Numerous studies have demonstrated that chronic stress during pregnancy (CSDP) can induce depression and hippocampal damage in offspring. It has also been observed that high levels of ...corticotropin-releasing hormone (CRH) can damage hippocampal neurons, and intraperitoneal injection of a corticotropin releasing hormone receptor 1 (CRHR1) antagonist decreases depression-like behavior and hippocampal neuronal damage in a mouse depression model. However, whether CSDP causes hippocampal damage and depression in offspring through the interaction of CRH and hippocampal CRHR1 remains unknown and warrants further investigation. Therefore, hippocampal Crhr1 conditional gene knockout mice and C57/BL6J mice were used to study these questions. Depression-related indexs in male offspring mice were examined using the forced swim test (FST), sucrose preference test (SPT), tail suspension test (TST) and open field test (OFT). Serum CRH levels were measured by enzyme-linked immunosorbent assay (ELISA). Golgi-Cox staining was used to examine the morphological changes of hippocampal neuronal dendrites. Neuronal apoptosis in the hippocampal CA3 regions was detected by terminal deoxynucleotidy transferase dUTP nick end labeling (TUNEL) staining. The levels of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR) and protein kinase B (AKT) proteins were measured by Western blot analysis. This study showed that CSDP induces depression-like behavior, hippocampal neuronal dendrite damage and apoptosis in male offspring mice. Conditional gene knockout of hippocampal Crhr1 in mice reduced CSDP-induced depression-like behavior, hippocampal neuronal dendrite damage and apoptosis in male offspring, and counteracted the CSDP-induced decreased expression of p-Akt and mTOR activity in male offspring hippocampus. These findings demonstrated that CSDP might inhibit the Akt/mTOR pathway by increasing the levels of CRH, leading to increased CRH-mediated activation of hippocampal CRHR1, thereby inducing synaptic impairment and apoptosis in hippocampal neurons, which in turn leads to depression-like behavior in offspring.
•Hippocampal CRHR1 conditional gene knockout prevented depression-like behavior in male offspring mice induced by CSDP.•It can inhibit synaptic damage and apoptosis in the hippocampal CA3 area of male offspring mice induced by CSDP.•It can up-regulate the decreased expression of p-Akt and mTOR activity in male offspring hippocampus induced by CSDP.•CSDP might through CRH combining with CRHR1, down-regulate Akt/mTOR, thereby leading to depression-like behavior.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Female, especially for pregnant female, are vulnerable to psychological stress. The morphology and metabolism of the maternal intestine are both obviously changed during pregnancy, thus making ...intestinal health status more fragile under psychological stress. The aim of the present study was to investigate the role of CRH and CRHR1 in the pregnant maternal intestine under psychological stress, thus exploring the mechanism of psychological stress in the pregnant maternal intestine. Bama miniature pigs were divided into the control and restraint stress groups from the first day of pregnancy. After restraint stress treatment for 18 consecutive days (D18), the plasma, duodenum, jejunum, ileum and colon were collected for study. Pregnant Bama miniature pigs subjected to restraint stress had significantly elevated CRH, adrenocorticotropic hormone (ACTH) and cortisol (COR) levels in plasma. Consistent with the increase in CRH levels, we observed enhanced oxidative stress levels in the intestine, which resulted in intestinal mucosal injury, including impaired intestinal morphology, a reduced number of goblet cells and proliferating cell nuclear antigen‐positive cells, decreased expression of MUC2 and tight junctions, and elevated expression of CRHR1 and caspase-3. Moreover, exogenous CRH could directly promote IPEC-J2 cell apoptosis and influence its cell cycle (S and G2 phase) through CRHR1, and antalarmin could alleviate this phenomenon. Therefore, our results illustrated that the intestinal dysfunction of pregnant Bama miniature pigs was caused by restraint stress, and these changes were associated with the enhanced expression of CRH and CRHR1 in the intestine.
Posttraumatic stress disorder (PTSD) is a highly frequent and disabling psychiatric condition among war-affected populations. The FK506-binding protein 5 (FKBP5) gene and the corticotropin-releasing ...hormone receptor 1 (CRHR1) gene have previously been implicated in an elevated risk of peritraumatic dissociation and PTSD development. Our aim was to investigate the association between FKBP5 and CRHR1 genotypes and PTSD diagnosis and severity among individuals who were affected by the Balkan wars during the 1990s.
This study included participants with current PTSD, remitted PTSD and healthy volunteers (N=719, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). FKBP5 rs1360780 and CRHR1 rs17689918 genotypes were determined using a KASP genotyping assay.
Tests for deviation from Hardy Weinberg equilibrium showed no significant results. Logistic and linear regression was used to examine the associations between the FKBP5 SNP rs1360780 and the CRHR1 SNP rs17689918 with PTSD diagnosis and severity, as well as general psychiatric symptom severity, separately for current and remitted PTSD patients. There were nominally significant associations under a dominant model between the rs1360780 C allele and PTSD diagnosis as well as symptom severity, which however, were not significant anymore after Bonferroni adjustment (α=0.002). For CRHR1 rs17689918 no significant associations were detected.
We found nominally, but not Bonferroni corrected significant associations between the FKBP5 polymorphism rs1360780 and PTSD susceptibility among individuals affected by the Balkan wars. For elucidating this gene's real resilience/vulnerability potential, environmental influences should be taken into account.
Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the ...hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD.
•This experiment showed that CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1.•And CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress.•It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) initiate hypothalamic-pituitary-adrenal axis activity through the release of CRF into the portal system ...as part of a coordinated neuroendocrine, autonomic, and behavioral response to stress. The recent discovery of neurons expressing CRF receptor type 1 (CRFR1), the primary receptor for CRF, adjacent to CRF neurons within the PVN, suggests that CRF also signals within the hypothalamus to coordinate aspects of the stress response. Here, we characterize the electrophysiological and molecular properties of PVN-CRFR1 neurons and interrogate their monosynaptic connectivity using rabies virus-based tracing and optogenetic circuit mapping in male and female mice. We provide evidence that CRF neurons in the PVN form synapses on neighboring CRFR1 neurons and activate them by releasing CRF. CRFR1 neurons receive the majority of monosynaptic input from within the hypothalamus, mainly from the PVN itself. Locally, CRFR1 neurons make GABAergic synapses on parvocellular and magnocellular cells within the PVN. CRFR1 neurons resident in the PVN also make long-range glutamatergic synapses in autonomic nuclei such as the nucleus of the solitary tract. Selective ablation of PVN-CRFR1 neurons in male mice elevates corticosterone release during a stress response and slows the decrease in circulating corticosterone levels after the cessation of stress. Our experiments provide evidence for a novel intra-PVN neural circuit that is activated by local CRF release and coordinates autonomic and endocrine function during stress responses.
The hypothalamic paraventricular nucleus (PVN) coordinates concomitant changes in autonomic and neuroendocrine function to organize the response to stress. This manuscript maps intra-PVN circuitry that signals via CRF, delineates CRF receptor type 1 neuron synaptic targets both within the PVN and at distal targets, and establishes the role of this microcircuit in regulating hypothalamic-pituitary-adrenal axis activity.
Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems.
We completed a genome-wide association study in 126,936 European ...American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption.
ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10−47); for African American, rs2066702 (p = 2.3 × 10−12). In the European American sample, we identified three additional genome-wide–significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10−12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10−13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10−9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post–genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10−9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells.
The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinical studies have elucidated the negative correlation between microtubules-associated protein 1 light chain 3-B (LC3B) protein expression and overall survival of breast cancer patients. Our ...previous data demonstrated corticortropin-releasing hormone family (CRHs) suppressed migration of breast cancer cells via CRH receptors (CRHRs). Here, we showed that the activation of CRHRs (CRHR1 and CRHR2) remarkably reduced the conversion of LC3BI to LC3BII and hence repressed macroautophagy/autophagy, resulting in migration inhibition. By means of RT-4 cells (expressing higher CRHR1) with stable CRHR1 silence which was constructed by lentivirus with short hairpin RNA, we further confirmed CRH-inhibited LC3BII conversion. Using CRHRs agonists and antagonists, we found CRHRs triggered a marked reduction in the number of LC3B dots in both RT-4 and Hela cells(expressing higher CRHR2) which stably express RFP-GFP-LC3B. Of note, this decreased amount of autophagosome was associated with activation of Phospholipase C β (PLCβ)-Inositol triphosphate (IP3)-mTOR signaling. Earle's Balanced Salt Solution (EBSS) decreased the expression of the key focal adhesion protein, paxillin, which was recovered by CRHRs ligands (CRH and UCN2). The effect of CRHRs ligands on paxillin resulted in the suppression of cell migration. Altogether, these data reveal a new link between CRHRs signaling and autophagy, and may help to envisage therapeutic strategies in cancer cell invasion.
•Activated CRHRs (G protein-coupled receptor) inhibit autophagy through inhibiting LC3BII accumulation.•PLCβ-IP3-mTOR signaling plays main role in CRHRs-inhibited autophagy.•Autophagy is required for CRHRs-inhibited migration.•CRHRs inhibit autophagy to block paxillin degradation, which repress migration of cancer cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Sevoflurane exposure elevated the CRH level and activate CRHR1 in mice hippocampal.•Sevoflurane exposure decreased nectin-1 expression in mice hippocampal.•Nectin-1 over expression can be used to ...decrease the neurotoxicity of sevoflurane.
In recent years, the neurotoxicity of general anesthetics in the developing brain has been studied and raised great concern as a major health issue to the public and physicians. Sevoflurane inhalation may induce neurotoxicity expressed as memory and learning impairment in young animals. In the current study, we investigated the role of nectin-1 and corticotrophin-releasing hormone receptor type 1 (CRHR1) in sevoflurane-induced learning deficits and dendritic spines loss in neonatal mice. Neonatal mice (P7) were treated with 3% sevoflurane with 60% O2 or 60% O2 for 6 h. Cognitive function was evaluated by Y Maze, Object recognition test, and Morris Water Maze. Hippocampal nectin-1 and L-afadin expression assessed using western blot analysis. The dendritic spines morphology of the hippocampus was determined using Golgi impregnation on 7 d and 2 months old. Sevoflurane exposed to neonatal mice decreased hippocampal nectin-1 levels from 1 h to 2 months after sevoflurane inhalation and attenuated working and spatial memory and spinal number in adulthood, which could be reversed by nectin-1 overexpression and CRHR1 antagonist Antalarmin. Nectin-1 knockdown caused spatial learning deficits and dendritic spine loss and lower L-afadin protein expression. Sevoflurane-induced nectin-1 and L-afadin expression decrease was mediated by CRHR1 signaling in the hippocampus. This information can be used to develop targeted intervention aimed at decreasing the neurotoxicity of sevoflurane inhalation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•In the general working population men report less anxiety than women.•The score of anxiety is associated with the exposure to abusive supervision.•Anxiety induced by abusive supervision is ...influenced by the CRHR1 genotype.•CRHR1 TAT/TAT in women increases the risk of anxiety induced by abusive supervision.
Previous findings suggest that exposure to social stress in the form of abusive supervision may increase the risk of anxiety disorders. In the present study, we examined the link between abusive supervision, the CRHR1 genotype and anxiety.
The data was collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1225 individuals returned both the questionnaire and the saliva kit. Abusive supervision was assessed with 5 items from the Tepper's “Abusive Supervision Scale”. Anxiety was measured by 5 items of the “Hopkins Symptom checklist”. Genotyping with regard to CRHR1 rs7209436 C/T, rs110402 G/A and rs242924 G/T was carried out using Taqman assay, and Phase v.2.1.1 was used to define the CRHR1 haplotype TAT versus CGG.
The analyses revealed that abusive supervision was associated with anxiety. In particular, we observed a strong effect of abusive supervision on anxiety in female TAT/TAT carriers (p = 0.000). Moreover, using TAT/TAT as a reference, TAT/CGG and CGG/CGG both showed protective effects (p = 0.015, p = 0.001, respectively). Thus, the association between abusive supervision and anxiety was strong among female TAT/TAT carriers was stronger than among female TAT/CGG and female CGG/CGG carriers. No such gene-environment interaction was seen in men.
Our data demonstrated that the CRHR1 TAT haplotype may exacerbate, whereas the CRHR1 CGG haplotype may reduce, the effect of abusive supervision on anxiety in female employees. Hence, the present study supports the theory that both gender and the CRHR1 genotype, moderate the responses to social stressors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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