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White matter alterations associated with chronic cannabis use disorder: a structural network and fixel-based analysis. 与慢性大麻使用障碍相关的白质改变:基于结构网络和固定颗粒的分析。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-11 DOI: 10.1038/s41398-024-03150-0
Suzan Maleki, Joshua Hendrikse, Karyn Richardson, Rebecca A Segrave, Sam Hughes, Edouard Kayayan, Stuart Oldham, Warda Syeda, James P Coxon, Karen Caeyenberghs, Juan F Domínguez D, Nadia Solowij, Dan I Lubman, Chao Suo, Murat Yücel

Cannabis use disorder (CUD) is associated with adverse mental health effects, as well as social and cognitive impairment. Given prevalence rates of CUD are increasing, there is considerable efforts, and need, to identify prognostic markers which may aid in minimising any harm associated with this condition. Previous neuroimaging studies have revealed changes in white matter (WM) organization in people with CUD, though, the findings are mixed. In this study, we applied MRI-based analysis techniques that offer complimentary mechanistic insights, i.e., a connectome approach and fixel-based analysis (FBA) to investigate properties of individual WM fibre populations and their microstructure across the entire brain, providing a highly sensitive approach to detect subtle changes and overcome limitations of previous diffusion models. We compared 56 individuals with CUD (median age 25 years) to a sample of 38 healthy individuals (median age 31.5 years). Compared to controls, those with CUD had significantly increased structural connectivity strength (FDR corrected) across 9 edges between the right parietal cortex and several cortical and subcortical regions, including left orbitofrontal, left temporal pole, and left hippocampus and putamen. Utilizing FBA, WM density was significantly higher in those with CUD (FWE-corrected) across the splenium of the corpus callosum, and lower in the bilateral cingulum and right cerebellum. We observed significant correlation between cannabis use over the past month and connectivity strength of the frontoparietal edge, and between age of regular use and WM density of the bilateral cingulum and right cerebellum. Our findings enhance the understanding of WM architecture alterations associated with CUD.

大麻使用障碍(CUD)与不良心理健康影响以及社会和认知障碍有关。鉴于 CUD 的患病率不断上升,人们正努力并需要确定预后标志物,以帮助最大限度地减少与这种疾病相关的任何危害。以往的神经影像学研究显示,CUD 患者的白质(WM)组织发生了变化,但研究结果不一。在这项研究中,我们应用了基于核磁共振成像的分析技术,这些技术提供了互补的机理见解,即连接组方法和基于固定点的分析(FBA),以研究整个大脑中单个白质纤维群的特性及其微观结构,提供了一种高灵敏度的方法来检测微妙的变化,并克服了以往扩散模型的局限性。我们将 56 名 CUD 患者(中位年龄为 25 岁)与 38 名健康人(中位年龄为 31.5 岁)进行了比较。与对照组相比,CUD 患者在右顶叶皮层与多个皮层和皮层下区域(包括左侧眶额叶、左侧颞极、左侧海马和丘脑)之间的 9 条边缘的结构连接强度显著增加(FDR 校正)。利用 FBA,在整个胼胝体脾中,CUD 患者的 WM 密度明显较高(经 FWE 校正),而在双侧钟乳体和右侧小脑中则较低。我们观察到,过去一个月吸食大麻与额顶叶边缘的连接强度之间、定期吸食大麻的年龄与双侧钟乳体和右侧小脑的 WM 密度之间存在明显的相关性。我们的研究结果加深了人们对与 CUD 相关的 WM 结构改变的理解。
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引用次数: 0
Association between social media use and depressive symptoms in middle-aged and older Chinese adults. 中国中老年人使用社交媒体与抑郁症状之间的关系。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-11 DOI: 10.1038/s41398-024-03142-0
Yanling Qi, Chenghe Zhang, Mei Zhou, Ruiyuan Zhang, Yuxiao Chen, Changwei Li

The burden of depressive symptoms among middle-aged and older Chinese during the COVID-19 pandemic is unclear, and the contribution of social media use to depressive symptoms in this population has not been studied. To address the gaps, we analyzed data from the China Health and Retirement Longitudinal Study, nationally representative biannual surveys among adults aged ≥45 years. Social media use and depressive symptoms were measured in the 2018 and 2020 surveys. We tested longitudinal associations between baseline (2018) social media activities and risk of depressive symptoms in two years among 9121 participants without depressive symptoms. We also evaluated whether social media activity could reduce depressive symptoms during this period among 5302 individuals with depressive symptoms at baseline. Depressive symptoms affected 36·0% of this population in 2020. Women, individuals living in rural areas, and residents of western China provinces were particularly affected. Among participants without depressive symptoms, engaging in social media activities at baseline was associated with a 24.0% (95% confidence interval [CI]: 10-36%) lower likelihood of developing depressive symptoms over the next two years. Among depressed participants, compared to individuals not using social media, those initiating three or more social media activities during this period had 1.24 (95% CI: 1.05-1.46) times higher chance of becoming non-depressed, and those using social media all the time were 1·36 (95% CI: 1·09-1·72) times more likely to become non-depressed. In conclusion, middle-aged and older Chinese adults have a substantial burden of depressive symptoms, and social media activities may help to prevent and reduce the symptoms.

在 COVID-19 大流行期间,中国中老年人的抑郁症状负担尚不明确,而社交媒体的使用对这一人群抑郁症状的影响也尚未研究。为了填补这些空白,我们分析了中国健康与退休纵向研究(China Health and Retirement Longitudinal Study)的数据,该研究每半年对年龄≥45 岁的成年人进行一次具有全国代表性的调查。在 2018 年和 2020 年的调查中测量了社交媒体的使用情况和抑郁症状。我们在 9121 名无抑郁症状的参与者中测试了基线(2018 年)社交媒体活动与两年后抑郁症状风险之间的纵向关联。我们还评估了基线有抑郁症状的 5302 人在此期间的社交媒体活动是否能减轻抑郁症状。2020 年,有抑郁症状的人群占总人口的 36-0%。女性、农村人口和中国西部省份的居民尤其受到影响。在没有抑郁症状的参与者中,基线时参与社交媒体活动与未来两年内出现抑郁症状的可能性降低 24.0%(95% 置信区间 [CI]:10-36%)有关。在抑郁症患者中,与不使用社交媒体的人相比,那些在此期间开始三次或三次以上社交媒体活动的人变得不抑郁的几率要高 1.24 倍(95% 置信区间:1.05-1.46),而那些一直使用社交媒体的人变得不抑郁的几率要高 1-36 倍(95% 置信区间:1-09-1-72)。总之,中国中老年人的抑郁症状负担沉重,而社交媒体活动可能有助于预防和减轻抑郁症状。
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引用次数: 0
Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder. 人类可卡因使用障碍中 DNA 甲基化和基因表达改变的多组学分析。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-09 DOI: 10.1038/s41398-024-03139-9
Eric Zillich, Hanna Belschner, Diana Avetyan, Diego Andrade-Brito, José Jaime Martínez-Magaña, Josef Frank, Naguib Mechawar, Gustavo Turecki, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Bru Cormand, Janitza L Montalvo-Ortiz, Markus M Nöthen, Anita C Hansson, Marcella Rietschel, Rainer Spanagel, Stephanie H Witt, Lea Zillich

Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.

大脑结构和功能的变化被认为是可卡因使用障碍(CUD)导致可卡因摄入过多、渴求和复吸的原因。表观遗传和转录变化被假定为 CUD 相关脑部改变的分子基础。在这里,我们利用布罗德曼第 9 区(BA9)的尸检脑组织,通过整合来自同一个体的表观遗传全甲基组(N = 42)和转录组(N = 25)数据,对 CUD 进行了多组学研究。在 N = 1 057 个差异表达基因(p
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引用次数: 0
Effects of depression and cognitive impairment on increased risks of incident dementia: a prospective study from three elderly cohorts. 抑郁症和认知障碍对增加痴呆症发病风险的影响:来自三个老年队列的前瞻性研究。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-08 DOI: 10.1038/s41398-024-03125-1
Yushun Yan, Hailin Xiang, Min Wang, Jinxue Wei, Huanhuan Fan, Yue Du, Yuanmei Tao, Yikai Dou, Yangrui Ma, Xiao Yang, Xiaohong Ma

Depression is usually accompanied with cognitive impairment and increases risk of incident dementia. However, evidence has been limited on the effect size of depression with cognitive impairment and their synergistic effect on future dementia. To explore this, we examined three large cross-country population-based prospective cohorts. Depressive symptoms were assessed by epidemiologic scale, while cognitive impairment was defined by subjective cognitive tests. Dementia was ascertained by self-reported physician-diagnosed conditions. Cox proportional hazard models were employed to determine the hazard ratio (HR) and 95% confidence interval (95% CI), with adjustments of potential confounding variables. Addictive and multiplicative interactions were calculated to evaluate the synergistic effect. A total of 64,706 participants were included at baseline (mean age: 63.9, female: 55.2%), where 4197 (6.5%) individuals had depressive symptoms only, 28,175 (43.5%) individuals had cognitive impairment only, 11,564 (17.9%) individuals had both, and 20,770 (32.1%) individuals had neither. Compared with the neither group, all the other three groups had higher risks of subsequent dementia (depression only: HR 1.65, 95% CI 1.26-2.17; cognitive impairment only: HR 2.71, 95% CI 2.33-3.14; depression with cognitive impairment: HR 3.51, 95% CI 2.95-4.17). There was insignificant additive (RERI, 0.15, 95% CI -0.45-0.75; AP, 0.042, 95% CI -0.13-0.21; SI, 1.06, 95% CI 0.83-1.37) and multiplicative (0.78, 95% CI 0.58-1.06) interaction between depression and cognitive impairment on subsequent dementia. We found depression with cognitive impairment has higher risks of dementia than either condition alone and no significant synergistic effect exists between these two factors.

抑郁症通常伴有认知障碍,会增加罹患痴呆症的风险。然而,关于抑郁症与认知障碍的效应大小以及它们对未来痴呆症的协同效应的证据还很有限。为了探讨这一问题,我们研究了三个大型跨国人群前瞻性队列。抑郁症状通过流行病学量表进行评估,认知障碍则通过主观认知测试进行界定。痴呆症通过自我报告的医生诊断情况来确定。在对潜在混杂变量进行调整后,采用 Cox 比例危险模型确定危险比(HR)和 95% 置信区间(95% CI)。计算了成瘾性和乘法交互作用,以评估协同效应。基线研究共纳入 64706 名参与者(平均年龄:63.9 岁,女性:55.2%),其中 4197 人(6.5%)仅有抑郁症状,28175 人(43.5%)仅有认知障碍,11564 人(17.9%)两者都有,20770 人(32.1%)两者都没有。与两组均无痴呆症的患者相比,其他三组患者罹患痴呆症的风险都更高(仅有抑郁症:HR 1.65,95% CI 1.26-2.17;仅有认知障碍:HR 2.71,95% CI 2.33-3.14;抑郁症伴有认知障碍:HR 3.51,95% CI 2.33-3.14):HR 3.51,95% CI 2.95-4.17)。抑郁症和认知障碍对继发性痴呆的交互作用不显著(RERI, 0.15, 95% CI -0.45-0.75;AP, 0.042, 95% CI -0.13-0.21;SI, 1.06, 95% CI 0.83-1.37),而两者之间的交互作用是相乘的(0.78, 95% CI 0.58-1.06)。我们发现,抑郁症合并认知障碍的痴呆症风险高于单独两种情况,这两种因素之间不存在显著的协同效应。
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引用次数: 0
Importin α4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice. 导入蛋白α4缺乏会诱导小鼠出现精神障碍相关的行为缺陷和神经炎症。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-08 DOI: 10.1038/s41398-024-03138-w
Koki Sakurai, Makiko Morita, Yoshiatsu Aomine, Mitsunobu Matsumoto, Tetsuji Moriyama, Emiko Kasahara, Atsuo Sekiyama, Mayumi Otani, Rieko Oshima, Kate L Loveland, Masami Yamada, Yoshihiro Yoneda, Masahiro Oka, Takatoshi Hikida, Yoichi Miyamoto

Importin α4, which is encoded by the Kpna4 gene, is a well-characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-κB. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, decreased social interaction, and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-κB activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-κB genes and proinflammatory cytokines such as TNFα, Il-1β or Il-6 in the prefrontal cortex or basolateral amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full length, but also a nuclear transport-deficient truncation mutant of importin α4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult microglia and astrocytes and subsequent transcription factor analysis suggested increases in polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin α4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.

由 Kpna4 基因编码的导入素 α4 是一种特征明确的核-细胞质转运因子,已知它能介导转录因子(包括 NF-κB)的转运。在这里,我们报告了 Kpna4 基因敲除(KO)小鼠表现出与精神障碍相关的行为异常,如焦虑相关行为、社会交往减少和感觉运动门控缺陷。与之前的研究预测 Kpna4 缺失会导致 NF-κB 活性减弱相反,我们在 KO 小鼠的前额叶皮层或杏仁基底外侧观察到 NF-κB 基因和促炎细胞因子(如 TNFα、Il-1β 或 Il-6)的表达水平显著增加。此外,对原代细胞炎症反应的研究发现,Kpna4 缺陷细胞的炎症反应增加,而加入全长的导入蛋白 α4,以及核转运缺陷的截短突变体后,炎症反应都得到了缓解,这表明导入蛋白 α4 的非转运功能也起到了作用。此外,对分选的成体小胶质细胞和星形胶质细胞进行的 RNAseq 以及随后的转录因子分析表明,Kpna4 KO 细胞中多聚核抑制因子复合体 2(PRC2)的活性增加。综上所述,导入素α4缺乏会诱导小鼠出现精神障碍相关的行为缺陷,同时炎症反应加剧,神经胶质细胞中PRC2的活性也可能发生改变。
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引用次数: 0
The association between patterns of exposure to adverse life events and the risk of chronic kidney disease: a prospective cohort study of 140,997 individuals. 不良生活事件暴露模式与慢性肾脏病风险之间的关系:对 140,997 人进行的前瞻性队列研究。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-07 DOI: 10.1038/s41398-024-03114-4
Chunyang Li, Jie Chen, Yilong Chen, Chao Zhang, Huazhen Yang, Shaobin Yu, Huan Song, Ping Fu, Xiaoxi Zeng

Exposure to adverse life events is linked to somatic disorders. The study aims to evaluate the association between adverse events at varying life stages and the risk of chronic kidney disease (CKD), a condition affecting about 10% population worldwide. This prospective cohort study included 140,997 participants from the UK Biobank. Using survey items related to childhood maltreatment, adulthood adversity and catastrophic trauma, we performed latent class analysis to summarize five distinct patterns of exposure to adverse life events, namely "low-level exposure", "childhood exposure", "adulthood exposure", "sexual abuse" and "child-to-adulthood exposure". We used Cox proportional hazard regression to evaluate the association of patterns of exposure to adverse life events with CKD, regression-based mediation analysis to decompose the total effect, and gene-environment-wide interaction study (GEWIS) to identify interactions between genetic loci and adverse life events. During a median follow-up of 5.98 years, 2734 cases of incident CKD were identified. Compared with the "low-level exposure" pattern, "child-to-adulthood exposure" was associated with increased risk of CKD (hazard ratio 1.37, 95% CI 1.14 to 1.65). BMI, smoking and hypertension mediated 11.45%, 9.79%, and 4.50% of this total effect, respectively. Other patterns did not show significant results. GEWIS and subsequent analyses indicated that the magnitude of the association between adverse life events and CKD differed according to genetic polymorphisms, and identified potential underlying pathways (e.g., interleukin 1 receptor activity). These findings underscore the importance of incorporating an individual's psychological encounters and genetic profiles into the precision prevention of CKD.

不良生活事件与躯体疾病有关。这项研究旨在评估不同生命阶段的不良事件与慢性肾脏病(CKD)风险之间的关系。这项前瞻性队列研究包括来自英国生物库的 140,997 名参与者。利用与童年虐待、成年期逆境和灾难性创伤相关的调查项目,我们进行了潜类分析,总结出了五种不同的不良生活事件暴露模式,即 "低水平暴露"、"童年期暴露"、"成年期暴露"、"性虐待 "和 "儿童至成年期暴露"。我们采用 Cox 比例危险回归评估不良生活事件暴露模式与 CKD 的关系,采用基于回归的中介分析分解总效应,并采用全基因环境交互作用研究(GEWIS)确定基因位点与不良生活事件之间的交互作用。在中位 5.98 年的随访期间,共发现了 2734 例慢性肾功能衰竭病例。与 "低水平暴露 "模式相比,"儿童至成年期暴露 "与慢性肾脏病风险增加有关(危险比为1.37,95% CI为1.14至1.65)。体重指数、吸烟和高血压分别占总影响的 11.45%、9.79% 和 4.50%。其他模式没有显示出明显的结果。GEWIS 和后续分析表明,不良生活事件与慢性肾脏病之间的关联程度因基因多态性而异,并确定了潜在的潜在途径(如白细胞介素 1 受体活性)。这些发现强调了将个人的心理遭遇和遗传特征纳入 CKD 精准预防的重要性。
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引用次数: 0
Circadian clock dysregulation: a potential mechanism of depression in obstructive sleep apnea patients. 昼夜节律失调:阻塞性睡眠呼吸暂停患者抑郁的潜在机制。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-07 DOI: 10.1038/s41398-024-03134-0
Agata Gabryelska, Szymon Turkiewicz, Piotr Kaczmarski, Adrian Gajewski, Piotr Białasiewicz, Dominik Strzelecki, Maciej Chałubiński, Marcin Sochal

Obstructive sleep apnea (OSA) is characterized by co-occurrence with affective disorders. Our study aims to investigate the association of circadian clock gene expressions, and the presence and severity of depressive symptoms in OSA patients. The study included 184 individuals, who underwent polysomnography (PSG) and had their peripheral blood collected in the evening before and the morning after the PSG. Patients were divided into two groups: the OSA (apnea-hypopnea index (AHI) > 5) and the control group (AHI < 5). RNA was extracted from peripheral blood leukocytes. Expression levels of the selected genes (BMAL1, CLOCK, PER1, CRY1, NPAS2, and NR1D1) were assessed by qRT-PCR. Questionnaire data was collected in the morning (including the Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Chronotype Questionnaire (CQ), and Montgomery-Åsberg Depression Rating Scale (MADRS)). The expression of all examined circadian clock genes in OSA patients was upregulated in the morning compared to the evening (except NPAS2). No differences were observed between OSA and control groups at either time point. Additionally, there was a positive correlation between the severity of depressive symptoms (assessed with MADRS) and morning expression of circadian genes in the group of OSA patients. Finally, in multivariable linear regression, ISI score (B = 0.750, p < 0.001), AM score of CQ (B = 0.416, p = 0.007), and morning PER1 gene expression (B = 4.310, p = 0.042) were found to be predictive factors for greater severity of depression symptoms in OSA patients. Dysregulated circadian clock gene expression in OSA patients is linked to depressive symptom severity, suggesting circadian disruption may underlie affective symptoms in OSA.

阻塞性睡眠呼吸暂停(OSA)的特点是与情感障碍并存。我们的研究旨在探讨昼夜节律时钟基因表达与 OSA 患者抑郁症状的存在和严重程度之间的关联。这项研究包括 184 名接受多导睡眠图(PSG)检查的患者,并在 PSG 检查的前一天晚上和第二天早上采集了他们的外周血。患者被分为两组:OSA(呼吸暂停-低通气指数(AHI)大于 5)和对照组(AHI
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引用次数: 0
Restoring social deficits in IRSp53-deleted mice: chemogenetic inhibition of ventral dentate gyrus Emx1-expressing cells. 恢复 IRSp53 缺失小鼠的社交障碍:对腹侧齿状回 Emx1 表达细胞的化学抑制。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-07 DOI: 10.1038/s41398-024-03104-6
Su Hyun Kim, Bomee Lee, Seong Mi Lee, Yangsik Kim

IRSp53 is a synaptic scaffold protein reported to be involved in schizophrenia, autism spectrum disorders, and social deficits in knockout mice. Identifying critical brain regions and cells related to IRSp53 deletion is expected to be of great help in the treatment of psychiatric problems. In this study, we performed chemogenetic inhibition within the ventral dentate gyrus (vDG) of mice with IRSp53 deletion in Emx1-expressing cells (Emx1-Cre;IRSp53 flox/flox). We observed the recovery of social deficits after chemogenetic inhibition within vDG of Emx1-Cre;IRSp53 flox/flox mice. Additionally, chemogenetic activation induced social deficits in Emx1-Cre mice. CRHR1 expression increased in the hippocampus of Emx1-Cre;IRSp53 flox/flox mice, and CRHR1 was reduced by chemogenetic inhibition. Htd2, Ccn1, and Atp61l were decreased in bulk RNA sequencing, and Eya1 and Ecrg4 were decreased in single-cell RNA sequencing of the hippocampus in Emx1-Cre;IRSp53 flox/flox mice compared to control mice. This study determined that the vDG is a critical brain region for social deficits caused by IRSp53 deletion. Social deficits in Emx1-Cre;IRSp53 flox/flox mice were recovered through chemogenetic inhibition, providing clues for new treatment methods for psychiatric disorders accompanied by social deficits.

据报道,IRSp53 是一种突触支架蛋白,与精神分裂症、自闭症谱系障碍和基因敲除小鼠的社交障碍有关。识别与IRSp53缺失相关的关键脑区和细胞有望对精神疾病的治疗大有帮助。在这项研究中,我们对表达Emx1细胞(Emx1-Cre;IRSp53 flox/flox)的IRSp53缺失小鼠腹侧齿状回(vDG)进行了化学抑制。我们观察到,在Emx1-Cre;IRSp53 flox/flox小鼠的vDG内进行化学抑制后,社交障碍得到了恢复。此外,化学遗传激活也诱发了Emx1-Cre小鼠的社交障碍。CRHR1在Emx1-Cre;IRSp53 floatx/flox小鼠海马中的表达增加,CRHR1在化学基因抑制下减少。与对照组小鼠相比,Emx1-Cre;IRSp53 flox/flox小鼠海马的大体RNA测序结果显示Htd2、Ccn1和Atp61l减少,单细胞RNA测序结果显示Eya1和Ecrg4减少。这项研究确定,vDG是IRSp53缺失导致社交障碍的关键脑区。Emx1-Cre;IRSp53缺失/flox小鼠的社交障碍可通过化学抑制恢复,这为伴有社交障碍的精神疾病的新治疗方法提供了线索。
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引用次数: 0
Trajectories and predictors of suicidal ideation in clinical characteristics and pharmacological treatments for major depressive disorder: a study based on a national multi-centered prospective cohort. 重度抑郁障碍临床特征和药物治疗中自杀意念的轨迹和预测因素:基于全国多中心前瞻性队列的研究。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-06 DOI: 10.1038/s41398-024-03115-3
Ruoxi Ding, Xuequan Zhu, Lei Feng, Le Xiao, Ling Zhang, Ping He, Gang Wang

Suicidal ideation (SI) is a significant precursor and risk marker for suicide behaviors in major depressive disorder (MDD). Exploration of SI trajectory from a longitudinal framework are essential for treatment guidelines and clinical management of suicide risk. This study sought to explore SI trajectories and its associated clinical, sociodemographic characteristics, and initial treatment among patients with MDD. We used data from a non-interventional, national multi-centered prospective cohort study. 1 461 patients with MDD were included in the growth mixture modeling using SI at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 6 months, 9 months, and 12 months as the indicator. A multinomial regression was employed with SI trajectory as the outcome and anhedonia, depressive symptoms, atypical depressive symptoms, pharmacological treatments, and other covariates as the predictors. Four distinct SI trajectories were identified: a consistently low SI trajectory(50.7%), a persistently mild SI trajectory(20.6%), a fast declined SI trajectory(8.9%), and a slowly declined trajectory(19.8%). Compared to those with a consistently low SI trajectory, a higher score of anhedonia was associated with an increased risk of experiencing persistently mild (RRR = 1.20, 95%CI: 1.05, 1.38) and slowly declined SI (1.54, 95%CI: 1.32, 1.80). Severity of depressive symptom was also positively associated with the risk of experiencing persistently mild (1.15, 95%CI: 1.13, 1.18) and slowly declined SI (1.17, 95%CI: 1.14, 1.21). And the risk of experiencing slowly declined SI was higher for those use SSRI(1.49, 95%CI: 1.02, 2.31), and for those use antidepressant and antipsychotic/mood stabilizer combined therapy (3.78, 95%CI: 1.48, 9.61). The findings of this study are potentially useful for clinical practice as critical indicators of profiles and interventions for prognosis among patients with MDD. Further research is warranted to explore potential modifiable factors and the association between SI trajectories and suicide behavior.

自杀意念(SI)是重度抑郁障碍(MDD)患者自杀行为的重要前兆和风险标志。从纵向框架中探索自杀意念的轨迹对于自杀风险的治疗指南和临床管理至关重要。本研究旨在探索 SI 轨迹及其相关的临床、社会人口学特征以及 MDD 患者的初始治疗。我们使用了一项非干预性、全国性多中心前瞻性队列研究的数据。以基线、2 周、4 周、8 周、12 周、6 个月、9 个月和 12 个月时的 SI 为指标,对 1 461 名 MDD 患者进行了生长混合建模。以 SI 轨迹为结果,以失乐症、抑郁症状、非典型抑郁症状、药物治疗和其他协变量为预测因素,采用多项式回归。结果发现了四种不同的 SI 轨迹:持续低 SI 轨迹(50.7%)、持续轻度 SI 轨迹(20.6%)、快速下降 SI 轨迹(8.9%)和缓慢下降 SI 轨迹(19.8%)。与持续低 SI 轨迹的患者相比,失乐症得分越高,出现持续轻度 SI(RRR = 1.20,95%CI:1.05, 1.38)和缓慢 SI(1.54,95%CI:1.32, 1.80)的风险越高。抑郁症状的严重程度也与出现持续轻度(1.15,95%CI:1.13,1.18)和缓慢下降的 SI(1.17,95%CI:1.14,1.21)的风险呈正相关。而使用 SSRI(1.49,95%CI:1.02,2.31)和抗抑郁药与抗精神病药/情绪稳定剂联合疗法(3.78,95%CI:1.48,9.61)的患者出现 SI 缓慢下降的风险更高。这项研究的结果可能对临床实践很有帮助,因为它是预测 MDD 患者预后的概况和干预措施的关键指标。我们有必要开展进一步研究,探索潜在的可改变因素以及 SI 轨迹与自杀行为之间的关联。
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引用次数: 0
Cacna1c deficiency in forebrain glutamatergic neurons alters behavior and hippocampal plasticity in female mice. 前脑谷氨酸能神经元缺乏 Cacna1c 会改变雌性小鼠的行为和海马可塑性。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-06 DOI: 10.1038/s41398-024-03140-2
Srivaishnavi Loganathan, Danusa Menegaz, Jan Philipp Delling, Matthias Eder, Jan M Deussing

CACNA1C, coding for the α1 subunit of L-type voltage-gated calcium channel (LTCC) Cav1.2, has been associated with multiple psychiatric disorders. Clinical studies have revealed alterations in behavior as well as in brain structure and function in CACNA1C risk allele carriers. These findings are supported by rodent models of Cav1.2 deficiency, which showed increased anxiety, cognitive and social impairments as well as a shift towards active stress-coping strategies. These behavioral alterations were accompanied by functional deficits, such as reduced long-term potentiation (LTP) and an excitation/inhibition (E/I) imbalance. However, these preclinical studies are largely limited to male rodents, with few studies exploring sex-specific effects. Here, we investigated the effects of Cav1.2 deficiency in forebrain glutamatergic neurons in female conditional knockout (CKO) mice. CKO mice exhibited hyperlocomotion in a novel environment, increased anxiety-related behavior, cognitive deficits, and increased active stress-coping behavior. These behavioral alterations were neither influenced by the stage of the estrous cycle nor by the Nex/Neurod6 haploinsufficiency or Cre expression, which are intrinsically tied to the utilization of the Nex-Cre driver line for conditional inactivation of Cacna1c. In the hippocampus, Cav1.2 inactivation enhanced presynaptic paired-pulse facilitation without altering postsynaptic LTP at CA3-CA1 synapses. In addition, CA1 pyramidal neurons of female CKO mice displayed a reduction in dendritic complexity and spine density. Taken together, our findings extend the existing knowledge suggesting Cav1.2-dependent structural and functional alterations as possible mechanisms for the behavioral alterations observed in female Cav1.2-Nex mice.

编码 L 型电压门控钙通道(LTCC)Cav1.2 α1 亚基的 CACNA1C 与多种精神疾病有关。临床研究发现,CACNA1C 风险等位基因携带者的行为以及大脑结构和功能都发生了改变。Cav1.2 缺乏症的啮齿类动物模型也证实了这些研究结果,该模型显示焦虑、认知和社交障碍增加,并转向积极的压力应对策略。这些行为改变伴随着功能缺陷,如长期电位(LTP)降低和兴奋/抑制(E/I)失衡。然而,这些临床前研究主要局限于雄性啮齿动物,很少有研究探讨性别特异性效应。在这里,我们研究了雌性条件性基因敲除(CKO)小鼠前脑谷氨酸能神经元中 Cav1.2 缺失的影响。CKO小鼠在新环境中表现出过度运动、焦虑相关行为增加、认知障碍和主动压力应对行为增加。这些行为改变既不受发情周期阶段的影响,也不受Nex/Neurod6单倍体缺失或Cre表达的影响,这与利用Nex-Cre驱动系条件性失活Cacna1c有内在联系。在海马中,Cav1.2失活增强了突触前的成对脉冲促进,而不会改变CA3-CA1突触的突触后LTP。此外,雌性 CKO 小鼠的 CA1 锥体神经元显示出树突复杂性和棘密度的降低。总之,我们的研究结果扩展了现有的知识,表明依赖于Cav1.2的结构和功能改变是雌性Cav1.2-Nex小鼠行为改变的可能机制。
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引用次数: 0
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Translational Psychiatry
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