Mature astrocytes as source for astrocyte repopulation after deletion in the medial prefrontal cortex: Implications for depression.

The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.

LEPR/FOS/JUNB signaling pathway contributes to chronic restraint stress-induced tumor proliferation.

BACKGROUND & AIMS: Psychosocial stress has become an unavoidable part of life, which was reported to promote tumor development. Chronic stress significantly promotes the norepinephrine (NE) secretion and the expression of leptin receptor (LEPR), leading to tumor invasion, metastasis, and proliferation. However, the mechanism of chronic stress-induced tumor proliferation remains unclear. METHODS: To reveal the effect of chronic stress on tumor proliferation, subcutaneous tumor models combined with chronic restraint stress (CRS) were established. Combined with the transcript omics database of liver cancer patients, the target pathways were screened and further verified by in vitro experiments. RESULTS: The results showed that the CRS with subcutaneous tumor transplantation (CRS + tumor) group exhibited significantly larger tumor sizes than the subcutaneous tumor transplantation (tumor) group. Compared with the tumor group, CRS obviously increased the mRNA levels of LEPR, FOS, and JUNB of tumor tissues in the CRS + tumor group. Furthermore, the treatment with norepinephrine (NE) significantly elevated the survival rate of H22 cells and enhanced the expression of LEPR, FOS, and JUNB in vitro. Silencing LEPR significantly reduced the expression of FOS and JUNB, accompanied by a decrease in H22 cell viability. CONCLUSIONS: Our study demonstrated that CRS activates the LEPR-FOS-JUNB signaling pathway by NE, aggravating tumor development. These findings might provide a scientific foundation for investigating the underlying pathological mechanisms of tumors in response to chronic stress.

Effects of dexmedetomidine on depression-like behaviour in chronic restraint stress mice: Involvement of specific brain regions.

It is crucial to develop novel antidepressants. Dexmedetomidine (DEX) can exert antidepressant effects, but its underlying mechanism remains unclear. We used chronic restraint stress (CRS) to induce depression-like behaviour in mice and administered low-dose DEX (2 µg/kg per day) during CRS modelling or one injection of high-dose DEX (20 µg/kg) after CRS. The results of the behavioural tests revealed that both methods ameliorated CRS-induced depression. The brain slices of the mice were subjected to immunohistochemical staining for c-fos and phosphorylated ERK (pERK). Results showed that the continuous low-dose DEX-treated group, but not the single high-dose DEX-treated group expressed less c-fos in the nucleus locus coeruleus (LC) with a mean optical density (MOD) of 0.06. Other brain regions, including the dentate gyrus (DG), pyriform cortex (Pir), anterior part of paraventricular thalamic nucleus (PVA), arcuate nucleus (Arc), and core or shell of accumbens nucleus (Acbc or Acbs), presented differences in c-fos expression. In contrast, the low-dose DEX-treated group exhibited three-fold greater pERK expression in the LC of the CRS mice, with a MOD of 0.15. Pir, cingulate cortex (Cg) and, anterior and posterior part of paraventricular thalamic nucleus (PVA and PVP) exhibited pERK expression differences due to distinct reagent treatments. These changes indicate that the responses of brain regions to different DEX administration methods and doses vary. This study confirmed the ability of DEX to ameliorate CRS-induced depression and identified candidate target brain regions, thus providing new information for the antidepressant mechanism of DEX.

Orexin improves chronic restraint stress induced depressive-like behavior via modulating the lateral septum in mice.

The orexin system participates in the regulation of depression; however, its effects show significant heterogeneity, indicating the involvement of complex downstream neural circuit mechanisms. The lateral septum (LS), located downstream of the orexin system, contributes to depression. However, the effects and mechanisms underlying the orexin-mediated modulation of the LS in patients with depression remain unclear. Herein, we applied fiber photometry, chemogenetics, neuropharmacology, and in vitro electrophysiology to show that LS orexinergic afferents are sensitive to acute restraint and that chronic restraint stress (CRS) inhibits LS-projecting orexin neurons. Chemogenetic activation of LS orexinergic afferents or injection of orexin-A into the LS improved CRS-induced depression-like behavior. In vitro perfusion of orexin-A increased the action potential of somatostatin neurons in the LS. Overall, this study provides evidence that orexin improves depressive-like behavior by modulating the LS, and that this effect is probably mediated by the upregulation of LS somatostatin neurons.

Chronic restraint stress-induced hyperalgesia is modulated by the periaqueductal gray neurons projecting to the rostral ventromedial medulla in mice.

Stress-induced hyperalgesia (SIH) is induced by repeated or chronic exposure to stressful or uncomfortable environments. However, the neural mechanisms involved in the modulatory effects of the periaqueductal gray (PAG) and its associated loops on SIH development hav e not been elucidated. In the present study, we used chronic restraint stress (CRS)-induced hyperalgesia as a SIH model and manipulated neuronal activity via a pharmacogenetic approach to investigate the neural mechanism underlying the effects of descending pain-modulatory pathways on SIH. We found that activation of PAG neurons alleviates CRS-induced hyperalgesia; on the other hand, PAG neurons inhibition facilitates CRS-induced hyperalgesia. Moreover, this modulatory effect is achieved by the neurons which projecting to the rostral ventromedial medulla (RVM). Our data thus reveal the functional role of the PAG-RVM circuit in SIH and provide analgesic targets in the brain for clinical SIH treatment.

The role of gut microbiota in chronic restraint stress-induced cognitive deficits in mice.

BACKGROUND: Chronic stress induces cognitive deficits. There is a well-established connection between the enteric and central nervous systems through the microbiota-gut-brain (MGB) axis. However, the effects of the gut microbiota on cognitive deficits remain unclear. The present study aimed to elucidate the microbiota composition in cognitive deficits and explore its potential in predicting chronic stress-induced cognitive deficits. METHODS: Mice were randomly divided into control and chronic restraint stress (CRS) groups. The mice subjected to CRS were further divided into cognitive deficit (CRS-CD) and non-cognitive deficit (CRS-NCD) groups using hierarchical cluster analysis of novel object recognition test results. The composition and diversity of the gut microbiota were analyzed. RESULTS: After being subjected to chronic restraint distress, the CRS-CD mice travelled shorter movement distances (p = 0.034 vs. CRS-NCD; p < 0.001 vs. control) and had a lower recognition index than the CRS-NCD (p < 0.0001 vs. CRS-NCD; p < 0.0001 vs. control) and control mice. The results revealed that 5 gut bacteria at genus levels were significantly different in the fecal samples of mice in the three groups. Further analyses demonstrated that Muricomes were not only significantly enriched in the CRS-CD group but also correlated with a decreased cognitive index. The area under the receiver operating curve of Muricomes for CRS-induced cognitive deficits was 0.96. CONCLUSIONS: Our study indicates that the composition of the gut microbiota is involved in the development of cognitive deficits induced by chronic restraint stress. Further analysis revealed that Muricomes have the potential to predict the development of chronic stress-induced cognitive deficits in mice.

Chronic restraint stress induces abnormal behaviors in pain sensitivity and cognitive function in mice: the role of Keap1/Nrf2 pathway.

Stress is a series of physical and psychological responses to external and internal environmental stimuli. Growing studies have demonstrated the detrimental impacts of acute restraint stress (ARS) and chronic restraint stress (CRS) on animal behavior. However, the related pathogenesis and therapeutic mechanisms remain unclear. Hence, the present study aimed to examine whether unfolded protein response (UPR) and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) pathway are associated with ARS- and CRS- induced abnormal behaviors of pain sensitivity and cognitive function. We here used four behavioral tests to evaluate pain sensitivity and cognitive function in ARS and CRS mice. CRS markedly decreased Paw Withdrawal Mechanical Threshold (PWMT) and Tail-flick Latency (TFL) scores, whereas ARS altered TFL but had no effect on PWMT scores. Additionally, CRS, but not ARS, significantly changed behaviors in nest building behavior and MWMT. Intriguingly, the expression of Keap1 and Nrf2 protein were decreased in the spinal cord and hippocampus in CRS mice, but not in ARS mice. Moreover, neither the ARS nor the CRS groups significantly differed from the control group in terms of endoplasmic reticulum stress (ERS). Taken together, this study demonstrated that CRS could induce abnormal pain sensitivity and cognitive function probably via Keap1/Nrf2 pathway in spinal cord and hippocampus. It is therefore likely that effective intervention of Keap1/Nrf2 pathway may contribute to preventing and treating hyperalgesia and cognitive dysfunction in CRS.

Oral microbiota dysbiosis alters chronic restraint stress-induced depression-like behaviors by modulating host metabolism.

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.

A chronic stress-induced microbiome perturbation, highly enriched in Ruminococcaceae_UCG-014, promotes colorectal cancer growth and metastasis.

Purpose: Mounting evidence indicates that psychological stress adversely affects cancer progression including tumor growth and metastasis. The aim of this study was to investigate the role of chronic stress-induced microbiome perturbation in colorectal cancer (CRC) progression. Methods: Chronic restraint stress (CRS) was used to establish the chronic stress mouse model, behavioral tests were used for the CRS model evaluation. Subcutaneous xenograft model and lung metastasis model were established to investigate the growth and metastasis of CRC promoted by CRS exposure. 16S rRNA gene sequencing and liquid chromatograph-mass spectrometer (LC-MS) were applied to observe the effects of CRS exposure on the alteration of the gut microbiome and microbial metabolites. Bioinformatics analysis and correlation analyses were applied to analyse the changes in the frequency of body mass, tumor volume, inflammatory factors, neuroendocrine hormones and metabolites of the gut microbiota. Results: In this study, we identifed that CRS exposure model was appropriately constructed by achieving expected increases in disease activity index and enhanced depressive-like behaviors. CRS exposure can promote growth and metastasis of CRC. Besides, the data indicated that CRS exposure not only increased the neuro- and immune-inflammation, but also weakened the gut mucosal immunological function. The 16s rRNA gene sequencing data showed that CRS exposure increased the abundance of g_Ruminococcaceae_UCG_014. Furthermore, the LC-MS data indicated that with only 2 exceptions of carpaine and DG (15:0/20:4(5Z,8Z,11Z,14Z)/0:0), the majority of these 24 metabolites were less abundant in CRS-exposed mice. Bioinformatics analysis and correlation analyses indicated that only Ruminoscoccaceae-UCG-014 was significantly associated with inflammation (IL-6), neurotransmission (5-HT), and microbial metabolism (PS). Conclusion: CRS exposure altered diversity, composition and metabolites of the gut microbiome, with Ruminococcaceae_UCG-014 perturbation consistently correlated to inflammatory responses, suggesting a particular role of this bacterial genus in CRC growth and metastasis.

Chronic restraint stress promotes oral squamous cell carcinoma development by inhibiting ALDH3A1 via stress response hormone.

BACKGROUND: Chronic restraint stress (CRS) has iteratively been reported to be possibly implicated in the development of numerous cancer types. However, its role in oral squamous cell carcinoma (OSCC) has not been well elucidated. Here we intended to evaluate the role and mechanism. METHODS: The effects of CRS were investigated in xenograft models of OSCC by using transcriptome sequencing, LC-MS, ELISA and RT-PCR. Moreover, the role of CRS and ALDH3A1 on OSCC cells was researched by using Trans-well, flow cytometry, western blotting, immunofluorescence, ATP activity and OCR assay. Furthermore, immunohistochemical staining was employed to observe the cell proliferation and invasion of OSCC in xenotransplantation models. RESULTS: CRS promoted the progression of OSCC in xenograft models, stimulated the secretion of norepinephrine and the expression of ADRB2, but decreased the expression of ALDH3A1. Moreover, CRS changed energy metabolism and increased mitochondrial metabolism markers. However, ALDH3A1 overexpression suppressed proliferation, EMT and mitochondrial metabolism of OSCC cells. CONCLUSION: Inhibition of ALDH3A1 expression plays a pivotal role in CRS promoting tumorigenic potential of OSCC cells, and the regulatory of ALDH3A1 on mitochondrial metabolism may be involved in this process.

[Establishment and evaluation of a premenstrual syndrome rat model induced by progesterone-withdrawal and emotional-stimulation].

Premenstrual syndrome(PMS) lacks a highly consistent and feasible animal model that aligns with diagnostic and therapeutic standards in both traditional Chinese medicine(TCM) and western medicine, resulting in a lack of reliable experimental carriers for studying its pathogenesis and pharmacological effects. This study aims to systematically analyze the biological implications of PMS from the perspective of the "disease-syndrome-symptom" correlation and establish preparation and evaluation methods for an improved animal model of this disease. Firstly, clinical symptom gene sets related to the Qi stagnation syndromes due to liver depression and blood stasis in PMS in both modern medicine and TCM diagnostic standards were collected through GeneCards, DisGeNET, Mala-Cards, and the System of Foundational Diagnostic Association(SoFDA) database, as well as published literature. Based on the interaction information between genes, a "disease-syndrome-symptom" correlation network of PMS was established. Based on data mining results, an improved rat model of PMS was prepared by combining chronic restraint stress with the classical progesterone-withdrawal mo-del to simulate emotional depression caused by external environmental stimuli during the clinical onset process, inducing pathological damage from both physiological and emotional dimensions. The evaluation of the improved model before and after modification included open field experiment scores, organ indices, ovarian pathological changes, serum levels of estradiol(E_2), follicle-stimulating hormone/luteinizing hormone(FSH/LH), 5-hydroxytryptamine(5-HT), dopamine(DA), norepinephrine(NE), as well as coagulation parameters and hemorheology indexes. By calculating the degree, betweenness, and closeness centrality of nodes in the "disease-syndrome-symptom" correlation network, 163 core genes with topological importance were identified. Further biological function mining results indicated that core genes in PMS mainly participated in the regulation of the "nervous-endocrine-immune" system and pathways related to circulatory disorders. Mapping analysis of clinical phenotype symptom gene sets suggested significant correlations between core genes in PMS and depressive symptoms and pain symptoms caused by blood stasis. Compared with the simple progesterone withdrawal model, rats subjected to combined injections and restraint stress showed more significant abnormalities in open field experiment scores, ovarian tissue pathology, serum neurotransmitter levels of 5-HT and DA, as well as serum hormone levels of E_2 and FSH/LH. The modified modeling conditions exacerbated the pathological changes in blood rheology, coagulation function, and red blood cell morphology in model rats, confirming that the improved rat model could characterize the "nervous-endocrine-immune" system disorder and circulatory system disorders in the occurrence and progression of PMS, consistent with the clinical diagnostic and therapeutic standards of both TCM and western medicine. The establishment of the improved rat model of PMS can provide a reliable experimental carrier for elucidating the pathogenesis of PMS and discovering and evaluating therapeutic drugs. It also provides references for objectively reflecting the clinical characteristics of PMS in TCM and western medicine and precision treatment.

Biomarkers Screening and Mechanisms Analysis of the Restraint Stress-Induced Myocardial Injury in Hyperlipidemia ApoE-/- Mice.

OBJECTIVES: To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. METHODS: The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. RESULTS: Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. CONCLUSIONS: Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death (SCD) caused by hyperlipidemia combined with the restraint stress.

Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway.

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity-linked protein expressions and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB)- mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA-12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF-TrkB-mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity-linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF-TrkB-mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

Transcranial Direct Current Stimulation (tDCS) Promotes state-dependent Effects on Neuroinflammatory and Behavioral Parameters in rats Chronically Exposed to Stress and a Hyper-Palatable Diet.

Chronic stress is a common condition affecting health, often associated with unhealthy eating habits. Transcranial direct current stimulation (tDCS) has been proposed to address these issues. Thus, this research investigated the effects of tDCS on biometric, behavioral, and neurochemical parameters in chronically stressed rats fed a hyper-palatable cafeteria diet (CAFD). The study lasted 8 weeks, with CAFD exposure and/or chronic restraint stress model (CRS - 1 h/day, 5 days/week, for 7 weeks) started concurrently. tDCS or sham sessions were applied between days 42 and 49 (0.5 mA, 20 min/day). CAFD increased body weight, caloric consumption, adiposity, and liver weight. It also altered central parameters, reducing anxiety and cortical levels of IL-10 and BDNF. In turn, the CRS resulted in increased adrenals in rats with standard diet (SD), and anxiety-like and anhedonic behaviors in rats with CAFD. tDCS provided neurochemical shifts in CAFD-fed stressed rats increasing central levels of TNF-α and IL-10, while in stressed rats SD-fed induced a decrease in the adrenals weight, relative visceral adiposity, and serum NPY levels. These data demonstrated the anxiolytic effect of CAFD and anxiogenic effect of stress in CAFD-fed animals. In addition, tDCS promoted state-dependent effects on neuroinflammatory and behavioral parameters in rats chronically exposed to stress and a hyper-palatable diet. These findings provide primary evidence for additional mechanistic and preclinical studies of the tDCS technique for stress-related eating disorders, envisioning clinical applicability.

High-performance fluorescence probe for fast and specific visualization of norepinephrine in vivo and depression-like mice.

Norepinephrine (NE), as an important neurotransmitter, is closely associated with the pathogenesis of anxiety and depressive disorders. Effective monitoring of NE fluctuation aids in the diagnosis of depression and the therapeutic assessment of the antidepressant intervention. The construction of novel fluorescent probes with high specificity towards NE for imaging in depression models is still in demand urgently. In this work, a novel resorufin-based red-emitting fluorescent probe for real-time tracking NE was developed. NE can significantly increase the fluorescence of probe LNE by triggering deprotection of carbonothioate ligand via nucleophilic substitution. The probe LNE demonstrated significant NE selectivity and sensitivity over other analytes in vitro. In addition, probe LNE showed a fast response time (<10 min), and the change in fluorescence signal was positively linked with NE concentration, which could be utilized to track the dysregulation of NE in vivo. More importantly, this powerful probe was successfully employed for real-time visual and imaging of NE in living cells and depression-like behavior animals.

TIP60 mediates stress-induced hypertension via promoting glutamatedmPFC-to-vCA1 release.

Hypertension is well-known to be influenced by genetic and environmental factors. Managing stress is one of the non-pharmacologic approaches to treating hypertension. It is, therefore, imperative to unravel the molecular mechanism by which stress conditions influence hypertension. In this study, TIP60 expressions in human blood samples and cell lines, glutamatedmPFC-to-vCA1 release, and receptor expressions in the Stress-induced hypertension mice were determined using western blotting, CSF (obtained by microdialysis), and ELISA. The study reports increased protein expressions of TIP60 in the peripheral blood of hypertensive patients and in cell lines representing hypertension. In Chronic restraint stress (CRS) conditions TIP60 expression and vCA1 glutamate release were found to be up-regulated, with high SBP and DSP indicating hypertension was induced. After electrical stimulation at the dmPFC, release of glutamate in the vCA1 increased, indicating that activity within the dmPFC drives the release of glutamate in the vCA1, which was blocked by injecting MG149 (a TIP60 inhibitor) into dmPFC. To further determine whether TIP60 was involved in glutamate release and eventually results in hypertension, MG149 was also injected i.p. alongside CRS modeling. The increased glutamate release, NR2B, and IL-18 expressions as well as the CRS-induced hypertension was therefore reversed by chronic application with MG149. Altogether, these results suggest that TIP60 influences the glutamatedmPFC-to-vCA1 release and receptor expressions. This study, therefore, proposes that stressful condition induces increased expression of TIP60 which lead to the transcription of genes that result in conditions that favors glutamate release and receptor expressions hence triggering hypertension.

Effects of ACTH6-9-Pro-Gly-Pro Peptide on the Levels of Pro- and Anti-Inflammatory Cytokines in Wistar Rats under Conditions of Chronic Restraint Stress.

We evaluated the effect of ACTH6-9-Pro-Gly-Pro (ACTH6-9-PGP) peptide on the serum levels of pro- and anti-inflammatory cytokines in experimental animals under conditions of chronic restraint stress. Stress exposure over 2 weeks led to an increase in the levels of IL-1ß, IL-6, and IFNγ in rats. Daily intraperitoneal injection of ACTH6-9-PGP in a dose of 5 µg/kg before stress exposure significantly decreased the levels of IL-6 and IFNγ by 4.8 and 49.3% respectively. Administration of the peptide in a dose of 50 µg/kg decreased the levels of IL-1ß and IFNγ by 51.2 and 39.7%, respectively. However, no changes in the cytokine levels were observed after injection of the peptide in a dose of 500 µg/kg. Thus, ACTH6-9-PGP administered in doses of 5 and 50 µg/kg prevented the stress-induced changes in the levels of pro- and inflammatory cytokines.

Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain.

BACKGROUND: Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect. METHODS: In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain-blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated. RESULTS: We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response. CONCLUSIONS: Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.

Betaine attenuate chronic restraint stress-induced changes in testicular damage and oxidative stress in male mice.

SCOPE: Male fertility and sperm quality are negatively affected by psychological stress. Chronic restraint stress (CRS) is a common psychological stress that has a negative effect on sperm. Betaine (BET), an active ingredient isolated from Lycium barbarum, has anti-oxidant, anti-inflammatory and other pharmacological activities. This study aims to explore whether betaine has a therapeutic effect on sperm deformity and vitality under CRS and its mechanism. METHODS AND RESULTS: Chronic restraint stress was induced in 8-week-old male C57BL/6 J mice by fixation for 6 h a day for 35 days. Mice were intraperitoneally injected with betaine (BET) or normal saline (NS) for 14 days. Thirty-five days later, the animals were sacrificed. The results showed that the detrimental effects of CRS on testes as evident by disrupted histoarchitecture, increased oxidative stress, inflammation and apoptosis that compromised male fertility. BET injections can reverse these symptoms. CONCLUSIONS: BET can improve spermatogenesis dysfunction caused by CRS, which may provide potential dietary guidance.

TIP60 buffers acute stress response and depressive behaviour by controlling PPARγ-mediated transcription.

Tat-interacting protein 60 (TIP60) as nuclear receptors (NRs) coregulator, acts as a tumor suppressor and also has promising therapeutic potential to target Alzheimer's disease. Stress has been implicated in many psychiatric disorders, and these disorders are characterized by impairments in cognitive function. Until now, there are no experimental data available on the regulatory effect of TIP60 in acute stress and depression. There is also no definitive explanation on which specific modulation of target gene expression is achieved by TIP60. Here, we identify TIP60 as a novel positive regulator in response to acute restraint stress (ARS) and a potentially effective target of antidepressants. Firstly, we discovered increased hippocampal TIP60 expressions in the ARS model. Furthermore, using the TIP60 inhibitor, MG149, we proved that TIP60 function correlates with behavioral and synaptic activation in the two-hour ARS. Secondly, the lentivirus vector (LV)-TIP60overexpression (OE) was injected into the hippocampus prior to the chronic restraint stress (CRS) experiments and it was found that over-expressed TIP60 compensates for TIP60 decrease and improves depression index in CRS. Thirdly, through the intervention of TIP60 expression in vitro, we established the genetic regulation of TIP60 on synaptic proteins, confirmed the TIP60 function as a specific coactivator for PPARγ and found that the PPARγ-mediated TIP60 function modulates transcriptional activation of synaptic proteins. Finally, the LV-TIP60OE and PPARγ antagonist, GW9662, were both administered in the CRS model and the data indicated that blocking PPARγ significantly weakened the protective effect of TIP60 against the CRS-induced depression. Conclusively, these findings together support TIP60 as a novel positive factor in response to acute stress and interacts with PPARγ to modulate the pathological mechanism of CRS-induced depression.