Fluoxetin suppresses tau phosphorylation and modulates the interaction between tau and tubulin in the hippocampus of CUMS rats.

Depression is considered a crucial psychiatric disease correlated with neuronal-dysfunctions induced by stress-stimuli. This study aimed to investigate effect of Fluoxetine (FL) on chronic unpredictable mild stress (CUMS) and explore the associated mechanisms. CUMS rat model was established by treating with lots of stresses. CUMS rats were administered FL, SB216763 (SB), Wortmannin (WT) alone or in combination. CUMS rats were administered 1 % sugar water to conduct sugar water consumption experiment. Acet-Tub, Tyr-Tub, tau46, p-tau-Ser199/202, p-tau-Ser396, p-tau-Ser231, expression was examined using immunohistochemical assay and western blotassay. Interaction between tau and tubulin was evaluated with immunoprecipitation assay. Double immunohistochemical assay was used to identify interaction between Nestin and Tau. The results indicated that FL treatment only increased sugar consumption of CUMS rats (P < 0.05), but also strengthened effects of SB and WT. FL significantly treatment decreased tau phosphorylation (p-tau) in hippocampal tissues of rats compared to those of rats in CUMS group (P < 0.05). FL treatment markedly decreased Acet-Tub and increased Tyr-Tub expression in hippocampal tissues of rats compared to those of rats in CUMS group (P < 0.05). The effects of FL treatment on p-tau down-regulation and tubulin modulation in hippocampal tissues were independent from PI3K and GSK-3 signaling pathways. FL treatment could also enhance proliferation and total tau of newborn neurons of CUMS rats. FL treatment strengthened interaction between tau and botulin in hippocampal tissues of CUMS rats. In conclusion, Fluoxetin suppressed phosphorylation of tau and modulated the interaction between tau and tubulin in hippocampus of adult CUMS rats.

Long-Term Consumption of Green Tea Can Reduce the Degree of Depression in Postmenopausal Women by Increasing Estradiol.

Postmenopausal women face a higher risk of depression due to a combination of social and physiological factors. As a beverage rich in a variety of bioactive substances, green tea has significant effects on metabolism, inflammation and endocrine, and may reduce the risk of depression, but few studies have looked at the effects of green tea on postmenopausal women. Therefore, we designed this study to investigate the effects of long-term green tea consumption on inflammation, endocrine and depression levels in postmenopausal women. We investigated a tea-producing village and eventually included 386 postmenopausal women, both in the tea drinking and control groups. The results showed that there were significant differences in the degree of insomnia, degree of depression, BMI, SII and estradiol between the two groups. And, green tea consumption may reduce the risk of depression through the mediating pathway of sleep, SII and estradiol. In summary, long-term green tea consumption can reduce the risk of depression in postmenopausal women by reducing inflammation and increasing estradiol. This kind of living habit deserves further promotion.

MRI-based brain age prediction model for children under 3 years old using deep residual network.

Early identification and intervention of abnormal brain development individual subjects are of great significance, especially during the earliest and most active stage of brain development in children aged under 3. Neuroimage-based brain's biological age has been associated with health, ability, and remaining life. However, the existing brain age prediction models based on neuroimage are predominantly adult-oriented. Here, we collected 658 T1-weighted MRI scans from 0 to 3 years old healthy controls and developed an accurate brain age prediction model for young children using deep learning techniques with high accuracy in capturing age-related changes. The performance of the deep learning-based model is comparable to that of the SVR-based model, showcasing remarkable precision and yielding a noteworthy correlation of 91% between the predicted brain age and the chronological age. Our results demonstrate the accuracy of convolutional neural network (CNN) brain-predicted age using raw T1-weighted MRI data with minimum preprocessing necessary. We also applied our model to children with low birth weight, premature delivery history, autism, and ADHD, and discovered that the brain age was delayed in children with extremely low birth weight (less than 1000 g) while ADHD may cause accelerated aging of the brain. Our child-specific brain age prediction model can be a valuable quantitative tool to detect abnormal brain development and can be helpful in the early identification and intervention of age-related brain disorders.

Common and Distinct Functional Connectivity of the Orbitofrontal Cortex in Depression and Schizophrenia.

Schizophrenia and depression are psychiatric disorders with overlapping clinical and biological features. This study aimed to identify common and distinct neuropathological mechanisms in schizophrenia and depression patients using resting-state functional magnetic resonance imaging (fMRI). The study included 28 patients with depression (DEP), 29 patients with schizophrenia (SCH), and 30 healthy control subjects (HC). Intrinsic connectivity contrast (ICC) was used to identify functional connectivity (FC) changes at the whole-brain level, and significant ICC differences were found in the bilateral orbitofrontal cortex (OFC) across all three groups. Further seed-based FC analysis indicated that compared to the DEP and HC groups, the FC between bilateral OFC and medial prefrontal cortex (MPFC), right anterior insula, and right middle frontal gyrus were significantly lower in the SCH group. Additionally, the FC between right OFC and left thalamus was decreased in both patient groups compared to the HC group. Correlation analysis showed that the FC between OFC and MPFC was positively correlated with cognitive function in the SCH group. These findings suggest that OFC connectivity plays a critical role in the pathophysiology of schizophrenia and depression and may provide new insights into the potential neural mechanisms underlying these two disorders.

Trajectories of Efficacy and Cognitive Function During Electroconvulsive Therapy Course in Young Adults with Treatment-Resistant Depression.

Objective: Little is known about the effectiveness and cognitive side-effects of electroconvulsive therapy (ECT) in young adults with treatment-resistant depression (TRD). The primary aim of this prospective longitudinal observational trial was to examine the clinical features and cognitive outcomes of young adults with TRD undergoing ECT. Methods: Changes in depressive symptoms and objective and subjective cognitive function were assessed using repeated evaluation at baseline, after each ECT session, and at one-month follow-up using the Montgomery-Äsberg Depression Rating Scale (MADRS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Forward Digital Span Test (FDST), and part of the Columbia Subjective Side Effects Schedule. Results: Of 41 inpatients, 35 (85.4%) and 12 (29.3%) met the criteria for response and remission after ECT, respectively. The greatest clinical improvements occurred during the first 3-4 ECT sessions. While 34 patients reported subjective cognitive impairment increased with ECT, immediate and delayed memory (RBANS) significantly increased after ECT, consistent with FDST results. Objective cognition significantly improved during follow-up, but subjective cognition remained impaired. Conclusion: ECT is effective in young adults with TRD. Although subjective cognitive impairment increased during treatment, objective cognitive impairments were not observed.

Risk factors for hospital-acquired pneumonia among inpatients with mental disorders in a large mental health center within a tertiary general hospital.

BACKGROUND: Few researchers have investigated the incidence of and risk factors for hospital-acquired pneumonia (HAP) among inpatients with mental disorders in a general hospital. METHODS: This study included patients with mental disorders hospitalized in a large mental health center (situated in a general hospital) between January 1, 2017, and July 31, 2021 (excluding January 1, 2020- May 31, 2020). Risk factors for HAP were identified by logistic regression analysis after propensity score matching (PSM, 1:4) for gender, age, duration of observation, and hospital ward. RESULTS: The study included 16,864 patients. HAP incidence rate was 1.15% overall, 2.11% in closed wards, 0.75% in open wards, 4.45% in patients with organic mental disorders, 1.80% in patients with schizophrenia spectrum disorders, and 0.84% in patients with mood disorders. Risk factors for HAP after PSM were hypoproteinemia, chronic liver disease, use of clozapine, hospitalization during the previous 180 days, body mass index (BMI) ≤18.5 kg/m2, cholinesterase inhibitor use, and mood stabilizer use. CONCLUSIONS: HAP was common among inpatients with mental disorders. Risk factors for HAP in patients with mental disorders include hypoproteinemia, chronic liver disease, hospitalization during the past 180 days, BMI ≤18.5 kg/m2, and use of clozapine, cholinesterase inhibitors, or mood stabilizers.

Risk factors for community-acquired pneumonia among inpatients with mental disorders in a tertiary general hospital.

Introduction: Community-acquired pneumonia (CAP) is an important cause of hospitalization and death in patients with mental disorders. It is critical to understand the risk factors of CAP and determine prevention strategies to reduce CAP. The aim of this study is to explore the characteristics of inpatients with mental disorders who have CAP and analyze the risk factors. Methods: This retrospective study included 16,934 inpatients with mental disorders who were admitted for the first time to a tertiary general hospital between January 2017 and July 2021 (excluding January 2020-May 2020). Risk factors for CAP were identified by logistic regression analysis after propensity score matching (PSM, 1:4) for age, gender, and BMI. Results: The CAP rate of inpatients with mental disorders was 1.78%. Inpatients who had CAP had a significantly prolonged hospital stay, and were more often admitted to a closed ward or the ICU. After PSM, the multivariable analysis revealed that clozapine use (OR = 3.212, 95% CI = 1.744-5.915, P < 0.001), schizophrenia spectrum disorder (OR = 2.785, 95% CI = 1.684-4.607, P < 0.001), alcohol consumption (OR = 2.549, 95% CI = 1.586-4.096, P < 0.001), cardiovascular disease (OR = 2.299, 95% CI = 1.362-3.879, P = 0.002), Charlson comorbidity index (CCI) ≥ 3 (OR = 2.092, 95% CI = 1.342-3.260, P = 0.001), organic mental disorder (OR = 1.941, 95% CI = 1.194-3.156, P = 0.007), antipsychotic drug use (OR = 1.886, 95% CI = 1.312-2.711, P = 0.001), unmarried status (OR = 1.720, 95% CI = 1.164-2.541, P = 0.006) and junior high school education (OR = 1.591, 95%CI = 1.010-2.508, P = 0.045) were independent risk factors for CAP in inpatients with mental disorders. Conclusion: CAP was common in inpatients with mental disorders. Patients with mental disorders have unique risk factors for CAP. Further research is required to explore the relationship and mechanism between different mental disorders, antipsychotic drugs and CAP.

Resting-state functional connectivity of salience network in schizophrenia and depression.

To explore the salience network (SN) functional alterations in schizophrenia and depression, resting-state functional magnetic resonance imaging (rs-fMRI) data from 29 patients with schizophrenia (SCH), 28 patients with depression (DEP) and 30 healthy controls (HC) were obtained. The SN was derived from data-driven group independent component analysis (gICA). ANCOVA and post hoc tests were performed to discover the FC differences of SN between groups. The ANCOVA demonstrated a significant group effect in FC with right inferior and middle temporal gyrus (ITG and MTG), left caudate, and right precentral gyrus. Post-hoc analyses revealed an opposite altered FC pattern between SN and right ITG and MTG for both patient groups. The DEP group showed a reduced FC between SN and right ITG and MTG compared with HC whereas the SCH group showed an increased FC. In addition, the SCH group showed decreased FC between SN and left caudate, and enhanced FC between SN and right precentral gyrus compared to the other two groups. Our findings suggest distinct FC of SN in schizophrenia and depression, supporting that the resting-state FC pattern of SN may be a transdiagnostic difference between depression and schizophrenia and may play a critical role in the pathogenesis of these two disorders.

DNA methylation of the Tacr2 gene in a CUMS model of depression.

Tacr2, the gene encoding the NK2 receptor, belongs to G protein-coupled receptors. Accumulating evidence has indicated that the tachykinin receptors may contribute to the pathophysiology of depression. During the last decade, some studies have shown that Tacr2 activation is involved in the modulation of emotional processes. However, the extent, to which stress impacts Tacr2 expression remains unclear. The molecular mechanisms underlying depression also remain poorly understood. In this study, we subjected adult male Sprague Dawley (SD) rats to chronic unpredictable mild stress (CUMS) to induce a depression-like phenotype. We then measured the body weight and performed the sucrose preference test, forced swimming test (FST) and open field test to detect the effects of stress on anhedonia and activity. Western blotting and real-time PCR were used to study the protein and mRNA expression levels of Tacr2, respectively, in the hypothalamus. To explore DNA methylation of the Tacr2 gene, we used methylated DNA immunoprecipitation sequencing (MeDIP-seq). Additionally, we used the bisulfite sequencing PCR (BSP) to further verify the DNA methylation levels of the Tacr2 receptor gene in rats. We found that the CUMS-sensitive rats exhibited a decrease in body weight and sucrose preference, a decrease in the distance traveled, rearing frequency and velocity in the open field test, and an increase in immobility time in the FST. Compared with the expression in the control rats, Tacr2 protein and mRNA expression in the hypothalamus significantly increased in the CUMS-sensitive rats; however, the DNA methylation levels of the Tacr2 gene were significantly lower than in the control rats. In summary, according to our findings, the stress-induced increase in Tacr2 expression in the hypothalamus correlated with a specific decrease in DNA methylation of the Tacr2 gene. These results may enrich the understanding of the pathological processes of depression and provide insights into therapeutic approaches for its treatment.

Histone modifications of the Crhr1 gene in a rat model of depression following chronic stress.

Multiple lines of evidence suggest a link between depression and changes in hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics, including altered regulation of the corticotrophin-releasing hormone (CRH) and its main receptor, corticotrophin-releasing hormone receptor 1 (CRHR1). However, the precise molecular mechanisms underlying depression remain poorly understood. In this study, we employed a model of depression in rats by subjecting animals to 21 days of chronic unpredictable mild stress (CUMS). Real-time PCR and western blotting were used to study the mRNA and protein expression levels of CRHR1 in the hypothalamus. In addition, chromatin immunoprecipitation assays were used to detect histone methylation at the Crhr1 gene promoter; the levels of histone H3 trimethylation at lysines 4 (H3K4) and 9 (H3K9) reflect active transcription and transcriptional repression, respectively. Rats exposed to CUMS exhibited significant reduction in locomotion and sucrose preference. These behavioral alterations were associated with elevated expression levels of CRHR1 mRNA and protein in the hypothalamus of rats in the CUMS group. We also found that the levels of H3K9 trimethylation at the Crhr1 gene promoter in the CUMS group were significantly lower than those in the control group, whereas H3K4 trimethylation levels were the same for both groups. Taken together, our findings suggest that the increase in CRHR1 expression in the hypothalamus of stressed rats correlates with a decrease in the repressive chromatin state caused by reduced H3K9 trimethylation levels. These data are the first in vivo evidence of a role for chromatin modifications in the regulation of Crhr1 gene expression in the hypothalamus, and may provide novel insight into therapeutic approaches to treat depression.

Differential expression of hippocampal EphA4 and ephrinA3 in anhedonic-like behavior, stress resilience, and antidepressant drug treatment after chronic unpredicted mild stress.

Stress exposure is one of the major risk factors of depression, but the mechanism is not understood. While some individuals show resilience to stress exposure, antidepressants only partially reduce stress-induced depression in both humans and rodents. Stress could dysregulate the remodeling of neuronal dendrites and spines in hippocampus while antidepressants could recover the deficiency induced by stress. EphA4 and its ligand ephrinA3 are critical in the remodeling of neuronal dendrites and spines, but the relationship between ephrinA3/EphA4, stress-induced depression and antidepressants treatment is largely unknown. Based on a rat chronic unpredicted mild stress (CUMS) model, we investigated ephrinA3/EphA4 expression in stress susceptibility, stress resilience, treatment response and treatment resistance in rats. CUMS led to downregulation of EphA4 expression and upregulation of ephrinA3 expression in the hippocampus of stress-susceptible rats, but not in stress-resilient rats. Dysregulated EphA4 and ephrinA3 can be rescued by fluoxetine administration in drug responders, but not in fluoxetine resistant rats. These data provide insights into the potential role of EphA4 and ephrinA3 after stressor exposure, stress adaptation, fluoxetine response and drug treatment refraction.

Negative life events and corticotropin-releasing-hormone receptor1 gene in recurrent major depressive disorder.

Major depressive disorder (MDD) is a long-term, recurrent condition that often takes a chronic course. It seems imperative that research should be focused on gaining a better understanding of what predicts recurrent MDD. As a major mediator of the stress response, corticotropin-releasing-hormone receptor 1 (CRHR1) has been demonstrated to be an important contributor to the pathogenesis of MDD. In this study, we show a significant increase in the G-allele (rs242939) of the CRHR1 gene in the recurrent MDD group compared with the control group, and an overrepresentation of G-G-T hyplotype of the CRHR1 gene in recurrent MDD. We also demonstrate the interaction of the CRHR1 gene and negative life events in recurrent MDD. These results suggest that the CRHR1 gene could modify the susceptibility to developing recurrent MDD following negative life events in adulthood.

Interaction between CRHR1 and BDNF genes increases the risk of recurrent major depressive disorder in Chinese population.

BACKGROUND: An important etiological hypothesis about depression is stress has neurotoxic effects that damage the hippocampal cells. Corticotropin-releasing hormone (CRH) regulates brain-derived neurotrophic factor (BDNF) expression through influencing cAMP and Ca2+ signaling pathways during the course. The aim of this study is to examine the single and combined effects of CRH receptor 1 (CRHR1) and BDNF genes in recurrent major depressive disorder (MDD). METHODOLOGY/PRINCIPAL FINDING: The sample consists of 181 patients with recurrent MDD and 186 healthy controls. Whether genetic variations interaction between CRHR1 and BDNF genes might be associated with increased susceptibility to recurrent MDD was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). CRHR1 gene (rs1876828, rs242939 and rs242941) and BDNF gene (rs6265) were identified in the samples of patients diagnosed with recurrent MDD and matched controls. Allelic association between CRHR1 rs242939 and recurrent MDD was found in our sample (allelic: p = 0.018, genotypic: p = 0.022) with an Odds Ratio 0.454 (95% CI 0.266-0.775). A global test of these four haplotypes showed a significant difference between recurrent MDD group and control group (chi-2 = 13.117, df = 3, P = 0.016. Furthermore, BDNF and CRHR1 interactions were found in the significant 2-locus, gene-gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method. CONCLUSION: Our results suggest that an interaction between CRHR1 and BDNF genes constitutes susceptibility to recurrent MDD.

Chronic mild stress induces fluoxetine-reversible decreases in hippocampal and cerebrospinal fluid levels of the neurotrophic factor S100B and its specific receptor.

Chronic mild stress (CMS) affects the hippocampal structure and function in the rat. S100B, a calcium-binding protein secreted by astrocytes, has been shown to be increased in serum of patients with depression and associated with good therapeutic response and clinical outcome. This work aimed to study the impact of CMS and fluoxetine on depressive-like behaviors in rats, as well as the concomitant expression of the astroglial protein S100B and of its receptor RAGE (receptor for advanced glycation end products) in the hippocampus and Cerebrospinal fluid of the same group of animals. S100B and sRAGE (circulating soluble form of RAGE) were measured in CSF by ELISA, and S100B and RAGE were measured in hippocampal slices by Western blot. Our study has demonstrated that stress and depression decrease S100B and RAGE/SRAGE expression and antidepressant treatment reverses or blocks these effects. This result suggested that S100B/RAGE interactions may be involved in the development and maintenance of depression and may play an important role in the mechanism of antidepressants' therapeutic action.