress in laboratory mice. To put the effects of handling method in perspective with chronic stress, we compared handling methods to a validated paradigm of unpredictable chronic mild stress (UCMS). We housed mice of two strains (Balb/c and C57BL/6) and both sexes either under standard laboratory conditions (CTRL) or under UCMS. Half of the animals from each housing condition were tail handled and half were tunnel handled twice per week, once during a cage change and once for a routine health check. We found strain dependent effects of handling method on behavioural measures of anxiety: tunnel handled Balb/c mice interacted with the handler more than tail handled conspecifics, and tunnel handled CTRL mice showed increased open arm exploration in the elevated plus-maze. Mice undergoing UCMS showed increased plasma corticosterone levels and reduced sucrose preference. However, we found no effect of handling method on these stress-associated measures. Our results therefore indicate that routine tail handling can affect behavioural measures of anxiety, but may not be a significant source of chronic husbandry stress. Our results also highlight strain dependent responses to handling methods.
... The translational relevance of animal models of depression has traditionally been evaluated based on their predictive, construct and face validity 84 . It is generally accepted that CUS paradigms in rodents fulfill all these criteria, since they replicate many symptoms of depression seen in humans (good face validity), show specific and selective responses to antidepressants (good predictive validity), and have sound theoretical basis (good construct validity) 85,86 . However, as with other animal models of depression, CUS-based paradigms themselves have several important conceptual and methodological limitations. ...
Widespread, debilitating and often treatment-resistant, depression and other stress-related neuropsychiatric disorders represent an urgent unmet biomedical and societal problem. Although animal models of these disorders are commonly used to study stress pathogenesis, they are often difficult to translate across species into valuable and meaningful clinically relevant data. To address this problem, here we utilized several cross-species/cross-taxon approaches to identify potential evolutionarily conserved differentially expressed genes and their sets. We also assessed enrichment of these genes for transcription factors DNA-binding sites down- and up- stream from their genetic sequences. For this, we compared our own RNA-seq brain transcriptomic data obtained from chronically stressed rats and zebrafish with publicly available human transcriptomic data for patients with major depression and their respective healthy control groups. Utilizing these data from the three species, we next analyzed their differential gene expression, gene set enrichment and protein–protein interaction networks, combined with validated tools for data pooling. This approach allowed us to identify several key brain proteins (GRIA1, DLG1, CDH1, THRB, PLCG2, NGEF, IKZF1 and FEZF2) as promising, evolutionarily conserved and shared affective ‘hub’ protein targets, as well as to propose a novel gene set that may be used to further study affective pathogenesis. Overall, these approaches may advance cross-species brain transcriptomic analyses, and call for further cross-species studies into putative shared molecular mechanisms of affective pathogenesis.
... Researchers led by Catherine Belzung, for example, recommend avoiding the use of severe stressors such as water and food deprivation and painful stressors. Firstly, they do not reflect the etiology of depression in humans, and secondly, they have a generalized effect on the physical state of the animal, which may interfere with the measures of the CUMS-induced effects [69]. For example, Harris R et al. used saline injection as one of the stressful factors in the CUMS protocol [10]. ...
Major depressive disorder (MDD) is one of the most common mood disorders worldwide. A lack of understanding of the exact neurobiological mechanisms of depression complicates the search for new effective drugs. Animal models are an important tool in the search for new approaches to the treatment of this disorder. All animal models of depression have certain advantages and disadvantages. We often hear that the main drawback of the chronic unpredictable mild stress (CUMS) model of depression is its poor reproducibility, but rarely does anyone try to find the real causes and sources of such poor reproducibility. Analyzing the articles available in the PubMed database, we tried to identify the factors that may be the sources of the poor reproducibility of CUMS. Among such factors, there may be chronic sleep deprivation, painful stressors, social stress, the difference in sex and age of animals, different stress susceptibility of different animal strains, handling quality, habituation to stressful factors, various combinations of physical and psychological stressors in the CUMS protocol, the influence of olfactory and auditory stimuli on animals, as well as the possible influence of various other factors that are rarely taken into account by researchers. We assume that careful inspection of these factors will increase the reproducibility of the CUMS model between laboratories and allow to make the interpretation of the obtained results and their comparison between laboratories to be more adequate.
... CUMS involved exposure to a variety of mild stressors, including 24 h of food deprivation, 24 h of water deprivation, 1 h of exposure to empty bottles, 8 h of cage tilt (45 • ), overnight illumination, 24 h of habitation in a soiled cage (200 ml of water in 100 g of sawdust bedding), 30 min of forced swimming at 8 • C, 2 h of physical restraint, and 24 h of exposure to a foreign object (e.g., a piece of plastic) (Nollet et al., 2013). Mice were daily received 2 of those stressors combination that were prior randomly scheduled for a 28-d period. ...
Depression is accompanied by excessive neuroinflammation. Liver X receptor β (LXRβ) has been reported as a newly emerging target that exerts systemic and organic inflammation modulation. However, the modulatory mechanism in alleviating neuroinflammation are far from being revealed. In the current study, depression-related behaviors in mice were induced by chronic unpredictable mild stress (CUMS) and corticosterone (CORT) drinking. Mice received either TO901317, PLX-5622 and intra- bilateral basolateral amygdale (BLA) injection of rAAV9-hSyn-hM3D(Gq)-eGFP to activate LXRβ, eliminate microglia and pharmacogenetic activate neurons in BLA, respectively, followed by behavioral tests. Microglial pro-inflammatory and pro-phagocytic activation, as well as nuclear factor-κB (NF-κB) signaling pathway, NLRP3 inflammasome activation and interleukin-1β (IL-1β) release in BLA were investigated. Moreover, pro-inflammatory activation of BV2 cells-induced by CORT with or without TO901317 was detected. Neuroinflammation indicated by IL-1β release was measured in a co-culture system of HT22-primary microglia with or without TO901317. Our results indicated that chronic stress induced depression-related behaviors, which were accompanied with microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation in BLA. Accordingly, pharmacological activation of LXRβ inhibited microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation, and IL-1β release both in vivo and in vitro. Finally, both elimination of microglia and pharmacogenetic activation of neurons in BLA protected mice from chronic stress-induced depression-related behavior. Collectively, pharmacological activation of neuronal-microglial LXRβ alleviates depression-related behavior by modulating excessive neuroinflammation via inhibiting NF-κB signaling pathway and NLRP3 inflammasome activation.
... Mice were randomly assigned to receive chronic unpredictable mild stress (CUMS), corticosterone (CORT) drinking, or control group. CUMS protocol was involved a variety of mild stressors, including 24 h of food deprivation, 24 h of water deprivation, 1 h of exposure to empty bottles, 8 h of cage tilt (30°), overnight illumination, 24 h of habitation in a soiled cage (200 ml of water in 100 g of sawdust bedding), 5 min of forced swimming (FS) at 8°C, 2 h of physical restraint, and 24 h of exposure to a foreign object (e.g., a piece of plastic) (17). Mice in CUMS group were daily received two of those stressors combination that were prior randomly scheduled for a 4-week period. ...
Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders.
... In cohort #3, mice were exposed to CRS to induce a working memory deficit in the Y maze test, and to test the capacity of reversal of GL-I-54. In cohorts #5 and #6, mice were subjected to UCMS, and each animal's coat state was scored (0 = well-groomed, smooth coat, 1=soiled coat or bald patches) weekly for seven coat regions, as in [68]. Behavioral screen included: anxiety-like avoidance behavior (EPM, open-field, OF; Novelty Suppressed Feeding, NSF; and the Phenotyper Test [67], PT), Sucrose Consumption; (SC), immobility in the FST and cognitive function (Y-maze alternation task [55,58,69]). ...
Chronic stress is a risk factor for Major Depressive Disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2- and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side-effects. This study investigated the activity profiles and behavioral efficacy of two enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.
... The CUMS model was revised from a report on models of depression that allow investigation of key biological correlates of depression (Nollet et al., 2013). Except for group 1 rats, which were normally reared (5-6 rats/cage), the others were reared individually in a separate cage and given two different stimuli randomly daily; each stimulus was administered four times in 21 days. ...
Background: Depression is a common mental disorder, and its morbidity rate is expected to rank second among all mental disorders by 2020. Hence, traditional Chinese medicines gradually attract the attention of many researchers because of their various targets and low toxicity. Huolisu oral solution (HLS) is a Chinese medicine compound preparation, which is present in the Chinese Pharmacopoeia. It is used clinically mainly for the treatment of neurasthenia, perimenopausal syndrome, and insomnia, or depression associated with cerebrovascular disease. Despite the fact that HLS has been used as an antidepressant in clinics, the underlying mechanism is still an untouched domain. To provide a theoretical basis for the clinical application, a series of assessment methods, such as the tail suspension test (TST), forced swim test (FST), and locomotor activity test in mice and rat models of chronic unpredictable mild stress (CUMS), have been conducted in our study.
Objective: The aim of the study was to explore the antidepressive effect and mechanism of HLS.
Methods: CUMS was induced in rats to simulate a depression-like behavior. Neurotransmitters and hormones were detected by enzyme-link immunosorbent assay (ELISA). Pathomorphology examination of the hippocampus was obtained by using the TSView 7 image analysis system. The active ingredients of HLS were also determined by high-performance liquid chromatography (HPLC).
Results: HLS could alleviate the depression-like behavior of the model rats. Biochemical analysis showed that HLS enhanced the levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in the hippocampus and diminished these in the serum of the CUMS rats. HLS could also decrease the concentration of corticosterone (CORT), adrenocorticotropic hormone (ACTH), and β-endorphin (β-EP) in blood. The pathohistological examination revealed that the hippocampus and adrenal gland were improved after treatment with HLS.
Conclusions: This study concluded that HLS could alleviate depression-like behaviors in the rats exposed to CUMS, and the potential mechanism may be related to the regulation of the monoamine neurotransmitters, the hypothalamic–pituitary–adrenal (HPA) axis, and the β-EP. These findings hint that HLS is likely to be a potentially effective agent for treating depression.
... These results agreed with different studies that showed an increased immobilization time, which was considered a measure of behavioral despair [63][64][65]. This prolonged time of immobility in the TST and FST can be reversed using antidepressants [66,67]. Importantly, studies declared that anhedonia was linked to an increased immobility time [68]. ...
Depression-induced cognitive impairment has recently been given more attention in research. However, the relationship between depression and different types of memory is still not clear. Chronic unpredictable mild stress (CUMS) is a commonly used animal model of depression in which animals are exposed to chronic unpredictable environmental and psychological stressors, which mimics daily human life stressors. This study investigated the impact of different durations of CUMS on various types of memory (short- and long-term spatial memory and recognition memory) and investigated CUMS’ impact on the ultrastructural level by histological assessment of the hippocampus and prefrontal cortex. Twenty male C57BL/J6 mice (6 weeks old, 21.8 ± 2 g) were randomly divided into two groups (n = 10): control and CUMS (8 weeks). A series of behavioral tasks were conducted twice at weeks 5–6 (early CUMS) and weeks 7–8 (late CUMS). A tail-suspension test (TST), forced swimming test (FST), elevated zero maze (EZM), elevated plus maze (EPM), open field test (OFT), and sucrose-preference test (SPT) were used to assess anxiety and depressive symptoms. The cognitive function was assessed by the novel object recognition test (NORT; for recognition memory), Y-maze (for short-term spatial memory), and Morris water maze (MWM: for long-term spatial memory) with a probe test (for reference memory). Our data showed that 8 weeks of CUMS increased the anxiety level, reported by a significant increase in anxiety index in both EPM and EZM and a significant decrease in central preference in OFT, and depression was reported by a significant increase in immobility in the TST and FST and sucrose preference in the SPT. Investigating the impact of CUMS on various types of memory, we found that reference memory is the first memory to be affected in early CUMS. In late CUMS, all types of memory were impaired, and this was consistent with the abnormal histological features of the memory-related areas in the brain (hippocampus and prefrontal cortex).
... The hippocampus shows high sensitivity and responsiveness to stress [36], and its structure and function can be affected by stress. In animal models, chronic stress may significantly reduce hippocampal volume [37][38][39]. Notably, clinical studies [40] have shown that depression patients have a smaller hippocampal size relative to controls. One important reason for the decrease in hippocampal volume induced by stress is the loss of neurons. ...
Stress, which refers to a combination of physiological, neuroendocrine, behavioral, and emotional responses to novel or threatening stimuli, is essentially a defensive adaptation under physiological conditions. However, strong and long-lasting stress can lead to psychological and pathological damage. Growing evidence suggests that patients suffering from mild and moderate brain injuries and diseases often show severe neurological dysfunction and experience severe and persistent stressful events or environmental stimuli, whether in the acute, subacute, or recovery stage. Previous studies have shown that stress has a remarkable influence on key brain regions and brain diseases. The mechanisms through which stress affects the brain are diverse, including activation of endoplasmic reticulum stress (ERS), apoptosis, oxidative stress, and excitatory/inhibitory neuron imbalance, and may lead to behavioral and cognitive deficits. The impact of stress on brain diseases is complex and involves impediment of recovery, aggravation of cognitive impairment, and neurodegeneration. This review summarizes various stress models and their applications and then discusses the effects and mechanisms of stress on key brain regions—including the hippocampus, hypothalamus, amygdala, and prefrontal cortex—and in brain injuries and diseases—including Alzheimer’s disease, stroke, traumatic brain injury, and epilepsy. Lastly, this review highlights psychological interventions and potential therapeutic targets for patients with brain injuries and diseases who experience severe and persistent stressful events.
... We next investigated the role of ABIN activity in the antidepressant effect of ketamine in an animal model of depression. Unpredictable chronic mild stress (UCMS) is a widely used, well-validated, and reliable behavioral model of depression that induces a robust and long-lasting depression-like phenotype in mice 40,[60][61][62][63][64][65][66][67] . Because there are reports that the effects of ketamine differ based on stress exposure 68,69 , we tested whether ABIN activation is also crucial for the ability of ketamine to reverse the effects of stress in mice exposed to UCMS. ...
Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear. Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice. Chemogenetic inhibition of ABIN activity blocks the antidepressant effects of ketamine, indicating that this activity is necessary for the behavioral effects. Conversely, chemogenetic activation of ABINs without any change in neuron numbers mimics both the cellular and the behavioral effects of ketamine, indicating that increased activity of ABINs is sufficient for rapid antidepressant effects. These findings thus identify a specific cell population that mediates the antidepressant actions of ketamine, indicating that ABINs can potentially be targeted to limit ketamine’s side effects while preserving its therapeutic efficacy. Rawat et al. demonstrate that activation of adult-born immature hippocampal neurons is necessary and sufficient for the acute antidepressant effects of low-dose ketamine in mice.
... To better investigate the antidepressant mechanisms of ZSS, we established a CUMS-induced mouse depression model, which has been widely used in simulating human depression [18,19]. ...
Context. Ziziphi Spinosae Semen (ZSS) is a well-known Chinese herbal medicine used in the treatment of depression and anxiety in China. ZSS contains several active components, such as alkaloids, saponins, and flavonoids. Objective. This study aimed to explore the synergistic effect of alkaloids and saponins from ZSS in alleviating depression in a mouse model. Materials and Methods. Modeling depression with chronic unpredictable stimuli. Pharmacodynamic methods (tail suspension test and forced swimming test) were used to evaluate the antidepressant effects of alkaloids, saponins, and combinations thereof from ZSS. The mechanisms underlying the effect were examined by measuring the levels of monoamine neurotransmitters in the hippocampus and frontal cortex of mice. Results. Compared with the model group, alkaloids therapy (AZSS), saponins therapy (SZSS), and combination therapy significantly reduced the immobility time in behavioral tests ( P < 0.05 ). The contents of noradrenaline (NE), dopamine (DA), and serotonin (5-HT) in the hippocampus and frontal cortex of depressed mice were increased in the drug treatment groups, especially in the combination group, which increased by 14.65%, 87.72%, 33.44%, 25.64%, 25.39%, and 70.78%, respectively. Several groups showed better results ( P < 0.05 ), especially the combination of alkaloids and saponins. Discussion and Conclusion. The saponins and alkaloids from ZSS exhibited a synergistic effect in improving the behavior of depressed mice. More importantly, the combination of alkaloids (15 mg·kg−1) and saponins (110 mg·kg−1) was effective in alleviating depression in mice, especially in terms of changing the level of DA in the hippocampus.
Stress, encompassing psychological, physical, and physiological challenges, is an important factor affecting an individual's well-being and potentially leading to psychiatric, neurodegenerative, immune, and metabolic disorders. However, not everyone exposed to stress develops these conditions, highlighting the concept of resilience. Resilience is a dynamic process categorized into four dimensions: pre-existing resilience capacity, ongoing resilience processes, post-stress resilience outcomes, and recovery from psychopathologies. These dimensions involve genomic, cellular, and systemic interactions influenced by genetic factors, early life experiences, adult life experiences in addition to community/environmental factors, and health behaviors. The biological response to stress encompasses endocrine, autonomic, immunological, and behavioral components, modulated by stressor characteristics and individual traits. Due to the limitations in studying stress and resilience in humans, translational models using rodents and cell cultures are essential. Rodent models include acute, chronic, and traumatic stress paradigms, aiding the study of stress-related behavioral and molecular outcomes. Additionally, early life stress models, such as prenatal stress and maternal separation, provide insights into developmental impacts. In this review, first, rodent models for lifelong stress exposure will be summarized considering their validity, advantages, and limitations. Subsequently, an overview of models designed to enhance resilience capacity and process in rodents, and later the behavioral models employed to study the outcomes of resilience will be given. Lastly, the focus will be shifted to cell culture and iPSCs models. Finally, future considerations focused on improving translational models used to study stress and resilience will be discussed. It is aimed to provide an overview of designs for translational stress and resilience models to access more effective translational biomarkers associated with stress and resilience. Stress and resilience are complex phenomena influenced by various factors, spanning molecular to behavioral levels. Integrating data across dimensions remains crucial for unraveling the complexities of stress-related disorders and resilience.
Objectives:
This study sought to identify pathways affected by rat cortical RNA that were changed after treatment with fluoxetine or imipramine.
Methods:
We measured levels of cortical RNA in male rats using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (0.9% NaCl), fluoxetine (10 mg/kg/day) or imipramine (20 mg/kg/day) for 28 days. Levels of coding and non-coding RNA in vehicle treated rats were compared to those in treated rats using ANOVA in JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify pathways involving the changed RNAs.
Results:
18,876 transcripts were detected; there were highly correlated changes in 1010 levels of RNA after both drug treatments that would principally affect the metabolism of polyamines, mRNA splicing, regulation of RAS by GAPs, neddylation and GPCR ligand binding. Using our previously published data, we compared changes in transcripts after treatment with antipsychotic and mood stabilising drugs.
Conclusions:
Our study shows there are common, correlated, changes in coding and non-coding RNA in the rat cortex after treatment with fluoxetine or imipramine; we propose the pathways affected by these changes are involved in the therapeutic mechanisms of action of antidepressant drugs.
Major depressive disorder is the most common psychiatric disorder worldwide. To understand mechanisms and search for new approaches to treating depression, animal models are crucial. Chronic mild stress (CMS) is the most used animal model of depression. Although CMS is considered a robust model of depression, conflicting results have been reported for emotion-related behaviors, which the intrinsic characteristics of each rodent strain could explain. To further shed light on the impact of genetic background on the relevant parameters commonly addressed in depression, we examined the effect of 4-weeks CMS on anxiety and depression-related behaviors and body weight gain in three strain mice (BALB/c, C57BL/6, and CD1) of both sexes. CMS reduced body weight gain in C57BL/6NCrl and CD1 male mice. C57BL/6 animals exhibited a more pronounced anxious-like behavior than CD1 and BALB/c mice in the light-dark box (LDB) and the elevated plus maze (EPM) tests, whereas BALB/c animals exhibited the more robust depressive-like phenotype in the splash test (ST), tail suspension test (TST) and forced-swimming test (FST). Under CMS, exposure did not affect anxiety-related behaviors in any strain but induced depression-like behaviors strain-dependently. CMS C57BL/6 and CD1 mice of both sexes showed depression-like behaviors, and CMS BALB/c male mice exhibited reduced depressive behaviors in the FST. These results suggest a differential effect of stress, with the C57BL/6 strain being more vulnerable to stress than the CD1 and BALB/c strain mice. Furthermore, our findings emphasize the need for researchers to consider mouse strains and behavioral tests in their CMS experimental designs.
Keywords: Animal model; Anxiety; Behavior; Depression; Sex differences; Stress vulnerability.
Inequality represents an extreme environment to which humans must respond. One phenomenon that contributes to this growing extreme is precarity or the intersection of uncertainty and some form of inequality. While precarity has an important intellectual history in the fields of sociology and sociocultural anthropology, it has not been well studied in the field of human biology. Rather human biologists have engaged with the study of closely related concepts such as uncertainty and resource insecurity. In this article, we propose that human biology take on the study of precarity as a novel way of investigating inequality. We first provide a brief intellectual history of precarity which is followed by a review of research on uncertainty and resource security in human biology which, while not exhaustive, illustrates some key gaps that precarity may aid us in addressing. We then review some of the pathways through which precarity comes to affect human biology and health and some of the evidence for why the unpredictable nature of precarity may make it a unique physiological stress. A case study based on research in Nuñoa, Peru provides an important example of how precarity can elucidate the influences of health in an extreme setting, albeit with insights that apply more broadly. We conclude that precarity holds important potential for the study of human biology, including helping us more effectively operationalize and study uncertainty, encouraging us to explore the predictability of resources and stressors, and reminding us to think about the intersectional nature of stressors.
The Probabilistic Reward Task (PRT) is a laboratory-based technique used to objectively quantify responsivity to reward. The PRT was initially designed to identify reinforcement learning deficits in clinical populations and subsequently was reverse-translated for use in preclinical studies with rats and monkeys. In this task, subjects make visual discriminations and asymmetric probabilistic contingencies are arranged such that correct responses to one stimulus (rich) are reinforced more often than correct responses to the other (lean). Numerous studies have demonstrated that healthy subjects reliably develop a response bias toward the richly rewarded stimulus, whereas humans with anhedonia and laboratory animals with a history of chronic stress exhibit a blunted response bias. This is important because anhedonia, the loss of responsivity to previously rewarding stimuli, is a behavioral phenotype that is a cardinal feature of multiple neuropsychiatric conditions and is without approved pharmacotherapeutic options. To aid in addressing this critical treatment gap, this report describes validation of the first PRT designed for mice, which are a commonly utilized species in preclinical research toward neuropsychiatric medications development. Results reveal orderly psychophysical functions in response to asymmetric probabilistic contingencies in mice, with signal detection outcomes comparable to previous PRT findings in humans, rats, and monkeys. Taken together, such robust cross-species continuity in task performance confirms that the mouse is well-positioned to serve in bidirectional research efforts between human and animal laboratories. These efforts may accelerate the development of treatment options for anhedonia in the different neuropsychiatric conditions in which it is prominent.
Seabuckthorn (Hippophae rhamnoides L.), which is enriched with flavonoids, including isorhamnetin, quercetin and kaempferol, is a representative example of "medicine food homology" targeting several diseases. Major depressive disorders seriously threaten mental health worldwide and may even lead to death. Chronic unpredictable mild stress (CUMS)-induced depressive-like symptoms in mice are usually considered as the highest similarity to the situation in humans. Herein, we determined the potential functions of the flavonoid-enriched fraction from Seabuckthorn, which was named SBF, in treating major depressive disorder in mice. In the CUMS-induced mouse model, the intake of SBF reversed their depressive behaviors and relieved the CUMS-disturbed levels of neurotrophins, neurotransmitters, stress-related hormones, and inflammation-related cytokines. Additionally, the treatment of depressive mice with SBF showed ability to regulate the gut microbiota, especially in decreasing the abundance of Lactobacillaceae, while increasing the abundance of Lachnospiraceae at the family level. The results suggest the beneficial effects of Seabuckthorn flavonoids in functioning as a health food supplement to treat major depressive disorders.
The nest building behavior of mice with a model of Alzheimer’s disease was studied. For this purpose, animals belonging to one of three genotype variants (homozygotes, heterozygotes, and wild-type) placed in separate cages were provided with nest-building material. At the end of the experiment, the nests built by the mice were removed from the cages and photographed. The obtained images were segmented by color, and the results were used for statistical analysis, which revealed that there were no statistically significant differences between the nests of wild-type and heterozygous mice, while the differences between the nests of wild-type and homozygous mice were statistically significant: homozygous mice with Alzheimer’s disease model built significantly less developed nests compared to those of wild-type mice. This is due to the fact that wild-type mice used pre-gnawed cardboard fragments to a greater extent in nest construction, which was practically not observed in homozygous mice.Keywordsnest-building behavior5xFADAlzheimer’s diseasephotometry
Astrocytes, despite some shared features as glial cells supporting neuronal function in gray and white matter, participate and adapt their morphology and neurochemistry in a plethora of distinct regulatory tasks in specific neural environments. In the white matter, a large proportion of the processes branching from the astrocytes' cell bodies establish contacts with oligodendrocytes and the myelin they form, while the tips of many astrocyte branches closely associate with nodes of Ranvier. Stability of myelin has been shown to greatly depend on astrocyte-to-oligodendrocyte communication, while the integrity of action potentials that regenerate at nodes of Ranvier has been shown to depend on extracellular matrix components heavily contributed by astrocytes. Several lines of evidence are starting to show that in human subjects with affective disorders and in animal models of chronic stress there are significant changes in myelin components, white matter astrocytes and nodes of Ranvier that have direct relevance to connectivity alterations in those disorders. Some of these changes involve the expression of connexins supporting astrocyte-to-oligodendrocyte gap junctions, extracellular matrix components produced by astrocytes around nodes of Ranvier, specific types of astrocyte glutamate transporters, and neurotrophic factors secreted by astrocytes that are involved in the development and plasticity of myelin. Future studies should further examine the mechanisms responsible for those changes in white matter astrocytes, their putative contribution to pathological connectivity in affective disorders, and the possibility of leveraging that knowledge to design new therapies for psychiatric disorders.
Traxoprodil is a selective N-methyl-d-aspartate receptor subunit 2B (NR2B) receptor inhibitor with rapid and long-lasting antidepressant effects. However, the appropriate dosage, duration of administration, and underlying mechanism of traxoprodil’s antidepressant effects remain unclear. The purpose of this study is to compare the antidepressant effects of traxoprodil in different doses and different durations of administration and to explore whether traxoprodil exerts antidepressant effects via the brain-derived neurotrophic factor/extracellular signal-regulated kinase/cAMP-response element binding protein (BDNF/ERK/CREB) and protein kinase B/Forkhead box O/building information modelling (AKT/FOXO/Bim) signaling pathway. Mice were randomly divided into control group, chronic unpredictable mild stress (CUMS) + vehicle group, CUMS + traxoprodil (10 mg/kg, 20 mg/kg, and 40 mg/kg) groups, and CUMS + fluoxetine (5 mg/kg) group, followed by a forced swimming test, tail suspension test, and sucrose preference test. Western blotting and immunohistochemistry were used to measure the protein expression of BDNF, p-ERK1/2, p-CREB, NR2B, AKT, FOXO1, FOXO3a, and Bim. Compared with the control group, CUMS treatment increased immobility time; decreased sucrose preference; reduced expression of BDNF, p-ERK1/2, and p-CREB; and increased expression of AKT, FOXO, and Bim in the hippocampus. These alterations were ameliorated by administration of 20 mg/kg or 40 mg/kg of traxoprodil after 7 or 14 days of administration and with 10 mg/kg of traxoprodil or 5 mg/kg of fluoxetine after 21 days of administration. At the 7-day and 14-day timepoints, traxoprodil displayed dose-dependent antidepressant effects, with 20 and 40 mg/kg doses of traxoprodil producing rapid and strong antidepressant effects. However, at 21 days of administration, 10 and 20 mg/kg doses of traxoprodil exerted more pronounced antidepressant effects. The mechanism of traxoprodil’s antidepressant effects may be closely related to the BDNF/ERK/CREB and AKT/FOXO/Bim signaling pathway.
Objective:
Depression is positively correlated with the high incidence and low survival rate of cancers, while more cancer patients suffer depression. However, the interaction between depression and cancer, and possible underline mechanisms are unclear.
Methods:
Chronic unpredictable mild stress (CUMS) was used to induce depression, and smoke to induce lung cancer in lung cancer vulnerable AJ mice. After 8 weeks, sucrose preference and forced swimming behaviors were tested. Blood corticosterone concentration, and levels of cytokines, lung cancer-related factors, brain-derived neurotrophic factor (BDNF) and apoptosis-related factors in the lung, amygdala and hippocampus were measured.
Results:
Compared to control group, CUMS or smoke decreased sucrose consumption and increased immobility time, which were deteriorated by stress+smoke. CUMS, smoke or both combination decreased mononuclear viability and lung TNF-α concentration, increased serum corticosterone and lung interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, IL-12 and HSP-90α concentrations. Furthermore, stress+smoke caused more increase in corticosterone and IL-10, but decreased TNF-α. In parallel, in the lung, Bcl-2/Bax and lung cancer-related factors CDK1, CDC20, P38α etc were significantly increased in stress+smoke group. Moreover, CUMS decreased BDNF, while CUMS or smoke increased TrkB and P75 concentrations, which were exacerbated by stress+smoke. In the amygdala, except for CUMS largely increased Bax/Bcl-2 and decreased TrkB, each single factor decreased BDNF and IL-10, but increased P75, IL-1β, IL-12, TNF-α concentrations. Changes in Bax/Bcl-2, IL-10 and TNF-α were further aggravated by the combination. In the hippocampus, except for CUMS largely increased P75 concentration, each single factor significantly increased Bax/Bcl-2 ratio, IL-1β and TNF-α, but decreased BDNF, TrkB and IL-10 concentrations. Changes in Bax, Bax/Bcl-2, IL-10 and TNF-α were further aggravated by the combination.
Conclusion:
These results suggest that a synergy between CUMS and smoke exposure could promote the development of depression and lung cancer, through CUMS increased the risk of cancer occurrence, and conversely lung cancer inducer smoke exposure deteriorated depressive symptoms.
Mood disorders, including major depressive disorder and bipolar disorders, are frequent and heterogeneous psychiatric diseases. In order to better understand their pathophysiology, a new research area based on dimensions has emerged. It consists of exploring domains derived from fundamental behavioral components to link them to neurobiological systems. Beyond mood, emotional biases differentiate mood states in patients. Mania episodes are associated with positive biases, i.e. emotional stimuli become more rewarding and less aversive, while the opposite characterizes depression. The objective of this thesis was to identify hedonic bias in mouse models of depression and mania, and to study the underlying neural mechanisms. Using the GBR 12909-induced mouse model of mania, we found apart from the classical mania-like phenotype characterized by hyperlocomotion, strong negative olfactory and gustatory hedonic biases, at the opposite of what we expected. On the contrary, we uncovered a negative olfactory hedonic bias in the corticosterone-induced mouse model of depression, as we predicted. This bias was accompanied by specific basolateral amygdala (BLA) circuits activity disturbances. Furthermore, manipulating some of these BLA circuits activity thanks to chemogenetics was sufficient to partially improve the negative olfactory hedonic bias induced by chronic corticosterone administration. Taken together, our results highlight the interest of olfactory hedonic evaluation in mouse models of depression and mania, and demonstrate the causal role of BLA circuits in hedonic biases associated with depressive-like states.
Major depression is a disease having high lifetime prevalence, characterized by alterations in the affective and cognitive spheres. It is related to a complex aetiology, as both stress sensitivity and genetic factor contribute to vulnerability and is associated with cerebral, endocrine and neurotransmission alterations, such as decreased hippocampal functioning, modifications of the monoaminergic level or an hyperactivity of the hypothalamus-pituitary-adrenal axis. Chronic antidepressants enable to decrease the depression-related symptoms, but many drawbacks of such treatments made the discovery of new therapeutic targets urgent. Progress in this area needs valid animal models. Here, we review data on one of these models, the unpredictable chronic mild stress in mice. Data show that this protocol is associated with several behavioural and neurobiological alterations, suggesting that it induces features that are isomorphic to the human disease. Further, these alterations are induced by factors involved in the aetiology of major depression in humans. Finally, these modifications are sensitive only to chronic, but not acute, antidepressants used in the clinic. This review therefore suggests that the unpredictable chronic mild stress has an excellent predictive, etiologic and face validity and that it thus might be an excellent model of major depression.
Animal models of psychiatric disorders are usually discussed with regard to three criteria first elaborated by Willner; face, predictive and construct validity. Here, we draw the history of these concepts and then try to redraw and refine these criteria, using the framework of the diathesis model of depression that has been proposed by several authors. We thus propose a set of five major criteria (with sub-categories for some of them); homological validity (including species validity and strain validity), pathogenic validity (including ontopathogenic validity and triggering validity), mechanistic validity, face validity (including ethological and biomarker validity) and predictive validity (including induction and remission validity). Homological validity requires that an adequate species and strain be chosen: considering species validity, primates will be considered to have a higher score than drosophila, and considering strains, a high stress reactivity in a strain scores higher than a low stress reactivity in another strain. Pathological validity corresponds to the fact that, in order to shape pathological characteristics, the organism has been manipulated both during the developmental period (for example, maternal separation: ontopathogenic validity) and during adulthood (for example, stress: triggering validity). Mechanistic validity corresponds to the fact that the cognitive (for example, cognitive bias) or biological mechanisms (such as dysfunction of the hormonal stress axis regulation) underlying the disorder are identical in both humans and animals. Face validity corresponds to the observable behavioral (ethological validity) or biological (biomarker validity) outcomes: for example anhedonic behavior (ethological validity) or elevated corticosterone (biomarker validity). Finally, predictive validity corresponds to the identity of the relationship between the triggering factor and the outcome (induction validity) and between the effects of the treatments on the two organisms (remission validity). The relevance of this framework is then discussed regarding various animal models of depression.
Etiopathogenesis of depression and the cause of insensitivity to treatment remain poorly understood, although genetic makeup has been established as a contributing factor. The isogenicity of inbred mouse strains provides a useful tool for investigating the link between genes and behavior or drug response. Hence, our aim was to identify inbred mouse strains (among A/J, BALB/c, C3H, C57BL/6, CBA, DBA and FVB) sensitive to a 9-week period of unpredictable chronic mild stress (UCMS) and, from the fifth week onward, to the reversal effect of an antidepressant (AD) (imipramine, 20 mg/kg/day i.p.) on various depression-related changes: physical, behavioral and neuroendocrine states. UCMS induced a significant deterioration of the coat state (in all the strains), blunted emotional reactivity in the novelty-suppressed feeding (NSF) test (A/J, BALB/c, C57BL/6), and changes in the level of fecal corticosterone metabolites (BALB/c, C57BL/6, DBA, FVB). Imipramine treatment reversed the UCMS-induced alterations of the coat state (BALB/c, DBA), in the NSF test (A/J, BALB/c, C57BL/6) and in fecal corticosterone metabolites (BALB/c, C57BL/6). C3H, CBA and FVB mice were irresponsive to imipramine treatment. It is noteworthy that UCMS-induced physical or behavioral changes occurred without hypothalamo–pituitary–adrenal (HPA) axis alterations in some strains (A/J, C3H, CBA), although the AD-induced reversal of these changes in BALB/c and C57BL/6 was associated with HPA axis normalization. Finally, UCMS is shown to discriminate various alterations and to replicate in a strain-dependent manner diverse profiles reminiscent of human disease subtypes. UCMS may thus enable the selection of strains suitable for investigating specific depression-related features and could be an appropriate model for identifying genetic factors associated with increased vulnerability, specific symptoms of affective disorders, and AD resistance.
Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.
Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS-an already validated animal model of depression-with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression.
Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. The authors hypothesized that controlling several sources of clinical and technical variability and supporting their analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of major depression.
Large-scale gene expression was monitored in postmortem tissue from the anterior cingulate cortex and amygdala in paired male subjects with familial major depression and matched control subjects without major depression (N=14-16 pairs). Area dissections and analytical approaches were optimized. Results from the major depression group were compared with those from the UCMS study and confirmed by quantitative polymerase chain reaction and Western blot. Gene coexpression network analysis was performed on transcripts with conserved major depression-UCMS effects.
Significant and bidirectional predictions of altered gene expression were identified in amygdala between major depression and the UCMS model of depression. These effects were detected at the group level and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology. This phylogenetically conserved "molecular signature" of major depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks.
These studies demonstrate that the biological liability to major depression is reflected in a persistent molecular pathology that affects the amygdala, and support the hypothesis of maladaptive changes in this brain region as a putative primary pathology in major depression.
The limbic localization of the arginine vasopressin V(1b) receptor has prompted speculation as to a potential role of this receptor in the control of emotional processes. To investigate this possibility, we have studied the behavioral effects of SSR149415, the first selective and orally active non-peptide antagonist of vasopressin V(1b) receptors, in a variety of classical (punished drinking, elevated plus-maze, and light/dark tests) and atypical (fear/anxiety defense test battery and social defeat-induced anxiety) rodent models of anxiety, and in two models of depression [forced swimming and chronic mild stress (CMS)]. When tested in classical tests of anxiety, SSR149415 produced anxiolytic-like activity at doses that ranged from 1 to 30 mg/kg (i.p. or p.o.), but the magnitude of these effects was overall less than that of the benzodiazepine anxiolytic diazepam, which was used as a positive control. In contrast, SSR149415 produced clear-cut anxiolytic-like activity in models involving traumatic stress exposure, such as the social defeat paradigm and the defense test battery (1-30 mg/kg, p.o.). In the forced swimming test, SSR149415 (10-30 mg/kg, p.o.) produced antidepressant-like effects in both normal and hypophysectomized rats. Moreover, in the CMS model in mice, repeated administration of SSR149415 (10 and 30 mg/kg, i.p.) for 39 days improved the degradation of the physical state, anxiety, despair, and the loss of coping behavior produced by stress. These findings point to a role for vasopressin in the modulation of emotional processes via the V(1b) receptor, and suggest that its blockade may represent a novel avenue for the treatment of affective disorders.
In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression
in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene
was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short
allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in
relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides
evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by
his or her genetic makeup.
The endocannabinoid system has been implicated in the modulation of emotional processes.
These experiments aimed to investigate the effects of the cannabinoid CB1 receptor antagonist rimonabant (SR141716) in animal models measuring aspects of emotional reactivity and depression.
Rimonabant had weak anxiolytic-like activity in the elevated plus-maze and failed to affect flight and risk assessment activities in the mouse defense test battery (MDTB). It produced clear anxiolytic-like effects in the Vogel conflict test (.3-3 mg/kg intraperitoneal [i.p.]) and on defensive aggression in the MDTB (1 and 10 mg/kg, i.p.). The effects of rimonabant in the MDTB paralleled those observed with CB1 receptor knockout mice in this procedure. In the forced-swimming test in rats and the tonic immobility paradigm in gerbils, rimonabant (3 and 10 mg/kg per os [p.o.]) produced antidepressant-like effects that were comparable to those observed with the reference antidepressant, fluoxetine. In the chronic mild stress model in mice, repeated administration of rimonabant (10 mg/kg, p.o.) for 5 weeks improved the deleterious effects produced by stress.
These findings point further to a role for the endocannabinoid system in the modulation of emotional processes and suggest that it may be primarily involved in the adaptive responses to unavoidable stressful stimuli.
The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.
Gene microarrays may enable the elucidation of neurobiological changes underlying the pathophysiology and treatment of major depression. However, previous studies of antidepressant treatments were performed in healthy normal rather than 'depressed' animals. Since antidepressants are devoid of mood-changing effects in normal individuals, the clinically relevant rodent transcriptional changes could remain undetected. We investigated antidepressant-related transcriptome changes in a corticolimbic network of mood regulation in the context of the unpredictable chronic mild stress (UCMS), a naturalistic model of depression based on socio-environmental stressors. Mice subjected to a 7-week UCMS displayed a progressive coat state deterioration, reduced weight gain, and increased agonistic and emotion-related behaviors. Chronic administration of an effective (fluoxetine) or putative antidepressant (corticotropin-releasing factor-1 (CRF1) antagonist, SSR125543) reversed all physical and behavioral effects. Changes in gene expression differed among cingulate cortex (CC), amygdala (AMY) and dentate gyrus (DG) and were extensively reversed by both drugs in CC and AMY, and to a lesser extent in DG. Fluoxetine and SSR125543 also induced additional and very similar molecular profiles in UCMS-treated mice, but the effects of the same drug differed considerably between control and UCMS states. These studies established on a large-scale that the molecular impacts of antidepressants are region-specific and state-dependent, revealed common transcriptional changes downstream from different antidepressant treatments and supported CRF1 targeting as an effective therapeutic strategy. Correlations between UCMS, drug treatments, and gene expression suggest distinct AMY neuronal and oligodendrocyte molecular phenotypes as candidate systems for mood regulation and therapeutic interventions.
Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, anddl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 g/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 micrograms/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.
Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, and dl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.
Rats exposed chronically (5-9 weeks) to a variety of mild unpredictable stressors showed a reduced consumption of and preference for saccharin or sucrose solutions. Preference deficits took at least 2 weeks to develop and were maintained for more than 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 1 week of treatment with the tricyclic antidepressant DMI but returned to normal after 2-4 weeks of DMI treatment. DMI did not alter sucrose preference in unstressed animals. No significant changes were seen in saline preference either during stress or following drug treatment. DMI reduced blood corticosterone and glucose levels, but stress did not significantly alter either measure. The results are discussed in terms of an animal model of endogenous depression.
A reduction in sucrose and saccharine consumption following chronic stress is reported for the rat. This deficit may be related to consummatory deficits seen in endogenous depression. To further examine this state pharmacologically, stressed rats were treated with the antidepressant imipramine. Despite a general absence of appetitive effects (or in some cases mild anorexia) imipramine significantly restored saccharine consumption in a variety of tests. The pharmacological similarity of the deficit to the changes accompanying affective disorders further supports the potential applicability of the chronic stress model.
Public health researchers are sometimes required to make adjustments for multiple testing in reporting their results, which reduces the apparent significance of effects and thus reduces statistical power. The Bonferroni procedure is the most widely recommended way of doing this, but another procedure, that of Holm, is uniformly better. Researchers may have neglected Holm's procedure because it has been framed in terms of hypothesis test rejection rather than in terms of P values. An adjustment to P values based on Holm's method is presented in order to promote the method's use in public health research.
This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
Major depression is a multifactorial disorder with many etiologic variables that are interrelated through developmental pathways. The authors used structural equation modeling to generate a developmental model for the etiology of major depression in women.
Data from 1,942 adult female twins, interviewed up to four times over a 9-year period, were used to construct a developmental model to predict depressive episodes in the year before the most recent interview. Eighteen risk factors in five developmental tiers were considered: 1) childhood (genetic risk, disturbed family environment, childhood sexual abuse, and childhood parental loss), 2) early adolescence (neuroticism, self-esteem, and early-onset anxiety and conduct disorder), 3) late adolescence (educational attainment, lifetime traumas, social support, and substance misuse), 4) adulthood (history of divorce and past history of major depression), and 5) the last year (marital problems, difficulties, and stressful life events).
The best fitting model included six correlations and 64 paths, provided an excellent fit to the data, and explained 52% of the variance in liability to episodes of major depression. The findings suggest that the development of risk for major depression in women results from three broad pathways reflecting internalizing symptoms, externalizing symptoms, and psychosocial adversity.
Major depression is an etiologically complex disorder, the full understanding of which will require consideration of a broad array of risk factors from multiple domains. These results, while plausible, should be treated with caution because of problems with causal inference, retrospective recall bias, and the limitations of a purely additive statistical model.
Some animal models of depression, including the majority of the more recently introduced models, are better characterized as models of predisposition to depression. In the first part of this paper, we show that the basis for such a model could be either a procedure that increases the ease with which an analogue of major depression may be evoked, or a presentation analogous to dysthymia (chronic mild depression). We then consider how the concepts of predictive, face, and construct validity apply to such models. Next, we review the validity of the available models of predisposition to depression, which derive from genetics, genomics, developmental manipulations, and brain lesioning. Finally, we compare the performance of the different models, using a novel scoring system that formalizes the evaluation of animal models against each of the three sets of validation criteria.
Several recent studies on corticotropin-releasing factor (CRF) have suggested that this neuropeptide may play a role in depression. Consequently, CRF receptor antagonists have been proposed as potential new agents for the treatment of this condition. This study investigated the effects of a 4-week treatment with the well-known CRF(1) receptor antagonist, antalarmin, and the prototypical selective serotonin reuptake inhibitor (SSRI), fluoxetine, in the chronic mild stress (CMS) model in BALB/c mice. Animals were exposed to 9 weeks of CMS which rapidly (within 2 weeks) produced decrease of physical state (PS), body weight gain and blunted emotional response in the light/dark test. Chronic treatment with antalarmin (10 mg/kg ip) and fluoxetine (10 mg/kg ip) led to an improvement of CMS-induced modifications. These results suggest that CRF(1) receptor antagonists may represent potential antidepressants.
Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF(1) and V(1b) receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF(1) receptor antagonist SSR125543A, the V(1b) receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF(1) and V(1b) receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants.
Since rodent self-grooming behaviours are elicited by both comfort and stressful conditions, traditional measures such as duration, latency of onset and the number of bouts may be not suitable to dissociate between these opposite conditions. The aim of the current study was to improve and optimize ethological measurement of self-grooming in neurobehavioural stress research enabling differentiation between stress and no-stress situations. This protocol assists in the correct interpretation of animal grooming behaviours and detection of stress by measuring alterations in grooming microstructure in different test situations. While a general pattern of self-grooming uninterrupted cephalocaudal progression is normally observed in no-stress (comfort) conditions in mice and other rodents, the percentage of "incorrect" transitions between different stages and the percentage of interrupted grooming bouts may be used as behavioural marker of stress. The protocol can be a useful tool in neurobehavioural stress research including modelling stress-evoked states, pharmacological screening of potential antistress drugs or behavioural phenotyping of genetically modified animals.
Effects of unpredictable chronic mild stress (UCMS) on anhedonic-like behaviour, physical state, body weight, learning and memory were investigated in three strains of mice. These strains were chosen among 11 strains that were tested in a first experiment for their sucrose consumption and preference for sucrose solutions of different concentrations. In the second experiment, groups of mice of the CBA/H, C57BL/6 and DBA/2 strains were submitted to 7 weeks of UCMS. Measures of the sucrose consumption, the evaluation of the physical state and the measurement of body weight were weekly assessed. Following 4-week period of UCMS, sub-groups of stressed and non-stressed mice were submitted to the spontaneous alternation test in the Y-maze, and then to the water-maze test for spatial learning and memory. UCMS induced a significant decrease of the sucrose consumption in CBA/H and in C57BL/6 but not in DBA/2 mice. The UCMS effect on sucrose intake in CBA/H mice was associated with a body weight loss and a physical state degradation. Spatial learning in a water maze was not disturbed by UCMS, however, a long-term memory impairment was observed in CBA/H stressed mice during a probe test. In the Y-maze, UCMS did not modify spontaneous alternation. These results show both an anhedonic-like and an amnesic effect of UCMS in CBA/H mice. They also reveal a difference of sensitivity to UCMS according to the strain of mice.
This study aimed at investigating the relationship between anxiety-like and depressive-like behaviour in mice. Therefore, we assessed the behaviour of mice from eight different strains (FVB/NA, BALB/c, C57BL/6, DBA/2, 129/Sv, C3H/He, CBA and BA) confronted first to anxiety models (the elevated plus-maze and the free exploratory test) and then to tests of depressive-like behaviours (forced swim test and unpredictable subchronic mild stress). In the forced swim test, mice from the DBA/2, the BA and the C3H/He strains displayed higher immobility than mice from the 129/Sv, the BALB/c, the C57BL/6 and the CBA strains. In the subchronic mild stress, mice from the C57BL/6 and the CBA strains displayed low sensitivity when compared with mice from all the others strains. A stepwise multiple regression analysis suggests that behaviour in the elevated plus-maze is associated with the time of immobility in the forced swim test (20%) and with the susceptibility to the unpredictable subchronic stress procedure (31%). The behaviour in the free exploratory paradigm is slightly associated with behaviours in the two tests of depression. These results suggest that anxiety may be a factor contributing, among others, to the susceptibility to depressive-like behaviours.
Since C57 and 129 mice are the commonly used background strains, a better knowledge of all their behavioural characteristics is important in neuroscience research. Grooming is a complex and essential ritual in the rodent behavioural repertoire, normally proceeding in a cephalocaudal progression (paws-nose-face-body-legs-tail and genitals). Various stressors as well as genetic manipulations have been reported to alter mouse grooming and its patterning, underlying the importance of analysis of grooming behaviours in detail. Although strain differences between C57BL/6 and 129S1/SvImJ substrains have been assessed in many studies, no ethological analyses of their grooming have been performed. Here we show strain differences between these mice in spontaneous (novelty-induced) and artificial (water-induced) grooming. Overall, 129S1/SvImJ mice demonstrated less grooming activity, more interrupted and incomplete bouts, and more incorrect transitions (contrary to the cephalocaudal rule) between patterns, accompanied by lower vertical activity and higher defecation/urination in both tests. These results are consistent with general hypoactive anxious phenotype in 129S1/SvImJ mice and suggest that ethological analysis of mouse grooming may be used in neurobehavioural stress research, including behavioural phenotyping of both mutant and background mice.
This study investigated the antidepressant-like effects of a chronic treatment with either tramadol (20 mg/kg, i.p.) or desipramine (10 mg/kg, i.p.) in the unpredictable chronic mild stress model of depression in BALB/c mice. Mice were first submitted to a 2 week drug-free unpredictable chronic mild stress before the onset of the treatments. The unpredictable chronic mild stress regimen induced a degradation of the state of the coat and decreased the grooming behaviour in the splash test. These physical and behavioural abnormalities were counteracted by tramadol and desipramine. Furthermore, we observed neither a significant acceleration nor diminution by pindolol (5-HT1A/1B receptor antagonist, 10 mg/kg, i.p.) on the antidepressant-like actions of desipramine and tramadol whereas yohimbine (alpha2-adrenergic receptor antagonist, 2 mg/kg, i.p.) antagonized the antidepressant-like effects of both drugs during the unpredictable chronic mild stress regimen. The results of the study support the suggestion that antidepressant-like effect of tramadol and desipramine in mice in the unpredictable chronic mild stress model is mediated by the noradrenergic system rather than the serotonergic system.
The multiple risk factors for major depression are interrelated through poorly understood developmental pathways. In 2002, the authors presented a developmental model for major depression in women. Based on similar methods, they here present an analogous model for men.
Using data from 2,935 adult male twins, interviewed twice over a 2-4-year period, the authors constructed, by means of structural equation modeling, an integrated etiologic model for major depression that predicts depressive episodes over 1 year from 18 risk factors conceptualized as five developmental "tiers" reflecting childhood, early adolescence, late adolescence, adulthood, and the last year.
The best-fitting model, including six correlations and 76 paths, provided a good fit to the data, explaining 49% of the variance in the liability to depressive episodes. The overall results, similar to those seen in women, suggest that the development of major depression results from the action and interaction of three broad pathways of internalizing symptoms, externalizing symptoms, and adversity. Childhood parental loss and low self-esteem were more potent variables in the model in men than in women. Genetic risks for major depression had a broader spectrum of action in men than in women. The pathway to major depression through externalizing symptoms was not more prominent in men than in women.
Major depression in men, as in women, is an etiologically complex disorder influenced by risk factors from multiple domains that act in developmental time. The similarities in etiologic pathways to major depression for men and women outweigh the modest differences.
For small rodents, nests are important in heat conservation as well as reproduction and shelter. Nesting is easily measured in the home cages of mice, particularly with the advent of pressed cotton materials. The mice first shred the tightly packed material, then arrange it into a nest. Published studies have often used materials such as hay, twine or tissues, sometimes preshredded, and have assigned scores of the quality of the resulting nest with rather rudimentary rating scales; e.g., 0, no nest; 1, flat nest; 2, nest covering the mouse. The protocol described here uses pressed cotton squares and a definitive 5-point nest-rating scale. Any unshredded material left after a bout of nesting can also be weighed, providing a semi-independent objective assay of nesting ability. Nesting has been shown to be sensitive to brain lesions, pharmacological agents and genetic mutations. This is a simple, cheap and easily done test that, along with other tests of species-typical behavior, is a sensitive assay for identifying previously unknown behavioral phenotypes. The test needs to be done overnight, but it should take no more than 5 minutes to set up plus 1 minute to assess one nest and weigh the untorn residue.
Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.
Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.
Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists.
Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.
There have been few comparisons of strains and antidepressants in the unpredictable chronic mild stress (UCMS) paradigm in mice. This study was undertaken to determine the influence of such factors using four antidepressants drugs including the tricyclics imipramine (20 mg/(kgday)) and desipramine (10 mg/(kgday)), the tetracyclic maprotiline (20 mg/(kgday)) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10mg/(kgday)) in both Swiss and BALB/c mice. A 6-week UCMS regimen induced deterioration of the coat state and decreased grooming behaviours in the splash test in BALB/c mice but not Swiss mice. The four antidepressants reversed the UCMS-induced effects in BALB/c mice in both measures. However, imipramine and fluoxetine reached significance in the splash test while desipramine and maprotiline displayed only a trend. In conclusion, these results emphasize that BALB/c mice are more sensitive than Swiss mice for studying the effects of the UCMS model as well as for testing antidepressant-like properties.
The validity of animal models of predisposition to depression
- Willner
Willner, P., and Mitchell, P.J. 2002. The validity of
animal models of predisposition to depression.
Behav. Pharmacol. 13:169-188.
Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress
- Pothion
Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant
- Willner