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The mean (±S.E.M.) body weight of the rats in each group during the 21-day injection phase of the experiment. The repeated CORT-injection groups are shown in panel A, and the acute CORT-injection groups are shown in panel B. (a) Vehicle group differs from 40 mg/kg CORT to p ≤ .001, (b) vehicle group differs from 20 and 40 mg/kg CORT to p ≤ .001, (c) vehicle group differs from 10, 20 and 40 mg/kg CORT to p ≤ .001.
Source publication
Stress is recognized to precipitate depressive illness, yet the specific relationship between stress, glucocorticoids and depression is not well understood. We have recently shown that repeated corticosterone (CORT) injections reliably increase depression-like behavior on the forced-swim test in rats, suggesting that glucocorticoids can precipitate...
Contexts in source publication
Context 1
... effects of the CORT injections on body weight are shown in Fig. 1. The repeated CORT injections, but not the acute CORT injections, decreased body weight gain over the injection period. The statistical details of these observations are given below. Simple contrasts revealed that these effects were dependent on the dose of CORT-injected. On days 7, 14 and 21, the rats that were injected with 40 mg/kg ...
Context 2
... 14 and 21, the rats that were injected with 20 mg/kg of CORT weighed less than the rats that were injected with vehicle (p values < .0001). Additionally, on day 21, the rats that were injected with 10 mg/kg CORT weighed less than the rats that were injected with vehicle (p = .008). There were no other significant differences among the groups. Fig. 1B shows the mean body weight of the rats that received an acute CORT injection on the final day of the injection paradigm. These rats also gained weight over time, as shown by a significant effect of day [F(3,96) = 614.58, p < .0001]; however, the acute CORT injections did not affect weight gain, as there was no significant effect of ...
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Citations
... Chronic Corticosterone (CORT). Mice were exposed to CORT in the drinking water for 21 days 29,60 . CORT (Sigma-Aldrich, 27840) was dissolved in limiting amounts of 100% ethanol and mixed with animal facility-provided drinking water to a final concentration of 0.1 mg/ml CORT and 1% ethanol. ...
Nitrous oxide (N2O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a stress-associated hypoactivity state, persists following exposure, and is necessary for its antidepressant-like activity. Although NMDA-receptor antagonism is believed to be a primary mechanism of action for N2O, L5 neurons activate even when NMDA-receptor function is attenuated through both pharmacological and genetic approaches. By examining different molecular and circuit targets, we identify N2O-induced inhibition of calcium-sensitive potassium (SK2) channels as a key molecular interaction responsible for driving specific L5 activity along with ensuing antidepressant-like effects. These results suggest that N2O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions in distinct cortical cell types.
... better the pathophysiology of depression, several animal models have been established which allow for describing the behavioral changes in and molecular effects on brain structures at the same time (for a review, see [7]). One experimental model used to study the relationship between stress, depression and biochemical changes in the brain is chronic exposure of rodents to exogenous corticosterone (equivalent to cortisol in humans) [8]. It has previously been shown that chronic exposure to corticosterone not only induces changes in animal behavior but also leads to molecular and functional alterations in specific brain regions, particularly in the hippocampus [9][10][11]. ...
... Elevated cortisol levels can cause depressive symptoms, which has been demonstrated in patients with Cushing disease and in patients receiving glucocorticoid therapy (for a review, see [5,6]). To understand 3 of 21 The experimental design used in this work was adapted, with modifications, from studies by Johnson et al. [8] and Oliviera et al. [14], using chronic corticosterone injections (40 mg/kg s.c.) as a stressor, the evaluation of depression-like behavior in the forced swim test (FST), and a mass spectrometry-based lipidomic approach to determine changes in lipid metabolism. Using lipidomics, we evaluated the peripheral (plasma) and central (hippocampus) metabolic profiles of corticosterone-stressed rats co-treated with Ze 117 or escitalopram with the aim to obtaining new target and biomarker insights for clinical diagnosis and antidepressant intervention. ...
... Chronic injections of corticosterone in rodents have frequently been used to induce stress. This leads to behavioral changes reflecting symptoms of depression, such as reduced exploratory behavior, altered sleep patterns, and impaired cognition [8,28,29]. These changes mimic the aspects of depressive-like behaviors observed in humans. ...
Chronic stress is a key factor in the development of depression. It leads to hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis, which in turn increases the formation of glucocorticoids (GCs). Chronically elevated GC levels disrupt neuroplasticity and affect brain lipid metabolism, which may, ultimately, contribute to the development of depression. This study aimed to investigate the effects of the antidepressants St. John’s Wort extract and escitalopram on lipid metabolism in vivo. Therefore, repeated corticosterone injections were used to induce depression-like behavior in rats. Male Sprague–Dawley rats were stressed with corticosterone injections (40 mg/kg, s.c.) over 22 consecutive days and were concomitantly treated with varying doses of the St. John’s wort extract Ze 117 (30, 90 or 180 mg/kg, p.o.) or escitalopram (10 mg/kg, p.o.) and behavioral changes were evaluated using a modified forced swim test. The results indicate that repeated corticosterone injections significantly decreased the latency to first immobility. Furthermore, co-treatment of corticosterone with Ze 117 increased latency to first immobility significantly compared to rats treated with corticosterone alone. To further investigate the biochemical effects of corticosterone-induced stress, as well as the possible counter-regulation by antidepressants, the lipidomes of the plasma and hippocampus samples were analyzed by shotgun mass spectrometry. Corticosterone-induced stress significantly altered key lipid metabolites in the plasma but not in the hippocampal samples. In the hippocampus, however, specific glycerophospholipids such as lysophosphatidylethanolamines (LPEs) increased with escitalopram treatment and with Ze 117, both showing significant correlations with behavioral parameters. In summary, our study shows significant behavioral- and lipidome-altering processes with Ze 117 and escitalopram in rat plasma and hippocampal samples, thereby providing new targets and biomarker ideas for clinical diagnosis and antidepressant intervention.
... The reduced weight gain noted in dams treated with high levels of CORT during the post-partum phase aligns with findings from other studies involving post-partum or virgin rats (Johnson et al., 2006;Brummelte and Galea, 2010;Allen et al., 2022). In humans, weight loss is linked to depressive symptoms, and changes in weight and appetite are recognized as individual symptoms of depression (DSM-5, 2022). ...
Introduction
Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD).
Methods
This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 μg) or vehicle injection.
Results
Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally.
Discussion
This study brings new insights into the putative antidepressant-like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose–response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin.
... The prolonged activation of this axis contributes to the adverse effects following depression. These effects include pathological activity in the immune system and increased inflammatory factors, which can impact the functioning and structure of various organs, particularly the nervous system (Johnson et al. 2006;Mileva et al. 2017). Considering the significance of oxidative stress and inflammatory factors, especially TNFα and interleukin-1 in the pathogenesis of depression, using factors with antioxidant and anti-inflammatory properties can effectively reduce the damage caused by depression. ...
Depression, considered the most prevalent neuropsychiatric disorder, is multifactorial and complex. Oxidative stress and inflammation significantly contribute to its etiology. Conversely, methane, a novel therapeutic gas, has demonstrated efficacy in enhancing tissue resilience against ischemic injuries and inflammation. In this study, we investigated the effect of methane-rich saline (MRS) on depression using the chronic unpredictable mild stress (CUMS) model. Depressed rats received MRS treatment, and depression-like behaviors and cognitive function were assessed through sucrose preference, open field, forced swimming, and Morris water maze tests. Additionally, we measured serum corticosterone levels, antioxidant enzyme activity, hippocampal malondialdehyde (MDA), and TNFα levels, and investigated histological changes in the hippocampus. Our findings revealed that MRS significantly ameliorated Depressive-like behaviors and cognitive impairment. Furthermore, MRS administration regulated serum corticosterone levels and also MRS reduced hippocampal lipid peroxidation, TNFα, and hippocampus tissue damage. MRS likely exerts its effects by reducing oxidative stress and inflammatory factors and modulating the function of the hypothalamus-pituitary-adrenal (HPA) axis. These results demonstrate the protective effects of MRS on the hippocampus in CUMS animals.
... We used a continuous subcutaneous injection of CORT for 30 days to create external stress stimulation and induce depression model mice [39][40][41][42][43]. In the external stimulation process, the wallpaper adhered with the bionic plus nano-aromatic drugs was pasted on the wall of the mouse cage to relieve stress, thereby achieving the effect of preventing depression. ...
Depression is a mood disorder mainly clinically characterized by significant and persistent low spirits. Chronic stress is the leading cause of depression. However, traditional medicine has severe side effects in treating depression, ineffective treatment, and easy recurrence. Therefore, it is of great significance to prevent depression in the environment of chronic stress. In this study, aromatherapy was used for the prevention of depression. To solve the defects of intense volatility and inconvenience in using essential oils, we designed bionic nano-aromatic drugs and adhered them to the wallpaper. Inspired by the moldy wallpaper, we successively prepared the morphology-bionic nano-aromatic drugs, the function-bionic nano-aromatic drugs, and the bionic plus nano-aromatic drugs by referring to the morphology of microorganisms and substances in bacterial biofilms. Bionic nano-aromatic drugs remarkably promoted their adhesion on wallpaper. Molecular dynamics simulation explored its molecular mechanism. The essential oils, which were slowly released from the bionic nano-aromatic drugs, showed excellent biosecurity and depression prevention. These sustainedly released essential oils could significantly increase monoamine neurotransmitters in the brain under a chronic stress environment and had excellent neuroprotection. Besides, the bionic nano-aromatic drugs with simple preparation process and low cost had excellent application potential.
... In human patients suffering from depression and grief symptoms, dysregulations of the HPA axis, in particular increased basal cortisol concentrations, have been described (Mason and Duffy 2019;Roy et al., 1988). Similarly, repeated CORT injections in animal models are related to depressive-like behaviors (Johnson et al., 2006). Thus, we analyzed basal and post-stressor (FST) plasma CORT to understand if offspring loss could alter the mother's stress response. ...
... It is mainly characterized by the activation of hypothalamic-pituitary-adre nal (HPA) axis and the excessive release of blood adrenocorticotropic hormone (ACTH) and glucocorticoids (GCs), resulting in numerous adverse effects (2)(3)(4)(5)(6)(7)(8). So at present, a growing number of evidence have shown that repeated injection of corticosterone (CORT) is an ideal method to establish chronic stress model (9). In animals, chronic stress is one of the most dangerous risk factors that seriously harm health, growth performance, and economic benefits (10)(11)(12)(13)(14)(15). ...
This study aimed to explore alterations in growth performance, glycolipid metabolism disorders, intestinal mucosal barrier, cecal microbiota community, and metabolites in a chronic corticosterone (CORT)-induced stress (CCIS) broiler model. Results showed that compared with control (CON) broilers, in CCIS broilers: (i) the final body weight (BW), BW gain, and average daily gain were significantly reduced. (ii) The glycolipid metabolism disorder and impairement of intestinal immune barrier and physical barrier function were observed. (iii) Diversity and richness of cecal microbiota were obviously increased. From phylum to genus level, the abundances of Firmicutes and Faecalibacterium were significantly decreased, while the abundances of Proteobacteria, RuminococcaceaeUCG-005, and Escherichia coli (Shigella) were significantly increased. Microbial network analysis and function pathways prediction showed that cecal microbiota was mainly concentrated in translation, metabolism, nucleotide metabolism, and endocrine system. (iv) The main differential metabolites identified include steroids and their derivatives, amino acids, fatty acids, and carbohydrates; among which 37 metabolites were significantly upregulated, while 27 metabolites were significantly downregulated. These differential metabolites were mainly enriched in pathways related to steroid hormone biosynthesis and tyrosine metabolism. (v) Correlation between cecal microbiota and glycolipid metabolism indexes showed that BW and total cholesterol (TC) were positively correlated with Christensenellaceae_R.7_group and Escherichia_Shigella, respectively. Furthermore, the downregulated Faecalibacterium and Christensenellaceae were negatively correlated with the upregulated differentially expressed metabolites. These findings suggested that CCIS altered cecal microbiota composition and metabolites, which led to glycolipid metabolism disorder and impaired the nutritional metabolism and immune homeostasis, providing a theoretical basis for efforts to eliminate the harm of chronic stress to human health and animal production.
IMPORTANCE
The study aimed to determine the influence of altered intestinal mucosal barrier, cecum flora community, and metabolites on anti-growth performance, glycolipid metabolism disorders of chronic corticosterone (CORT)-induced stress (CCIS) broilers. Compared with control (CON) broilers, in CCIS broilers: (i) anti-growth performance, glycolipid metabolism disorder, and impaired intestinal immune barrier and physical barrier function were observed. (ii) From phylum to genus level, the abundances of Firmicutes and Faecalibacterium were decreased; whereas, the abundances of Proteobacteria, RuminococcaceaeUCG-005, and Escherichia coli (Shigella) were increased. (iii) Differential metabolites in cecum were mainly enriched in steroid hormone biosynthesis and tyrosine metabolism. (iv) Body weight (BW) and total cholesterol (TC) were positively correlated with Christensenellaceae_R.7_group and Escherichia_Shigella, respectively, while downregulated Faecalibacterium and Christensenellaceae were negatively correlated with upregulated metabolites. Our findings suggest that CCIS induces anti-growth performance and glycolipid metabolism disorder by altering cecum flora and metabolites, providing a theoretical basis for efforts to eliminate the effect of chronic stress on human health and animal production.
... Considering OFT mobility in the interpretation of mobility differences during the FST, the mean distance traveled in the OFT is not significantly different between males and females after CORT treatment (Figures 4A&D). Multiple observations of CORT increasing FST immobility, here and in previous studies, in conjunction with normal levels of mobility during the OFT, lead us to conclude that reduced mobility in the FST is not related to general mobility reduction and, instead, is related to despair-like behavior evoked by chronic stress (Johnson et al., 2006;Brymer et al., 2020;Allen et al., 2022;Johnston et al., 2023). ...
... Although the restraint was intentionally limited during CORT injections, a restraint was required for the tail vein injections, representing an additional stressor. However, past studies from our laboratory have shown that restraint stress does not cause significant changes in immobility in the FST compared to CORT (Gregus et al., 2005;Johnson et al., 2006), and the restraint does not alter Reelin expression in the DG SGZ in contrast to repeated CORT injections (Lussier et al., 2009). Profile counts are another limitation, and Reelin counts may be underestimated as slide scans were obtained at a single Z-axis (Mura et al., 2004). ...
Novel antidepressants are predominantly evaluated preclinically in rodent models of chronic stress in which animals experience a single prolonged exposure to chronic stress prior to treatment. Rodent models of a single episode of chronic stress translate poorly to human depressive disorders, which are commonly marked by recurring depressive episodes. Intravenous administration of Reelin has previously been shown to resolve immobility in the forced swim test of rats exposed to a single prolonged exposure to chronic stress. To determine whether Reelin has antidepressant-like properties in a model of recurring depressive episodes, Long–Evans rats (N = 57) were exposed to multiple cycles of chronic stress and stress-free periods before the administration of a single injection of Reelin during the final cycle of chronic stress. The animals then performed in the forced swim test and open field test before the post-mortem evaluation of Reelin cell counts in the sub-granular zone of the dentate gyrus to determine the impact of treatment on hippocampal Reelin levels and spleen white pulp to evaluate the role of Reelin treatment in peripheral inflammation. The results show a single Reelin injection reversed elevated levels of immobility in the forced swim test in both male and female subjects exposed to the cyclic chronic stress model of recurring depressive episodes. Treatment with Reelin also restored Reelin-positive cell counts in the dentate gyrus sub-granular zone and reversed atrophy of spleen white pulp. The results shown here indicate that treatment with Reelin could effectively resolve alterations in forced swim test behavior caused by the cyclic corticosterone model of recurring depressive episodes and that Reelin homeostasis is important for regulating stress-related inflammation. Future preclinical antidepressant research should incorporate models of multiple depressive episodes to improve the translation of preclinical rodent research to human depressive disorders.
... Drug and vehicle injection volumes were 2 mL/kg (i.p.), respectively. Doses of yohimbine (3 mg/kg) and corticosterone (1, 3 mg/kg) selected have been shown in earlier studies to be behaviorally active (Johnson et al., 2006;Koot et al., 2013). Post-administration, rats were returned to their home cages for 30 minutes until behavioral testing because approximately 30 minutes is required for yohimbine (Shepard et al., 2004) and corticosterone (Koot et al., 2013) to become behaviorally active after i.p. injection. ...
Background
Acute stress alters risk-based decision-making; however, the underlying neural and neurochemical substrates are underexplored. Given their well-documented stress-inducing effects in humans and laboratory animals, glucocorticoids such as cortisol and corticosterone and the α2-adrenoceptor antagonist yohimbine represent potent pharmacological tools to mimic some characteristics of acute stress.
Methods
Here, we analyzed the effects of the pharmacological stressors corticosterone and yohimbine given systemically on risk-based decision-making in male rats. Moreover, we investigated whether pharmacological stressor effects on risk-based decision-making involve dopamine D1 receptor stimulation in the dorsal prelimbic cortex (PL). We used a risk discounting task that requires choosing between a certain/small reward lever that always delivered 1 pellet and a risky/large reward lever that delivered 4 pellets with a decreasing probability across subsequent trials.
Results
Systemic administration of yohimbine increased the preference for the risky/large reward lever. By contrast, systemic single administration of corticosterone did not significantly promote risky choice. Moreover, co-administration of corticosterone did not enhance the effects of yohimbine on risky choice. The data further show that the increased preference for the risky/large reward lever under systemic yohimbine was lowered by a concurrent pharmacological blockade of dopamine D1 receptors in the PL.
Conclusions
Our rodent data provide causal evidence that stimulation of PL D1 receptors may represent a neurochemical mechanism by which the acute pharmacological stressor yohimbine, and possibly nonpharmacological stressors as well, promote risky choice.
... Novel object recognition test. This test assays recognition memory while leaving the spatial location of the objects intact and is believed to involve the hippocampus, perirhinal cortex, and raphe nuclei [149][150][151] . The basic principal is that animals explore novel environments and that with repeated exposure decreased exploration ensues (i.e., habituation; 152 ). ...
Biomarkers of biological age that predict the risk of disease and expected lifespan better than chronologi-cal age are key to efficient and cost-effective healthcare1–3. To advance a personalized approach to healthcare, such biomarkers must reliably and accurately capture individual biology, predict biological age, and provide scalable and cost-effective measurements. We developed a novel approach – image-based chromatin and epigenetic age (ImAge) that captures intrinsic progressions of biological age, which readily emerge as principal changes in the spatial organization of chromatin and epigenetic marks in single nuclei without regression on chronological age. ImAge captured the expected acceleration or deceleration of bio-logical age in mice treated with chemotherapy or following a caloric restriction regimen, respectively. Im-Age from chronologically identical mice inversely correlated with their locomotor activity (greater activity for younger ImAge), consistent with the widely accepted role of locomotion as an aging biomarker across species. Finally, we demonstrated that ImAge is reduced following transient expression of OSKM cassette in the liver and skeletal muscles and reveals heterogeneity of in vivo reprogramming. We propose that Im-Age represents the first-in-class imaging-based biomarker of aging with single-cell resolution.
