Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus.

Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 µg g(-1) ) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 µg g(-1) ) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-d-aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH-CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment.

Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study.

Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone. This study aimed to investigate the associations between testosterone levels, aggressive behavior, and manic symptoms using a network analysis among bipolar disorder (BD) patients in psychiatric emergency departments (PED). Data from January 2021 and March 2022 BD patients in PED were analyzed. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS). Aggression was assessed with subscale of the PANSS scale (PANSS-AG). The undirected network structures of testosterone levels, aggressive behavior, and manic symptoms were estimated, and centrality and bridge centrality indices were examined. Network stability was examined using the case-dropping procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. We recruited a total of 898 BD patients, with the mean YMRS score as 13.30 ± 9.58. The prevalence of level II aggression was 35.6% (95%CI = 32.5%-38.7%), level III aggression was 29.5% (95%CI = 26.3%-32.6%), and level VI aggression was 7.0% (95%CI = 5.4%-8.8%). The male participants had a mean testosterone level of 391.71 (Standard Deviation (SD):223.39) compared to 36.90 (SD:30.50) for female participants in the whole sample. Through network analysis, "Increased motor activity-energy" emerged as the central symptom, with the highest centrality expected influence, followed by "Emotional Instability" and "Disruptive/aggression behavior". Notably, "Emotional Instability" appeared to be the bridge symptom linking manic symptoms to aggressive behavior. Within the flow network model, "Speech rate and amount" exhibited the strongest positive correlation with testosterone levels, followed closely by "Disruptive/aggression behavior". The constructed network model demonstrated robust stability, with gender showing no significant impact on the structure. In this study, "Increased motor activity-energy" stood out as the most influential symptom, and "Speech rate and amount" acted as the main bridge symptom linking testosterone levels, aggressive behavior, and manic symptoms. Targeting the central and bridge symptoms may improve the outcomes of aggression interventions implemented among BD patients in psychiatric emergency care.

Resting-State Alpha Activity in the Frontal and Occipital Lobes and Assessment of Cognitive Impairment in Depression Patients.

Background: Major depressive disorder (MDD) becomes one of the psychiatric disorders characteristic of a combination of cognitive, emotional, and somatic symptoms. Additionally, cognitive impairment has the most significant impact on functional results. However, the evaluation of cognitive level is still based on various subjective questionnaires as there is no objective standard assessment yet. This research focuses on resting-state alpha activity to identify cognition in MDD patients using electroencephalography (EEG) signals. Methods: Ninety-two subjects were recruited: 44 patients with MDD and 48 healthy individuals as controls. Functional outcome and cognition were assessed using standardized instruments, and the EEG resting state signal of open and closed eyes was recorded. The comparison and correlation of cognitive levels with alpha power in the bilateral frontal region, bilateral central region, bilateral occipital region, and middle line was evaluated. Results: The relative alpha power in MDD group was significantly lower than that in the control group (P < 0.05). Through correlation analysis, it was shown that the bilateral frontal and occipital alpha power of MDD patients in the closed-eyes state was positively correlated with information processing rate, verbal learning, working memory, and attention retention. The alpha power of the bilateral frontal region in the open-eyes state was positively correlated with information processing rate, working memory, and attention retention (P < 0.05). Conclusion: The research indicates that the changes in frontal and occipital alpha activities may be a promising neurophysiological indicator of cognitive level to diagnose and treat response prediction.

Artificial intelligence technology and ultrasound-guided nerve block for analgesia in total knee arthroplasty.

BACKGROUND: Knee diseases are more common in middle-aged and elderly people, so artificial knee replacement is also more used in middle-aged and elderly people. Although the patient's pain can be reduced through surgery, often accompanied by moderate pain after surgery and neutralization, which not only increases the psychological burden of the patient, but also greatly reduces the postoperative recovery effect, and may also lead to the occurrence of postoperative adverse events in severe cases. AIM: To investigate the analgesic effect of artificial intelligence (AI) and ultrasound-guided nerve block in total knee arthroplasty (TKA). METHODS: A total of 92 patients with TKA admitted to our hospital from January 2021 to January 2022 were opted and divided into two groups according to the treatment regimen. The control group received combined spinal-epidural anesthesia. The research group received AI technique combined with ultrasound-guided nerve block anesthesia. The sensory block time, motor block time, visual analogue scale (VAS) at different time points and complications were contrasted between the two groups. RESULTS: The time of sensory block onset and sensory block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of sensory block in the research group was significantly longer than those in the control group (P < 0.05). The time of motor block onset and motor block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of motor block in the research group was significantly longer than those in the control group. The VAS scales of the research group were significantly lower than that of the control group at different time points (P < 0.05). The postoperative hip flexion and abduction range of motion in the research group were significantly better than those in the control group at different time points (P < 0.05). The incidence of complications was significantly lower in the research group than in the control group (P = 0.049). CONCLUSION: In TKA, the combination of AI technology and ultrasound-guided nerve block has a significantly effect, with fewer postoperative complications and significantly analgesic effect, which is worthy of application.

Agomelatine in the treatment of anhedonia, somatic symptoms, and sexual dysfunction in major depressive disorder.

Objective: This study evaluated the treatment outcomes of agomelatine on anhedonic state, anxiety/somatic symptoms, and sexual function in Chinese patients with major depressive disorder (MDD). Method: In total, 93 adult patients with MDD were enrolled, and 68 of them were included in a prospective, open-label, multicenter clinical study. All patients received agomelatine monotherapy during a 9-week treatment phase. The effectiveness of the treatment was reflected by the improvement of anhedonia and somatic symptoms based on the 17-item Hamilton Depression Rating Scale (HAMD-17). In addition, the Arizona Sexual Dysfunction Scale (ASEX), Sheehan Disability Scale (SDS), and Short Form of Quality-of-Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) were administered to all participants at baseline and at the 3-, 6-, and 9-week follow-ups. Results: After 9 weeks of treatment with agomelatine, the response and remission rates were 73.5% and 39.7%, respectively. Somatic symptoms significantly improved at week 9 (p < 0.001), and significant effects were also observed on the HAMD anhedonia items (p < 0.001). The patients exhibited lower levels of disease severity (the SDS score dropped from 15.52 ± 4.7 to 7.09 ± 5.62 at week 9; the ASEX score dropped from 21.89 ± 4.06 to 16.19 ± 4.79, p < 0.001) and higher levels of QOL (the Q-LES-Q-SF score dropped from 41.02 ± 5.99 to 50.49 ± 8.57, p < 0.001) during the follow-up. Furthermore, treatment with agomelatine improved depressive symptoms without causing serious adverse events. Conclusion: These analyses indicate that agomelatine is a treatment option for improving anhedonic status, anxiety/somatic symptoms, and sexual dysfunction in MDD patients.

Cognitive reserve in patients with mood disorders: Validation study of the Chinese version of the cognitive reserve assessment scale in health.

BACKGROUND: Cognitive reserve (CR) is closely associated with cognitive and functional outcome, disease severity, progression and prognosis in psychiatric patients; however, it has not been extensively tested in mood disorders. This study examined the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH) in mood disorder patients. METHODS: Altogether 166 subjects were recruited, 44 with major depressive disorder (MDD), 64 with bipolar disorder (BD), and 58 healthy controls. CR was assessed using the CRASH and the Cognitive Reserve Questionnaire (CRQ). RESULTS: Internal consistency (Cronbach's alpha) was 0.779 for the CRASH. The Receiver Operating Characteristic (ROC) curve analysis revealed an area under the ROC curve (AUC) value of 0.73 (95 % CI: 0.647-0.809). The optimal cut-off score of 51 generated the best combination of sensitivity (0.78) and specificity (0.43) for discriminating between patients with mood disorders and healthy controls. The CRASH score was highly correlated with the CRQ score in both mood disorder patients (rs = 0.586, P < 0.001) and healthy controls (rs = 0.627, P < 0.001), indicating acceptable convergent validity for the CRASH. Within the mood disorder sample, the CRASH score was associated with functional outcomes (FAST: rs = -0.243, P = 0.011). CONCLUSIONS: The CRASH is a useful tool to measure CR in mood disorder with acceptable psychometric properties and could be used in both research and clinical practice.

Suicidality and its associated factors among mood disorder patients in emergency department in China: a comparative study using propensity score matching approach.

Suicidality in mood disorder patients is common, especially in emergency department (ED), but the patterns and associated factors of suicidality are not clear. This study compared biomarkers and mental health symptoms (i.e., depression, anxiety, and psychiatric symptoms) between mood disorder patients with and without the whole range of suicidality comprising suicidal ideation (SI), suicide plan (SP), and suicide attempt (SA). This cross-sectional, comparative, convenient-sampling study was conducted between January 2021 and March 2022, in emergency department of Beijing Anding Hospital, China. Patients with mood disorders at a psychiatric emergency department were assessed, with measurements of suicidality, biomarkers, depressive, anxiety, and psychiatric symptoms were assessed using the 24 items-Hamilton Depression Rating Scale (HAMD-24), Hamilton Anxiety Rating Scale (HAMA), Young Manic Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS), respectively. The propensity score matching (PSM) method was used to identify patients in mood disorder with and without SI, SP, and SA. A generalized linear model (GLM) was used to assess the differences in biomarkers, depressive, anxiety, and psychiatric symptoms between patients in mood disorder with and without SI, SP, and SA. In total, 898 participated in this survey and completed the assessment. Illness duration was significantly negatively associated with SA (OR = 0.969, 95%CI = 0.939-0.999, P = 0.046). HAMD-24 total score was significantly positively associated with the SI (OR = 1.167, 95%CI = 1.134-1.201, p < 0.001), SP (OR = 1.159, 95%CI = 1.126-1.192, p < 0.001) and SA (OR = 1.189, 95%CI = 1.144-1.235, p < 0.001) of the matched samptched sample. However, YMRS total score was significantly negatively associated with the SI (OR = 0.928, 95%CI = 0.905-0.951, p < 0.001), SP (OR = 0.920, 95%CI = 0.897-0.944, p < 0.001) and SA (OR = 0.914, 95%CI = 0.890-0.938, p < 0.001) of the matched sample after adjusting for age, gender, marital status, and occupation. The duration of illness, severity of depressive symptoms and severity of manic symptoms appeared to be more likely to influence suicidality. Considering the significant risk of suicide in mood disorders on psychiatric emergency care, timely treatment and effective management of suicidality in this population group need to be developed.

Network analysis of comorbid depression, suicidality and biomarkers on HPA axis among mood disorder patients to psychiatric emergency services.

Rapid assessment and intervention of suicide risk are common and challenging in psychiatric emergency departments (PED). It is unclear whether distinct pathophysiological processes exist among depressive patients with suicidality. This study examined the network structures of biomarkers on Hypothalamic-Pituitary-Adrenal (HPA) axis, such as Adrenocorticotropic hormone (ACTH) and Corticosterone (Cort), as well as suicidality and depressive symptoms in mood disorder patients in PED. Mood disorder patients in PED were assessed with the measurements of suicidality and depressive symptoms, respectively. A network analysis was performed to identify central symptoms and bridge symptoms of this network and their links to ACTH and Cort. Network stability was examined using the case-dropping procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. A total of 1815 mood disorder patients were recruited. The prevalence of SI was 31.2% (95% CI: 28.15-34.21%), SP was 30.4% (95% CI: 27.39-33.41%), SA was 30.62% (95% CI: 27.61-33.64%) among psychiatric outpatients. The mean score of HAMD-24 was 13.87 ± 8.02. Network analysis revealed that 'Somatic anxiety' had the highest expected centrality, followed by 'Hopelessness' and 'Suicide attempt'. 'Corticosterone' and 'Retardation' may be the main bridge symptoms between depressive symptoms and the suicidality community. The network model showed a high degree of stability. Gender did not significantly influence the network structure. The central symptoms and key bridge symptoms identified could be potential targets for interventions of the HPA axis, which is designed for regular screening of a range of suicidal activity. In the light of this, timely treatment should be provided for psychiatric emergency care.

Heart failure and depression: A perspective from bibliometric analysis.

Background: Depression commonly occurs in heart failure patients, and negatively influences quality of life and disease prognosis. This study explored heart failure and depression-related research from a bibliometric perspective. Methods: Relevant publications were searched on June 24, 2022. The Bibliometrix package in R was used to conduct quantitative analyses including the trends in publications, and related countries, articles, authors and keywords. VOSviewer software was used to conduct the visualization map on co-word, co-author, and institution co-authorship analyses. CiteSpace software was used to illustrate the top keywords with citation burst. Results: A total of 8,221 publications in the heart failure and depression-related research field were published between 1983 and 2022. In this field, the United States had the most publications (N = 3,013; 36.65%) and highest total citation (N = 149, 376), followed by China, Germany, Italy and Japan. Author Moser and Duke University were the most productive author and institution, respectively. Circulation is the most influential journal. Apart from "heart failure" and "depression," "quality of life," "mortality" and "myocardial infarction" were the most frequently used keywords in this research area; whereas more recently, "self care" and "anxiety" have been used more frequently. Conclusion: This bibliometric analysis showed a rapid growth of research related to heart failure and depression from 1989 to 2021, which was mostly led by North America and Europe. Future directions in this research area include issues concerning self-care and anxiety about heart failure. As most of the existing literature were published in English, publications in other languages should be examined in the future.

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

A comparison of aggression between patients with acute schizophrenia and mania presenting to psychiatric emergency services.

OBJECTIVE: Aggression is common and challenging in psychiatric emergency departments (PED). However, the prevalence of aggression and its correlates in PED patients are not well documented. This study compared the prevalence of aggression between patients with acute schizophrenia and manic episodes. METHODS: In this cross-sectional study, patients at a psychiatric emergency department were assessed with measurements of aggression, psychotic and manic symptoms. RESULTS: A total of 4,172 patients were included. The prevalence of aggression was 54.8% (95%CI=53.3%-65.2%) in the whole sample, with 48.0% (95%CI=45.8%-50.1%) in patients with an acute schizophrenia episode, and 61.8% (95%CI=59.8%-63.9%) in patients with a manic episode. Multiple logistic regression analysis revealed that, within the acute schizophrenia episode group, male gender (OR=1.47, P<0.01), involuntary admission (OR=3.61, P<0.01) and more severe manic symptoms (OR=1.30, P<0.01) were significantly associated with aggression. Within the manic episode group, living in Beijing (OR=1.51, P<0.01), unemployment (OR=1.34, P=0.03), involuntary admission (OR=7.93, P<0.01), lower education (OR=0.95, P=0.01) and more severe psychotic symptoms (OR=1.05, P<0.01) were significantly associated with aggression. CONCLUSION: In this study, aggression appeared to be more common among patients with a manic episode than those with an acute schizophrenia episode. Considering the significant risk of aggression on psychiatric emergency care, appropriate and effective management of aggression in this population group need to be developed.

Cyberbully victimization and its association with residual depressive symptoms among clinically stable adolescents with psychiatric disorders during the COVID-19 pandemic: A perspective from network analysis.

Objective: This study examined the prevalence of cyberbullying and its relationship with residual depressive symptoms in this patient population during the COVID-19 outbreak using network analysis. Methods: This was a multicenter, cross-sectional study. Adolescent patients attending maintenance treatment at outpatient departments of three major psychiatric hospitals were included. Experience of cyberbullying was measured with a standard question, while the severity of Internet addiction and depressive symptoms were measured using the Internet Addiction Test and the Patient Health Questionnaire-9, respectively. The network structure of depression and cyberbully were characterized and indices of "Expected Influence" was used to identify symptoms central to the network. To identify particular symptoms that were directly associated with cyberbully, the flow function was used. Results: Altogether 1,265 patients completed the assessments. The overall prevalence of cyberbullying was 92.3% (95% confidence interval (CI): 90.8-93.7%). Multiple logistic regression analysis revealed that male gender (p = 0.04, OR = 1.72, 95%CI: 1.04-2.85) was significantly associated with higher risk of cyberbullying, while a relapse of illness during the COVID-19 pandemic was significantly associated with a lower risk of cyberbullying (p = 0.03, OR = 0.50, 95%CI: 0.27-0.93). In the network of depression and cyberbully, "Sad mood," "Anhedonia" and "Energy" were the most central (influential) symptoms. Furthermore, "Suicidal ideation" had the strongest negative association with cyberbully followed by "Guilt". Conclusion: During the COVID-19 pandemic, the experience of cyberbullying was highly prevalent among clinically stable adolescent psychiatric patients, particularly male patients. This finding should raise awareness of this issue emphasizing the need for regular screening and interventions for adolescent patients. Central symptoms (e.g., "Sad mood," "Anhedonia" and "Energy") identified in this study should be targeted in interventions and preventive measures.

Prevalence of Suicidality in Major Depressive Disorder: A Systematic Review and Meta-Analysis of Comparative Studies.

Background: Suicidality is common in major depressive disorder (MDD), but there has been no systematic review published about all aspects of suicidality. This meta-analysis and systematic review compared the prevalence of the whole range of suicidality comprising suicidal ideation (SI), suicide plan (SP), suicide attempt (SA), and completed suicide (CS), between patients with MDD and non-MDD controls. Methods: Major international (PubMed, PsycINFO, Web of Science, EMBASE) and Chinese (Chinese Nation Knowledge Infrastructure and WANFANG) databases were systematically and independently searched from their inception until January 12, 2021. Results: Fifteen studies covering 85,768 patients (12,668 in the MDD group and 73,100 in the non-MDD group) were included in the analyses. Compared to non-MDD controls, the odds ratios (ORs) for lifetime, past month, past year, and 2-week prevalence of SI in MDD were 2.88 [95% confidence interval (CI) = 0.30-27.22, p = 0.36], 49.88 (95% CI = 2-8.63, p < 0.001), 13.97 (95% CI = 12.67-15.41, p < 0.001), and 24.81 (95% CI = 15.70-39.22, p < 0.001), respectively. Compared to non-MDD controls, the OR for lifetime SP in MDD was 9.51 (95% CI = 7.62-11.88, p < 0.001). Compared to non-MDD controls, the ORs of lifetime and past-year prevalence of SA were 3.45 (95% CI = 1.58-7.52, p = 0.002), and 7.34 (95% CI = 2.14-25.16, p = 0.002), respectively, in MDD patients. No difference in the prevalence of CS between MDD and controls was found (OR = 0.69, 95% CI = 0.23-2.02, p = 0.50). Conclusions: MDD patients are at a higher risk of suicidality, compared to non-MDD controls. Routine screening for a range of suicidality should be included in the management of MDD, followed by timely treatment for suicidal patients. Systematic Review Registration: Identifier [INPLASY202120078].

Workplace violence and its association with quality of life among mental health professionals in China during the COVID-19 pandemic.

OBJECTIVE: Mental health professionals are often exposed to workplace violence (WPV) in China. This study examined the prevalence of WPV and the associated factors and quality of life (QOL) among frontline mental health professionals during the COVID-19 pandemic. METHODS: This national survey was carried out between March 15 and March 20, 2020. WPV and QOL were assessed with standardized measures. RESULTS: A total of 10,516 participants were included. The prevalence of overall WPV was 18.5% (95% CI: 17.9%-19.3%), while verbal abuse/threats was 15.8% and physical violence was 8.4%. Multiple logistic regression analysis revealed that male gender (OR = 1.42, p < 0.01), higher educational level (OR = 1.40, p < 0.01), working in tertiary hospitals (OR = 1.33, p < 0.01), caring for COVID-19 patients (OR = 3.10, p < 0.01) and having more severe anxiety symptom (OR = 1.21, p < 0.01) were positively associated with WPV. In contrast, working in inpatient departments (OR = 0.74, p < 0.01), having longer work experience (OR = 0.99, p = 0.03), and being a junior nurse (OR = 0.73, p < 0.01) were negatively associated with WPV. After controlling for the covariates, mental health professionals who experienced WPV had a lower overall QOL compared to those without WPV (F(1, 10515) = 68.28, p < 0.01). CONCLUSION: This study found that WPV was common among mental health professionals in China during the COVID-19 pandemic. Considering the negative impact of WPV on QOL and quality of patient care, appropriate measures to prevent WPV should be developed.

Suppressed Calbindin Levels in Hippocampal Excitatory Neurons Mediate Stress-Induced Memory Loss.

Calbindin modulates intracellular Ca2+ dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.

Early postnatal stress suppresses the developmental trajectory of hippocampal pyramidal neurons: the role of CRHR1.

Adverse experiences early in life hamper the development and maturation of the hippocampus, but how early-life stress perturbs the developmental trajectory of the hippocampus across various life stages and the underlying molecular mechanisms remain to be investigated. In this study, we stressed male mice from postnatal day 2 (P2) to P9, and examined the potential role of CRHR1 in postnatal stress-induced structural remodeling of hippocampal CA3 pyramidal neurons directly after stress (P9), in mid-adolescence (P35) and in adulthood (P90). We found that early-life stress exposure significantly reduced apical dendritic arborization and spine density in CA3 neurons on P9 and P90. Moreover, postnatally stressed neurons underwent increased pruning of spines, especially thin spines, between P35 and P90. These stress-induced immediate and long-term structural abnormalities could be abolished by daily systemic administration of the CRHR1 antagonist antalarmin (20 µg/g of body weight) during stress exposure. However, such treatment strategy failed to attenuate the deleterious stress effects in mid-adolescence on P35. We then extended antalarmin treatment until the end of the second postnatal week, and found that prolonged blockade of CRHR1 could prevent the mid-term impact of early postnatal stress on structural remodeling of CA3 neurons. Our study characterized the influences of early-life stress on the developmental trajectory of hippocampal pyramidal neurons, and highlighted the critical role of CRHR1 in modulating these negative outcomes evoked by early-life stress.

Dual gRNAs guided CRISPR/Cas9 system inhibits hepatitis B virus replication.

AIM: To screen and investigate the effective gRNAs against hepatitis B virus (HBV) of genotypes A-D. METHODS: A total of 15 gRNAs against HBV of genotypes A-D were designed. Eleven combinations of two above gRNAs (dual-gRNAs) covering the regulatory region of HBV were chosen. The efficiency of each gRNA and 11 dual-gRNAs on the suppression of HBV (genotypes A-D) replication was examined by the measurement of HBV surface antigen (HBsAg) or e antigen (HBeAg) in the culture supernatant. The destruction of HBV-expressing vector was examined in HuH7 cells co-transfected with dual-gRNAs and HBV-expressing vector using polymerase chain reaction (PCR) and sequencing method, and the destruction of cccDNA was examined in HepAD38 cells using KCl precipitation, plasmid-safe ATP-dependent DNase (PSAD) digestion, rolling circle amplification and quantitative PCR combined method. The cytotoxicity of these gRNAs was assessed by a mitochondrial tetrazolium assay. RESULTS: All of gRNAs could significantly reduce HBsAg or HBeAg production in the culture supernatant, which was dependent on the region in which gRNA against. All of dual gRNAs could efficiently suppress HBsAg and/or HBeAg production for HBV of genotypes A-D, and the efficacy of dual gRNAs in suppressing HBsAg and/or HBeAg production was significantly increased when compared to the single gRNA used alone. Furthermore, by PCR direct sequencing we confirmed that these dual gRNAs could specifically destroy HBV expressing template by removing the fragment between the cleavage sites of the two used gRNAs. Most importantly, gRNA-5 and gRNA-12 combination not only could efficiently suppressing HBsAg and/or HBeAg production, but also destroy the cccDNA reservoirs in HepAD38 cells. CONCLUSION: These results suggested that CRISPR/Cas9 system could efficiently destroy HBV expressing templates (genotypes A-D) without apparent cytotoxicity. It may be a potential approach for eradication of persistent HBV cccDNA in chronic HBV infection patients.

Stress during a critical postnatal period induces region-specific structural abnormalities and dysfunction of the prefrontal cortex via CRF1.

During the early postnatal period, environmental influences play a pivotal role in shaping the development of the neocortex, including the prefrontal cortex (PFC) that is crucial for working memory and goal-directed actions. Exposure to stressful experiences during this critical period may disrupt the development of PFC pyramidal neurons and impair the wiring and function of related neural circuits. However, the molecular mechanisms of the impact of early-life stress on PFC development and function are not well understood. In this study, we found that repeated stress exposure during the first postnatal week hampered dendritic development in layers II/III and V pyramidal neurons in the dorsal agranular cingulate cortex (ACd) and prelimbic cortex (PL) of neonatal mice. The deleterious effects of early postnatal stress on structural plasticity persisted to adulthood only in ACd layer V pyramidal neurons. Most importantly, concurrent blockade of corticotropin-releasing factor receptor 1 (CRF1) by systemic antalarmin administration (20 µg/g of body weight) during early-life stress exposure prevented stress-induced apical dendritic retraction and spine loss in ACd layer V neurons and impairments in PFC-dependent cognitive tasks. Moreover, the magnitude of dendritic regression, especially the shrinkage of apical branches, of ACd layer V neurons predicted the degree of cognitive deficits in stressed mice. Our data highlight the region-specific effects of early postnatal stress on the structural plasticity of prefrontal pyramidal neurons, and suggest a critical role of CRF1 in modulating early-life stress-induced prefrontal abnormalities.