Corticosterone Levels Research Articles

Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure.

Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive, dendrite-targeting GABAergic interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons (induced by Cre-mediated deletion of the γ2 GABAA receptor subunit gene selectively from SST neurons, SSTCre:γ2f/f mice) results in stress resilience. Similarly, chronic chemogenetic activation of SST neurons in the medial prefrontal cortex (mPFC) results in stress resilience but only in male and not in female mice. Here, we used RNA sequencing of the mPFC of SSTCre:γ2f/f mice to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female SSTCre:γ2f/f mice is characterized by resilience to chronic stress-induced transcriptome changes in the mPFC. Interestingly, the transcriptome of non-stressed SSTCre:γ2f/f (stress-resilient) male mice resembled that of chronic stress-exposed SSTCre (stress-vulnerable) mice. However, the behavior and the serum corticosterone levels of non-stressed SSTCre:γ2f/f mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of SSTCre:γ2f/f mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes suggesting stress-induced enhancement of mRNA translation. Behaviorally, the SSTCre:γ2f/f mice were not only resilient to chronic stress-induced anhedonia - they also showed an inversed, anxiolytic-like behavioral response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in the expression of putative stress resilience genes, through a sex-specific brain substrate.

Evaluation of ethanolic extract of Piper methysticum leaves on anxiolytic activity of mice

The ethanol extract of Piper methysticum, commonly known as kava, has shown promising results in reducing anxiety. Studies suggest it may have anxiolytic effects, potentially offering a natural alternative to conventional anxiety treatments. The ethanolic extract of Piper methysticum can increase the duration of action. It can also increase the time spent in open arm, entry in open arm (in elevated plus model) as well as increase the time spent in light field (in Light Dark field) thus we can conclude that it can also possesses Anxiolytic action. The ethanolic extract of Piper methysticum possesses an anxiolytic like activity without sedative side effect. The corticosterone level in mice is increased when they got anxiety. So when the plasma corticosterone level of mice is checked in control group its turn out to be 10.28±0.52. It gets decreased with increase in doses. When treated with low dose of Aqueous extract is 7.28±1.44 is less effective than low dose of Ethanolic extract that is 6.22±1.28. Same as that high dose of extract shows the corticosterone level was 6.24±2.28 which was also less effective than high dose of ethanolic extract which was 5.52±0.32. Most effectively stress was decreased when treated with the Standard drug (Alprazolam) which shows plasma corticosterone level was 1.24±0.36. The mice of Piper methysticum extract (300 &600 mg/kg/ p.o.) treated group showed significantly (p<0.05) increased in body water intake as compared to the control group. Results showed that synthesized extract is very effective for the treatment of anxiety. Keywords: Piper methysticum; anxiolytic activity; Anthraquinones; Light Dark model

The impact of long-term isolation on anxiety, depressive-like and social behavior in aging Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) male rats.

Aging is a complex process associated with multimorbidity. Hypertension, one of widespread states, is among main causes of age-related alterations in behavior, emotionality and sociability. We studied the effects of long-term isolated housing on anxiety, depressive-like and social behavior as well as changes in the adrenocortical and sympathetic systems in the aging normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Ten-month-old male rats of both strains were subjected to 90-day isolated or group housing. Surprisingly, social isolation induced only mild effect on anxiety without influencing other affective-related behaviors. No effects of isolated housing on sociability or social novelty preferences were revealed. Despite the adrenal gland hypertrophy in the SHRs, corticosterone levels remained stable within the period of isolation but the expression of nuclear glucocorticoid receptor (Nr3c1) mRNA in the adrenals was lower in the SHR as compared to WKY rats. Pre-existing hypertension, associated with SHR genotype, did not significantly contribute to the effects of social isolation. The data suggest that the aged WKY and SHR rats are relatively resilient to chronic social stress associated with isolated housing.

Validation of two enzyme immunoassays for non-invasive glucocorticoid measurement in a lacertid lizard (Podarcis muralis): effects of pharmacological and biological stimuli on faecal corticosterone metabolites and behaviour.

The assessment of stress-related hormone levels using non-invasive methods has gained popularity in mammal and bird welfare, yet its application in reptiles remains limited. Particularly, the exploration of physiological measures such as faecal corticosterone metabolites (FCMs) for reptilian welfare has scarcely been explored. This study aims to validate two enzyme immunoassays (5α-pregnane-3ß,11ß,21-triol-20-one and 11-oxoaetiocholanolone EIA) for monitoring FCM levels in the European common wall lizard (Podarcis muralis). We collected daily faecal samples before (baseline) and after (post-treatment phase) inducing elevated corticosterone levels using transdermal administration of corticosterone (pharmacological treatment) and handling/confinement (biological treatment). We also conducted daily behavioural observations to explore the relationship between stress-related corticosterone changes and behaviour. Although treatments induced significant increases in FCM levels, the effect was much larger in the pharmacological one. Transdermal corticosterone induced a cumulative increase in FCMs over the treatment period, with a higher response observed in females. In contrast, the biological treatment yielded smaller FCM peaks, with no significant sex differences. Overall, 5α-pregnane-3ß,11ß,21-triol-20-one EIA appeared to be more sensitive in detecting these effects. Regarding lizard behaviour, both treatments led to increased hiding and decreased basking compared to baseline. The effects were more pronounced in animals subjected to handling/confinement, despite smaller FCM increases. Our results confirm the suitability of an EIA for monitoring FCMs in both male and female common wall lizards and provide insights into the complexities of using integrated approaches to assess stress, highlighting the need for further research on direct measures to evaluate reptile welfare.

Mechanisms of Heat Stress on Neuroendocrine and Organ Damage and Nutritional Measures of Prevention and Treatment in Poultry

Heat stress (HS) due to high temperatures has adverse effects on poultry, including decreased feed intake, lower feed efficiency, decreased body weight, and higher mortality. There are complex mechanisms behind heat stress in poultry involving the neuroendocrine system, organ damage, and other physiological systems. HS activates endocrine glands, such as the pituitary, adrenal, thyroid, and gonadal, by the action of the hypothalamus and sympathetic nerves, ultimately causing changes in hormone levels: HS leads to increased corticosterone levels, changes in triiodothyronine and thyroxine levels, decreased gonadotropin levels, reduced ovarian function, and the promotion of catecholamine release, which ultimately affects the normal productive performance of poultry. Meanwhile, heat stress also causes damage to the liver, lungs, intestines, and various immune organs, severely impairing organ function in poultry. Nutrient additives to feed are important measures of prevention and treatment, including natural plants and extracts, probiotics, amino acids, and other nutrients, which are effective in alleviating heat stress in poultry. Future studies need to explore the specific mechanisms through which heat stress impacts the neuroendocrine system in poultry and the interrelationships between the axes and organ damage so as to provide an effective theoretical basis for the development of preventive and treatment measures.

Sex-dependent effects of early life sensory overstimulation on later life behavioral function in rats.

Children today are immersed in electronic technology shortly after birth as they now begin regularly watching television earlier than they did in the past. Many new programs geared towards infants contain lots of lights, color, and sounds, which may constitute a form of sensory overstimulation (SOS) that leads to cognitive and behavioral changes in children and adolescents. Here, we examined the impact of early life SOS exposure on later life behavioral and cognitive function in rodents by exposing developing male and female rats to excessive audiovisual stimulation from postnatal days (PND) 10-40 and assessing anxiety-like behavior, social motivation, compulsive behavior, and spatial learning/cognition from PND 50-60. To evaluate potential SOS effects on hypothalamic-pituitary-adrenal (HPA)-axis function, levels of the stress hormone corticosterone (CORT) were measured at 3 timepoints (e.g., PND 23, 41, 61) post-SOS exposure. Sensory overstimulated males exhibited reduced anxiety-like and compulsive behavior compared to controls, whereas females exhibited reduced social motivation but enhanced spatial learning/cognition compared to controls. No differences in baseline CORT levels were found at any age tested, suggesting no impact of early life SOS on later life basal HPA-axis function. Our results demonstrate sex-specific effects of early life SOS on distinct behavioral domains in early adult rats.

Hypothalamic corticotropin-releasing hormone neurons modulate sevoflurane anesthesia and the post-anesthesia stress responses

General anesthesia (GA) is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with GA causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRH neurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRH neurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRH neurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRH neurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signalling.

Our brain adapts to seasonal changes. Mis-adaptations may lead to seasonal patterns in several psychiatric disorders, but we know little regarding the underlying mechanisms. Our previous work identified two variants in the human circadian clock gene PERIOD3 (PER3), that is, P415A and H417R, which are associated with winter depression, but whether and how these variants lead to the disorder remain to be characterized. Here we find that male mice carrying human P415A and H417R display winter depression-like behaviours that are caused by the actions of P415A and H417R in the adrenal gland. Systemic corticosterone level is downregulated in adaptation to shortening of day length, while P415A and H417R eliminate this downregulation by increasing corticosterone synthesis. Enhanced glucocorticoid signalling represses the transcription of Tph2, which encodes the rate-limiting enzyme of serotonin synthesis, leading to increased depression-like behaviours. Taken together, our findings unveil a mechanism according to which human variants contribute to seasonal mood traits.

Hypothalamic corticotropin-releasing hormone neurons modulate sevoflurane anesthesia and the post-anesthesia stress responses.

General anesthesia (GA) is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with GA causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRH neurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRH neurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRH neurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRH neurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

The effect of methylphenidate on the reproductive function of female rats.

Research on the effects of methylphenidate on female fertility is limited. This study evaluated the effects of methylphenidate on reproductive function, oxidants, antioxidants, proinflammatory cytokines, prolactin, and cortisol in female rats. Forty-eight albino Wistar female rats were divided into four groups consisting of 12 rats, which were given pure water orally once daily for 7 days (HG-1), 10 mg/kg methylphenidate orally once daily for 7 days (MP-1), pure water orally once daily for 30 days (HG-2), and 10 mg/kg methylphenidate orally once daily for 30 days (MP-2). At the end of the treatment periods, tail vein blood was collected from six rats per group for prolactin and cortisol determination. Subsequently, euthanasia was performed and the ovaries were removed. Ovaries were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), and immunohistochemically. For breeding, the remaining six rats were mated with male rats for 1 month. Rats that failed to give birth were classed as infertile. A comparison of MP-1 and MP-2 groups to healthy controls revealed an elevation in MDA and corticosterone levels, and a decline in tGSH, SOD, and CAT levels (p < 0.001). Methylphenidate did not affect prolactin, IL-1β, and TNF-α levels (p > 0.05). MP-1 and MP-2 exhibited immunopositivity for 8-hydroxy-2'-deoxyguanosine (8-OHDG). MP-2 rats developed 66.7% infertility while MP-1, HG-1, and HG-2 rats did not. In ovaries, methylphenidate caused oxidative stress, but did not induce inflammation. Long-term use of methylphenidate caused increased cortisol levels and infertility.

Female Wistar Kyoto More Immobile rats with genetic stress hyper-reactivity show enhanced contextual fear memory without deficit in extinction of fear.

The prevalence of post-traumatic stress disorder (PTSD) is higher in females than males, but pre-clinical models are established almost exclusively in males. This study is aimed to investigate the stress-enhanced fear learning model of PTSD in females. The model mirrors PTSD symptomology in males, whereby prior stress leads to extinction resistant exaggerated contextual fear memory. As stress reactivity is highly relevant to the study and risk for PTSD, females of the stress hyper-reactive Wistar Kyoto More Immobile (WMI) and its nearly isogenic control the Wistar Kyoto Less Immobile (WLI) strains were employed. Prior studies have shown WMI females presenting unchanged or enhanced fear memory in the stress-enhanced fear learning paradigm compared WLIs. The present study confirmed the enhanced fear memory following contextual fear conditioning in WMIs compared to WLI females, but this increased fear memory was neither exaggerated by prior stress nor showed extinction deficit. The novel stressor of a glucose challenge test resulted in subtle strain- and prior stress-induced differences in plasma glucose responses. However, fasting plasma corticosterone levels were lower, and rose slower in response to glucose challenge in WMI females, suggesting a PTSD-like dysfunctional stress response. Hippocampal expressions of genes relevant to both learning and memory and the stress response were decreased in stressed WMIs compared to WLI females, further suggesting a marked dysregulation in stress-related functions like in PTSD. Thus, although WMI females do not show extinction-resistant enhanced fear memory, they do present other characteristics that are relevant to PTSD in women.

Meta-analysis of experimental studies of the effect of melatonin monotherapy on the levels of thyroid hormones and glucocorticoids in rats kept under standard condition

Melatonin is known to modulate circadian and seasonal rhythms in metabolism, reproduction, and behavior. However, the effect of exogenous melatonin supplementation on the functioning of the thyroid and adrenal glands in species without a clear seasonality in reproduction is still unclear. Using a meta-analysis of publications, to investigate the effect of melatonin monotherapy on the concentrations of pituitary thyroid-stimulating hormone, thyroid hormones (TG), pituitary adrenocorticotropic hormone and corticosterone (CS) in rats kept under standard laboratory conditions. In our work, using the Review Manager 5.3 program, we conducted a meta-analysis of publications examining the effect of melatonin monotherapy on the functioning of the thyroid gland (22 papers) and adrenal glands (20 papers) in rats kept under standard conditions. According to the results of our meta-analysis, the effects of melatonin on the levels of TG and CS depend on the dose and duration of therapy. A decrease in TG and CS was associated with therapy lasting no more than 4-5 weeks and with high doses of melatonin. An increase in CS and a trend toward increased TG levels were observed with longer therapy. However, a few studies have observed a decrease in TG with very long-term melatonin therapy (≥32 weeks). Among all TGs, total thyroxine (T4) showed maximum sensitivity to exogenous melatonin, which indicates the influence of melatonin on the secretory function of the thyroid gland. In addition, melatonin increased the relative weight of the adrenal glands. There was no convincing evidence that the effects of melatonin were influenced by the route and timing of administration, or the timing of blood sampling. As a result, exogenous melatonin can modulate TG and CS levels, even in species without a clear seasonality in reproductive function.

Ionizing radiation has negligible effects on the age, telomere length and corticosterone levels of Chornobyl tree frogs.

The accident that occurred at the Chornobyl nuclear power plant (Ukraine, 1986) contaminated a large extension of territory after the deposition of radioactive material. It is still under debate whether the chronic exposure to the radiation levels currently present in the area has long-term effects on organisms, such as decreases in longevity. Here, we investigate whether current levels of radiation in Chornobyl negatively impact the age of the Eastern tree frog Hyla orientalis. We also explore whether radiation induces changes in an ageing marker, telomere length or the stress hormone corticosterone. We found no effect of total individual absorbed radiation (including both external and internal exposure) on frog age (n = 197 individuals sampled in 3 consecutive years). We also did not find any relationship between individual absorbed radiation and telomere length, nor between individual absorbed radiation and corticosterone levels. Our results suggest that radiation levels currently experienced by Chornobyl tree frogs may not be high enough to cause severe chronic damage to semi-aquatic vertebrates such as this species. This is the first study addressing age and stress hormones in Chornobyl wildlife, and thus future research will confirm if these results can be extended to other taxa.

A new pharmacological strategy against treatment-resistant depression

Major depressive disorder affects more than 50 million people in the world. However, 50% of patients don't respond to two or more drugs or psychotherapeutic treatments, named treatment-resistant depression (TRD). In this work, we propose a new augmentation treatment against TRD based on combining Fluoxetine (FLX) and the N-terminal fragment Galanin, GAL(1–15). In Wistar Kyoto (WKY) rats, akin to endogenous depression genetically, we evaluate GAL(1–15)’s impact on FLX-induced behaviours on tests measuring despair and anhedonia. We explored GALR2 involvement using the antagonist M871 and an in vivo model with siRNA 5-HT1A knockdown. Also, the 5-HT1AR was analyzed by autoradiography binding in several brain regions. We analyze the corticosterone levels and a dexamethasone-suppressed corticotropin-releasing hormone stimulation to study the HPA axis regulation. Our results shows that only the combination of FLX + GAL(1–15) induced antidepressant effects in the WKY animals in Behavioural tests related to despair. This combination also reduced corticosterone levels in the WKY animals and modulated the functional characteristics of the serotoninergic receptor 5-HT1A in the prefrontal cortex. These novel results suggest combining GAL(1–15) with FLX is a new potentiation strategy in TRD cases. It shows the innovative potential of the interactions between the galaninergic and serotonergic systems to find new strategies and drugs against resistant depression.

Transient impact of chronic social stress on effort-based reward motivation in non-food restricted mice: involvement of corticosterone.

Chronic stress has been connected to a reduced effort and motivational deficits. To study effort-based motivation in rodents, operant conditioning is often employed. However, caloric restriction is typically imposed simultaneously. Since caloric restriction is a stressor in its own right, this procedure interferes with data interpretation. Here, we investigate whether chronic social defeat stress (CSD), lasting 10 consecutive days, would alter effort-based reward motivation in mice trained under ad libitum food conditions. Utilizing operant FED3 boxes in home cages, mice were trained within eight days to nose poke for palatable food. After training completion, operant memory was retained for at least 16 days, and mice demonstrated sustained effort, as assessed with a progressive ratio schedule, to obtain reward pellets. Directly after CSD exposure (10th day), mice exhibited reduced effort for palatable food rewards, but also displayed reduced nose poking in general. The effects of CSD on effort were short-lived, with no lasting impact on effort-based reward motivation one week post-stress. As corticosterone (CORT) levels were increased at day 10 of CSD, but not at day 17, we hypothesized that CORT might mediate the acute effects of CSD on effort-based reward motivation. Indeed, CORT administration [100 μg/ml], supplied via the drinking water, mirrored the CSD-induced CORT spike and temporarily reduced reward motivation. Our findings emphasize that CSD does not result in long-term deficits in reward motivation, suggesting a resilient adaptive response in mice under unrestricted feeding conditions. This study underscores the necessity of considering temporal dynamics of stress impacts and highlights the modulating effects of CORT. These insights contribute to a deeper understanding of the resilience mechanisms in motivational impairments and pave the way for further research into factors facilitating this resilience.

Non-coding RNA alterations in occlusal disharmony-induced anxiety-like behaviour.

Occlusal disharmony (OD) may induce anxiety-like behaviours; however, the underlying mechanism remains unclear. Herein, we explored the expression profiles of non-coding RNAs (ncRNAs), along with their biological function and regulatory network, in anxiety-like behaviour induced by OD. Occlusal disharmony was produced by anterior crossbite of C57BL/6 mice. Behavioural tests, corticosterone (CORT) and serotonin (5-HT) levels were used to measure anxiety. In addition, RNA sequencing was used to screen all differentially expressed (DE) ncRNAs. Moreover, the RNA-binding proteins interacting with ncRNAs were predicted by the ENCORI database and confirmed using western blots. The significant differences in behavioural tests and CORT suggested the successful induction of anxiety-like behaviour by OD. In OD mice, ncRNAs were significantly dysregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the DE ncRNAs were enriched in anxiety-related pathways. CircRNA10039 was upregulated, and PTBP1 was predicted to interact with circRNA10039. In addition, KEGG pathway analysis showed that PTBP1 may be associated with messenger RNA biogenesis and spliceosomes. OD induced by anterior crossbite can lead to the anxiety-like behaviours. During this process, ncRNA also changes. CircRNA10039 and PTBP1 may play a role in OD-induced anxiety-like behaviours.

Intranasal AdipoRon Mitigated Anxiety and Depression-Like Behaviors in 6-OHDA-Induced Parkinson 's Disease Rat Model: Going Beyond Motor Symptoms.

Depression and anxiety are prevalent neuropsychiatric conditions among patients with Parkinson's disease (PD), which may manifest prior to motor symptoms. As levodopa, a prominent treatment for PD motor symptoms, provides few benefits for mood-related abnormalities, tackling non-motor symptoms is particularly important. AdipoRon (Ad), an adiponectin agonist, has demonstrated neuroprotective effects by suppressing neuroinflammatory responses and activating the AMPK/Sirt-1 signaling pathway. This study looked at the potential advantages and underlying mechanisms of intranasal Ad in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). We found that Ad at doses of 1 and 10µg for 21 days exhibited anxiolytic- and antidepressant effects in the open field (OF) test, elevated plus maze (EPM), sucrose splash test, and forced swimming test in a PD model caused by a unilateral 6-OHDA injection into the medial forebrain bundle (MFB). The Ad also lowered the levels of corticosterone in the blood, decreased inflammasome components (NLRP3, caspase 1, and IL-1β), and increased Sirt-1 protein levels in the prefrontal cortex (PFC) of PD rats. We conclude that Ad ameliorates anxious and depressive-like behaviors in the PD rat model through stimulating the AMPK/Sirt-1 signaling and blocking the NLRP3 inflammasome pathways in the PFC.

Increased dopamine D2/D3 receptor and serotonin transporter availability in male rats after spontaneous remission from repeated social defeat-induced depression; a PET study in rats

Most pharmacological treatments for depression target monoamine transporters and about 50 % of treated patients attain symptomatic remission. Once remission is attained, it is hard to distinguish the changes on brain monoaminergic transmission induced by the antidepressants, from those associated to remission per se. In this study, we aimed at studying the brain of spontaneously remitted rats from repeated social defeat (RSD)-induced depression in terms of dopamine D2/D3 receptor and serotonin transporter (SERT) availability, showing absence of depressive symptoms 2 weeks after RSD. We combined behavioral tests and positron emission tomography (PET) with [11C]raclopride and [11C]DASB to explore the changes in dopamine D2/D3 receptor and serotonin transporter (SERT) availability, respectively. Male rats submitted to RSD showed increased peripheral corticosterone levels, decreased body weight and anhedonia, as measured with the sucrose preference test, 1 day after RSD, confirming depressive-like symptoms. These depressive-like symptoms were no longer present 2 weeks after RSD. Rats that recovered from depressive-like symptoms showed decreased D2/D3 receptor binding in the caudate putamen and increased SERT availability in the brainstem, insular cortex, midbrain and thalamus, compared to control non-stressed animals. Our study shows that remission of depressive-like symptoms does not just “normalize” monoaminergic transmission, as changes in dopaminergic and serotonergic neurotransmission linger in several brain regions even after depressive-like symptoms have already resolved. These results provide new insights into the brain changes associated to remission in the RSD-induced depression model in rats.

Glycyrrhizic acid and patchouli alcohol in Huoxiang Zhengqi attenuate intestinal inflammation and barrier injury via regulating endogenous corticosterone metabolism mediated by 11β-HSD1

Ethnopharmacological relevanceUlcerative colitis (UC), a chronic inflammatory bowel disease, has become a significant public health challenge due to the limited effectiveness of available therapies. Huoxiang Zhengqi (HXZQ), a well-established traditional Chinese formula, shows potential in managing UC, as suggested by clinical and pharmacological studies. However, the active components and mechanisms responsible for its effects remain unclear. Aim of studyThis study aimed to identify the bioactive components of HXZQ responsible for its therapeutic effects on UC and to elucidate their underlying mechanisms. Materials and methodsThe effect of HXZQ against dextran sodium sulfate (DSS) -induced colitis was investigated. Ingredients in HXZQ were characterized and analyzed in colitic mice using liquid chromatography–mass spectrometry (LC-MS) and gas chromatography–mass spectrometry (GC-MS). In vitro, biological activity of compounds was assessed using lipopolysaccharide (LPS)-induced Ana-1 cells and bone marrow-derived macrophages (BMDMs), tumor necrosis factor-alpha-induced Caco-2 cells, and isolated intestinal crypts from colitic mice. These results were confirmed in vivo. The targets of the components were identified through bioinformatics analysis and validated via molecular docking, enzyme inhibition assays, and in vivo experiments. Hematoxylin and eosin (HE) staining, periodic acid-Schiff (PAS) staining, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative real-time polymerase chain reaction (qPCR) were employed to confirm the pharmaceutical effects. ResultsA clinical equivalent dose of HXZQ (2.5 mL/kg) effectively treated DSS-induced colitis. 113 compounds were identified in HXZQ, with 35 compounds detected in colitic mice. Glycyrrhizic acid (GA) and patchouli alcohol (PA) emerged as key contributors to the anti-colitic effects of HXZQ. Further investigation revealed that HXZQ and its active components decreased the levels of pro-inflammatory cytokines TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) in colon, likely by inhibiting nuclear factor kappa-B (NF-κB) signaling pathway. This inhibition indirectly activated the intestinal farnesoid X receptor (FXR) signaling pathway, correcting bile acid imbalances caused by colitis. Additionally, these components significantly enhanced the expression of tight junction proteins ZO-1 and Occludin, as well as the adhesion protein E-cadherin, and reduced goblet cell loss, thereby repairing intestinal barrier injury. Mechanistically, GA and PA were found to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, leading to increased local active corticosterone levels in the intestine to exert anti-inflammatory effects. Notably, the inhibition of 11β-HSD1 with the selective inhibitor BVT ameliorated colitis in mice. ConclusionsHXZQ exhibits therapeutic effects on UC, primarily through GA and PA inhibiting 11β-HSD1. This suggests new natural therapy approaches for UC and positions 11β-HSD1 as a potential target for colitis treatment.

Effects of dietary Bacillus subtilis 14823 on growth performance, gut barrier integrity and inflammatory response of broilers raised in a stressful tropical environment

Heat stress (HS) has become a major concern for the poultry industry in many countries. HS impacts gut health by causing damaged mucosal microstructures, increased oxidative stress, weakened immunity, and heightened permeability to toxins and poultry pathogens. We investigated the potential benefits to broiler chickens subjected to HS of dietary supplementation with Bacillus subtilis 14823. Growth performance, gut barrier integrity, and expressions of inflammatory cytokines were analyzed. The results indicated that dietary supplementation with B. subtilis spores at concentrations of 1 × 106 CFU/g of feed (BS6 group) and 1 × 107 CFU/g of feed (BS7 group) improved body weight and body weight gain during d 0–42 (P < 0.05), while the feed intake of the BS7 group was highest (P < 0.05). Additionally, the BS6 group showed a better feed conversion ratio than the control (CON) group (P < 0.05). The BS7 group showed the lowest serum fluorescein isothiocyanate-dextran levels (P < 0.05), and both the BS6 and BS7 groups showed lower corticosterone levels than the CON group (P < 0.05). Additionally, both the BS6 and BS7 groups demonstrated increased villi height and villus height/crypt depth ratio, along with decreased crypt depth in the duodenum and ileum (P < 0.05). However, only the BS7 group exhibited greater improvements than the CON group in the jejunum at d 35. Furthermore, at d 14 and 35, mRNA expressions of occludin, claudin-1, and tight junction protein-1 in the jejunum were upregulated (P < 0.05), and expression levels of five inflammatory cytokine genes were downregulated in the ileum (P < 0.05). Our findings provide new insights and evidence supporting the application of B. subtilis 14823 for enhancing growth performance, gut barrier integrity, and modulating inflammatory cytokines in broilers.