首页 > 最新文献

Translational Psychiatry最新文献

英文 中文
Nighttime-specific differential gene expression in suprachiasmatic nucleus and habenula is associated with resilience to chronic social stress. 夜间特异性基因在蝶鞍上核和大脑后叶的不同表达与对慢性社会压力的恢复力有关。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03100-w
Priyam Narain, Aleksa Petković, Marko Šušić, Salma Haniffa, Mariam Anwar, Marc Arnoux, Nizar Drou, Giuseppe Antonio-Saldi, Dipesh Chaudhury

The molecular mechanisms that link stress and biological rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the body's central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress-naïve and stress-exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naïve mice at zeitgeber 16 (ZT16) in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naïve groups across time points. Our results reinforce the functional link between circadian gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homoeostatic stress responses.

将压力和生物节律联系起来的分子机制仍不清楚。哈氏核(Hb)是参与调节各种情绪相关行为的关键脑区,而视上核(SCN)则是人体的中央时钟。为了研究慢性社会压力对转录模式的影响,我们对未受压力和受压力影响的小鼠的Hb和SCN进行了基因表达分析。我们的分析表明,在Hb和SCN的Zeitgeber 16 (ZT16)处,抗逆小鼠和应激免疫小鼠的突触和细胞信号通路存在大量差异表达基因和富集。这种转录组特征具有夜间特异性,而且只在抗应激小鼠中观察到。相比之下,应激易感组和应激未感组在不同时间点的差异相对较小。我们的研究结果加强了昼夜节律基因表达模式与对应激的不同反应之间的功能性联系,从而突出了时间表达模式在同态应激反应中的重要性。
{"title":"Nighttime-specific differential gene expression in suprachiasmatic nucleus and habenula is associated with resilience to chronic social stress.","authors":"Priyam Narain, Aleksa Petković, Marko Šušić, Salma Haniffa, Mariam Anwar, Marc Arnoux, Nizar Drou, Giuseppe Antonio-Saldi, Dipesh Chaudhury","doi":"10.1038/s41398-024-03100-w","DOIUrl":"10.1038/s41398-024-03100-w","url":null,"abstract":"<p><p>The molecular mechanisms that link stress and biological rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the body's central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress-naïve and stress-exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naïve mice at zeitgeber 16 (ZT16) in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naïve groups across time points. Our results reinforce the functional link between circadian gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homoeostatic stress responses.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Defective regulation of the eIF2-eIF2B translational axis underlies depressive-like behavior in mice and correlates with major depressive disorder in humans. eIF2-eIF2B 翻译轴调节缺陷是小鼠抑郁样行为的基础,并与人类重度抑郁障碍相关。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-01 DOI: 10.1038/s41398-024-03128-y
Alinny R Isaac, Mariana G Chauvet, Ricardo Lima-Filho, Beatriz de A Wagner, Bruno G Caroli, Renata E P Leite, Claudia K Suemoto, Paula Villela Nunes, Fernanda G De Felice, Sergio T Ferreira, Mychael V Lourenco

Major depressive disorder (MDD) is a significant cause of disability in adults worldwide. However, the underlying causes and mechanisms of MDD are not fully understood, and many patients are refractory to available therapeutic options. Impaired control of brain mRNA translation underlies several neurodevelopmental and neurodegenerative conditions, including autism spectrum disorders and Alzheimer's disease (AD). Nonetheless, a potential role for mechanisms associated with impaired translational control in depressive-like behavior remains elusive. A key pathway controlling translation initiation relies on the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P) which, in turn, blocks the guanine exchange factor activity of eIF2B, thereby reducing global translation rates. Here we report that the expression of EIF2B5 (which codes for eIF2Bε, the catalytic subunit of eIF2B) is reduced in postmortem MDD prefrontal cortex from two distinct human cohorts and in the frontal cortex of social isolation-induced depressive-like behavior model mice. Further, pharmacological treatment with anisomycin or with salubrinal, an inhibitor of the eIF2α phosphatase GADD34, induces depressive-like behavior in adult C57BL/6J mice. Salubrinal-induced depressive-like behavior is blocked by ISRIB, a compound that directly activates eIF2B regardless of the phosphorylation status of eIF2α, suggesting that increased eIF2α-P promotes depressive-like states. Taken together, our results suggest that impaired eIF2-associated translational control may participate in the pathophysiology of MDD, and underscore eIF2-eIF2B translational axis as a potential target for the development of novel approaches for MDD and related mood disorders.

重度抑郁障碍(MDD)是导致全球成年人残疾的一个重要原因。然而,重度抑郁症的根本原因和发病机制尚未完全明了,许多患者对现有的治疗方案难以奏效。大脑 mRNA 翻译控制受损是包括自闭症谱系障碍和阿尔茨海默病(AD)在内的多种神经发育和神经退行性疾病的基础。然而,与翻译控制受损相关的机制在抑郁样行为中的潜在作用仍然难以捉摸。控制翻译起始的一个关键途径依赖于真核生物起始因子 2(eIF2α-P)α 亚基的磷酸化,这反过来又会阻断 eIF2B 的鸟嘌呤交换因子活性,从而降低全局翻译率。在这里,我们报告了在两个不同的人类队列中的 MDD 死后前额叶皮层和社会隔离诱导的抑郁样行为模型小鼠的额叶皮层中,EIF2B5(编码 eIF2Bε,eIF2B 的催化亚基)的表达减少。此外,在成年 C57BL/6J 小鼠中,使用安乃近或沙卢布林纳(eIF2α 磷酸酶 GADD34 的抑制剂)进行药理治疗可诱导抑郁样行为。ISRIB能直接激活eIF2B,而与eIF2α的磷酸化状态无关,这表明eIF2α-P的增加会促进抑郁样状态。综上所述,我们的研究结果表明,eIF2相关的翻译控制受损可能参与了MDD的病理生理学,并强调eIF2-eIF2B翻译轴是开发治疗MDD和相关情绪障碍新方法的潜在靶点。
{"title":"Defective regulation of the eIF2-eIF2B translational axis underlies depressive-like behavior in mice and correlates with major depressive disorder in humans.","authors":"Alinny R Isaac, Mariana G Chauvet, Ricardo Lima-Filho, Beatriz de A Wagner, Bruno G Caroli, Renata E P Leite, Claudia K Suemoto, Paula Villela Nunes, Fernanda G De Felice, Sergio T Ferreira, Mychael V Lourenco","doi":"10.1038/s41398-024-03128-y","DOIUrl":"10.1038/s41398-024-03128-y","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a significant cause of disability in adults worldwide. However, the underlying causes and mechanisms of MDD are not fully understood, and many patients are refractory to available therapeutic options. Impaired control of brain mRNA translation underlies several neurodevelopmental and neurodegenerative conditions, including autism spectrum disorders and Alzheimer's disease (AD). Nonetheless, a potential role for mechanisms associated with impaired translational control in depressive-like behavior remains elusive. A key pathway controlling translation initiation relies on the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P) which, in turn, blocks the guanine exchange factor activity of eIF2B, thereby reducing global translation rates. Here we report that the expression of EIF2B5 (which codes for eIF2Bε, the catalytic subunit of eIF2B) is reduced in postmortem MDD prefrontal cortex from two distinct human cohorts and in the frontal cortex of social isolation-induced depressive-like behavior model mice. Further, pharmacological treatment with anisomycin or with salubrinal, an inhibitor of the eIF2α phosphatase GADD34, induces depressive-like behavior in adult C57BL/6J mice. Salubrinal-induced depressive-like behavior is blocked by ISRIB, a compound that directly activates eIF2B regardless of the phosphorylation status of eIF2α, suggesting that increased eIF2α-P promotes depressive-like states. Taken together, our results suggest that impaired eIF2-associated translational control may participate in the pathophysiology of MDD, and underscore eIF2-eIF2B translational axis as a potential target for the development of novel approaches for MDD and related mood disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder. 前扣带回下源的静息态功能连接对重度抑郁症患者抗抑郁药疗效预测的贡献
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-01 DOI: 10.1038/s41398-024-03117-1
Yun Wang, Changshuo Wang, Jingjing Zhou, Xiongying Chen, Rui Liu, Zhifang Zhang, Yuan Feng, Lei Feng, Jing Liu, Yuan Zhou, Gang Wang

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

本研究调查了扣带下前皮层(sgACC)的静息态功能连接(rsFC)如何预测重度抑郁障碍(MDD)患者的抗抑郁反应。87名未接受药物治疗的重度抑郁症患者接受了基线静息态功能磁共振成像扫描。经过12周的艾司西酞普兰治疗后,患者被分为缓解抑郁组(RD,n = 42)和非缓解抑郁组(NRD,n = 45)。我们进行了两项分析:一项是以 sgACC 为种子的体素 rsFC 分析,以确定组间差异;另一项是基于 sgACC rsFC 图的预测模型,以预测疗效。豪夫变换用于解释预测性 rsFC 特征。与NRD组相比,RD组的sgACC与前顶叶网络(FPN)区域(包括双侧背外侧前额叶皮层(DLPFC)和双侧下顶叶小叶(IPL))之间的rsFC明显更高。这些 sgACC rsFC 测量值与症状改善呈正相关。基线 sgACC rsFC 还能显著预测 12 周后的治疗反应,平均准确率为 72.64%(p
{"title":"Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder.","authors":"Yun Wang, Changshuo Wang, Jingjing Zhou, Xiongying Chen, Rui Liu, Zhifang Zhang, Yuan Feng, Lei Feng, Jing Liu, Yuan Zhou, Gang Wang","doi":"10.1038/s41398-024-03117-1","DOIUrl":"10.1038/s41398-024-03117-1","url":null,"abstract":"<p><p>This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association between probable sarcopenia and dementia risk: a prospective cohort study with mediation analysis. 可能的肌肉疏松症与痴呆症风险之间的关系:前瞻性队列研究与中介分析。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-01 DOI: 10.1038/s41398-024-03131-3
Yitong Ling, Shiqi Yuan, Xiaxuan Huang, Shanyuan Tan, Hongtao Cheng, Li Li, Shuna Li, Liying Huang, Anding Xu, Jun Lyu

The role of alcohol consumption as a mediator in the risk between sarcopenia and dementia remains inadequately studied. There is currently limited research on whether the association between sarcopenia and the risk of Alzheimer's disease (AD) is influenced by genetic susceptibility. Our study incorporated a total of 483,637 baseline non-dementia participants, who were classified into groups of individuals with no sarcopenia and those with probable sarcopenia based on the definition. We employed Cox proportional hazards models to evaluate the association between probable sarcopenia and the risk of all cause dementia (ACD), AD, and vascular dementia (VD). We conducted mediation analysis to explore the role of alcohol consumption in the association between probable sarcopenia and the risk of ACD, AD, and VD. During the median follow-up period of 13.6 years, we documented 9000 new cases of ACD (including 4061 AD and 2025 VD). Fully adjusted multivariate model revealed a significant correlation between probable sarcopenia and elevated risk for ACD (HR = 1.54, 95% CI: 1.46-1.62, p < 0.001), AD (HR = 1.32, 95% CI: 1.21-1.43, p < 0.001), and VD (HR = 1.69, 95% CI: 1.52-1.89, p < 0.001). Mediation analysis elucidates that alcohol consumption explained 12.8%, 15.2%, and 11.1% of the associations of probable sarcopenia with the risk of ACD, AD, and VD, respectively. An interactive relationship prevails between probable sarcopenia and genetic factors (p for interaction <0.001), and regardless of the degree of genetic risk, probable sarcopenia correlates with an elevated AD risk. Our study reveals a significant association between probable sarcopenia and an increased risk of dementia, with alcohol consumption playing a mediating role in this association. There is an interaction between probable sarcopenia and genetic susceptibility related to the risk of AD.

关于饮酒在肌肉疏松症与痴呆症之间的风险中所起的中介作用,目前研究尚不充分。目前,关于肌肉疏松症与阿尔茨海默病(AD)风险之间的关系是否受遗传易感性影响的研究还很有限。我们的研究共纳入了 483 637 名基线非痴呆症参与者,并根据定义将他们分为无肌肉疏松症和可能患有肌肉疏松症两组。我们采用 Cox 比例危险模型来评估可能的肌肉疏松症与全因痴呆症(ACD)、注意力缺失症(AD)和血管性痴呆症(VD)风险之间的关系。我们还进行了中介分析,以探讨饮酒在可能的肌肉疏松症与全因痴呆症、注意力缺失症和血管性痴呆症风险之间的关联中的作用。在中位 13.6 年的随访期间,我们记录了 9000 例新的 ACD 病例(包括 4061 例 AD 和 2025 例 VD)。经充分调整的多变量模型显示,可能的肌肉疏松症与 ACD 风险升高之间存在显著的相关性(HR = 1.54,95% CI:1.46-1.62,P<0.05)。
{"title":"Association between probable sarcopenia and dementia risk: a prospective cohort study with mediation analysis.","authors":"Yitong Ling, Shiqi Yuan, Xiaxuan Huang, Shanyuan Tan, Hongtao Cheng, Li Li, Shuna Li, Liying Huang, Anding Xu, Jun Lyu","doi":"10.1038/s41398-024-03131-3","DOIUrl":"10.1038/s41398-024-03131-3","url":null,"abstract":"<p><p>The role of alcohol consumption as a mediator in the risk between sarcopenia and dementia remains inadequately studied. There is currently limited research on whether the association between sarcopenia and the risk of Alzheimer's disease (AD) is influenced by genetic susceptibility. Our study incorporated a total of 483,637 baseline non-dementia participants, who were classified into groups of individuals with no sarcopenia and those with probable sarcopenia based on the definition. We employed Cox proportional hazards models to evaluate the association between probable sarcopenia and the risk of all cause dementia (ACD), AD, and vascular dementia (VD). We conducted mediation analysis to explore the role of alcohol consumption in the association between probable sarcopenia and the risk of ACD, AD, and VD. During the median follow-up period of 13.6 years, we documented 9000 new cases of ACD (including 4061 AD and 2025 VD). Fully adjusted multivariate model revealed a significant correlation between probable sarcopenia and elevated risk for ACD (HR = 1.54, 95% CI: 1.46-1.62, p < 0.001), AD (HR = 1.32, 95% CI: 1.21-1.43, p < 0.001), and VD (HR = 1.69, 95% CI: 1.52-1.89, p < 0.001). Mediation analysis elucidates that alcohol consumption explained 12.8%, 15.2%, and 11.1% of the associations of probable sarcopenia with the risk of ACD, AD, and VD, respectively. An interactive relationship prevails between probable sarcopenia and genetic factors (p for interaction <0.001), and regardless of the degree of genetic risk, probable sarcopenia correlates with an elevated AD risk. Our study reveals a significant association between probable sarcopenia and an increased risk of dementia, with alcohol consumption playing a mediating role in this association. There is an interaction between probable sarcopenia and genetic susceptibility related to the risk of AD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Psilocybin increases optimistic engagement over time: computational modelling of behaviour in rats. 随着时间的推移,迷幻药会增加乐观的参与度:对大鼠行为的计算建模。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-30 DOI: 10.1038/s41398-024-03103-7
Elizabeth L Fisher, Ryan Smith, Kyna Conn, Andrew W Corcoran, Laura K Milton, Jakob Hohwy, Claire J Foldi

Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.

作为治疗抑郁症的一种新型药理干预措施,迷幻药已显示出良好的前景,迷幻药治疗后的急性效应与积极情绪的增加和悲观情绪的减少有关。尽管在治疗精神疾病的临床试验中证明了迷幻药的有效性,但人们对迷幻药影响的信息处理机制还不甚了解。在这里,我们将主动推理和强化学习计算模型与能够捕捉大鼠参与行为的新型双臂匪徒逆向学习任务相结合。该模型显示,大鼠在接受迷幻药后会通过提高任务参与度获得更多奖励,而任务参与度的提高是由遗忘率的改变和损失厌恶的降低所促成的。这些研究结果表明,迷幻药可能会通过改变信念更新而产生乐观偏差,这对缺乏乐观情绪的临床人群具有转化潜力。
{"title":"Psilocybin increases optimistic engagement over time: computational modelling of behaviour in rats.","authors":"Elizabeth L Fisher, Ryan Smith, Kyna Conn, Andrew W Corcoran, Laura K Milton, Jakob Hohwy, Claire J Foldi","doi":"10.1038/s41398-024-03103-7","DOIUrl":"10.1038/s41398-024-03103-7","url":null,"abstract":"<p><p>Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects. 在一项针对健康受试者的双盲安慰剂对照研究中,麦司卡林产生了急性剂量依赖性效应。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-30 DOI: 10.1038/s41398-024-03116-2
Aaron Klaiber, Yasmin Schmid, Anna M Becker, Isabelle Straumann, Livio Erne, Alen Jelusic, Jan Thomann, Dino Luethi, Matthias E Liechti

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.

经典迷幻剂重新引起了研究和治疗的兴趣。尽管人类使用麦司卡林的传统由来已久,但仍缺乏有关其剂量依赖性急性效应和药代动力学的现代数据。此外,麦司卡林的作用机制也未在人体中进行过研究。我们采用随机、双盲、安慰剂对照、交叉设计的方法,让 16 名健康受试者(8 名女性)分别服用安慰剂、麦司卡林(100、200、400 和 800 毫克)和 800 毫克麦司卡林以及血清素-5-羟色胺-2A(5-HT2A)受体拮抗剂酮赛林(40 毫克),以评估用药后 30 小时内的主观效应、自主神经效应、不良反应和药代动力学。剂量大于 100 毫克的麦司卡林会诱发剂量依赖性急性主观效应。剂量大于 100 毫克时,麦司卡林会增加收缩压和舒张压,剂量在 200-800 毫克之间没有差异。心率的增加与剂量有关。麦司卡林的药代动力学与剂量成正比。随着 100-800 毫克麦司卡林剂量的增加,主观效应的平均持续时间从 6.4 小时增加到 14 小时。服用 800 毫克剂量时,恶心和呕吐是常见的不良反应。同时服用酮塞林可减轻和缩短 800 毫克麦司卡林的急性效应,使其与 100 毫克和 200 毫克的剂量相当。在调查的剂量范围内,主观反应没有上限效应,但最高剂量的耐受性较低。这些结果可能有助于为今后的研究寻找剂量,并表明麦司卡林的急性效应主要由 5-HT2A 受体介导。
{"title":"Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects.","authors":"Aaron Klaiber, Yasmin Schmid, Anna M Becker, Isabelle Straumann, Livio Erne, Alen Jelusic, Jan Thomann, Dino Luethi, Matthias E Liechti","doi":"10.1038/s41398-024-03116-2","DOIUrl":"10.1038/s41398-024-03116-2","url":null,"abstract":"<p><p>Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT<sub>2A</sub>) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT<sub>2A</sub> receptors.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Contagion of depression: a double-edged sword. 抑郁症的传染:一把双刃剑。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-30 DOI: 10.1038/s41398-024-03124-2
Chen-Wei Huang, Ting Hu, Hong Zheng, Yi-Lin Wu, Jia-Mei Li, Yi-Ming Wang, Wen-Jun Su, Wei Wang, Yun-Zi Liu, Chun-Lei Jiang

Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders.

抑郁症是一个严重的心理健康问题,对经济有着广泛的影响,最近的研究表明,抑郁症可能会在人与人之间传播。然而,这种传染的机制仍不清楚,社会缓冲效应也未得到充分研究。本研究采用了三种啮齿动物模型,包括压力交叉模型、同居诱导模型和非接触诱导抑郁传染模型,来探索这些机制。在这里,我们报告说,与抑郁小鼠同居的天真小鼠表现出皮质酮水平升高和抑郁行为,而与应激小鼠同居的天真小鼠则不同,它们没有表现出这些变化,甚至减轻了应激小鼠的绝望情绪。非接触式同居不会产生显著的行为差异,但接触抑郁小鼠的垫料会降低天真小鼠的蔗糖偏好。这项研究引入了抑郁传染的可靠模型,表明抑郁传染的运作与应激传递无关。抑郁传染和社会缓冲之间的相互作用可能在不同的环境中有所不同。这些发现为抑郁传染机制和预防抑郁障碍的潜在策略提供了新的见解。
{"title":"Contagion of depression: a double-edged sword.","authors":"Chen-Wei Huang, Ting Hu, Hong Zheng, Yi-Lin Wu, Jia-Mei Li, Yi-Ming Wang, Wen-Jun Su, Wei Wang, Yun-Zi Liu, Chun-Lei Jiang","doi":"10.1038/s41398-024-03124-2","DOIUrl":"10.1038/s41398-024-03124-2","url":null,"abstract":"<p><p>Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission. 受体和新陈代谢对咖啡因防止酒精诱导刺激间叶多巴胺传导能力的影响。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-28 DOI: 10.1038/s41398-024-03112-6
Valentina Bassareo, Riccardo Maccioni, Giuseppe Talani, Simone Zuffa, Yasin El Abiead, Irene Lorrai, Tomoya Kawamura, Sofia Pantis, Roberta Puliga, Romina Vargiu, Daniele Lecca, Paolo Enrico, Alessandra Peana, Laura Dazzi, Pieter C Dorrestein, Pietro Paolo Sanna, Enrico Sanna, Elio Acquas

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

酒精和咖啡因的消费影响着全球数十亿人的生活。尽管最近有证据表明咖啡因会削弱酒精的强化作用,但却缺乏咖啡因对酒精刺激的间叶多巴胺(DA)功能的影响特征。酒精作为salsolinol的原药,可兴奋后腹侧被盖区(pVTA)的DA神经元,并增加核团外壳(AcbSh)的DA释放。在这里,我们展示了咖啡因通过对 A2A 腺苷受体(A2AR)的拮抗作用,阻止了酒精对间叶 DA 功能的依赖性激活,这种激活在体内是通过对 AcbSh DA 的脑微量透析评估的,在体外是通过对 pVTA DA 神经元发射的电生理记录评估的。因此,虽然A1R拮抗剂DPCPX不能阻止酒精对DA功能的影响,但咖啡因和A2AR拮抗剂SCH 58261都能阻止酒精依赖性体内pVTA产生salsolinol和AcbSh DA增加,以及酒精依赖性体外pVTA DA神经元兴奋。然而,咖啡因也能阻止直接的鲨烯醇和吗啡刺激的DA功能,这表明咖啡因也能发挥这些抑制作用,而不影响酒精诱导的鲨烯醇的形成或生物利用度。最后,pVTA 的非靶向代谢组学研究表明,咖啡因能拮抗酒精介导的对脂质信号转导和能量代谢相关分子(如磷脂酰胆碱、脂肪酰胺、肉毒碱)的影响,这可能代表咖啡因在损害酒精介导的刺激间叶 DA 传递方面的另一种与香豆素醇无关的机制。总之,这项研究的结果增强了咖啡因和 A2AR 拮抗剂在未来开发酒精使用障碍的预防/治疗策略方面的潜力。
{"title":"Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission.","authors":"Valentina Bassareo, Riccardo Maccioni, Giuseppe Talani, Simone Zuffa, Yasin El Abiead, Irene Lorrai, Tomoya Kawamura, Sofia Pantis, Roberta Puliga, Romina Vargiu, Daniele Lecca, Paolo Enrico, Alessandra Peana, Laura Dazzi, Pieter C Dorrestein, Pietro Paolo Sanna, Enrico Sanna, Elio Acquas","doi":"10.1038/s41398-024-03112-6","DOIUrl":"10.1038/s41398-024-03112-6","url":null,"abstract":"<p><p>The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A<sub>2A</sub> adenosine receptors (A<sub>2A</sub>R), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A<sub>1</sub>R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A<sub>2A</sub>R antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A<sub>2A</sub>R antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting auditory verbal hallucinations in schizophrenia: effective connectivity changes induced by low-frequency rTMS. 针对精神分裂症患者的听觉言语幻觉:低频经颅磁刺激引起的有效连接变化
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-28 DOI: 10.1038/s41398-024-03106-4
Xie Yuanjun, Muzhen Guan, Tian Zhang, Chaozong Ma, Lingling Wang, Xinxin Lin, Chenxi Li, Zhongheng Wang, Ma Zhujing, Huaning Wang, Fang Peng

Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as an effective intervention for alleviating symptoms of psychiatric disorders, particularly schizophrenia characterized by persistent auditory verbal hallucinations (AVH). However, the underlying mechanism of its action remain elusive. This study employed a randomized controlled design to investigate the impact of low-frequency rTMS on the neural connectivity at the stimulate site, specifically left temporoparietal junction (TPJ), in schizophrenia patients with suffering from AVH. Using Dynamic Causal Modeling (DCM), this study assessed changes in directed connectivity patterns and their correlations with clinical symptomatology. The results demonstrated significant improvements in AVH. Notably, significant changes in connectivity were observed, including both abnormal functional connectivity and effective connectivity among multiple brain regions. Particularly, the inhibition effects from the left precentral gyrus and left medial superior frontal gyrus to the left TPJ were closely associated with improvements in AVH. These findings underscore the potential of rTMS to effectively modulate neural pathways implicated in hallucinations in schizophrenia, thereby providing a neurobiological foundation for its therapeutic effects.

低频重复经颅磁刺激(rTMS)已成为一种有效的干预措施,可减轻精神疾病的症状,尤其是以持续性听觉言语幻觉(AVH)为特征的精神分裂症。然而,其潜在的作用机制仍然难以捉摸。本研究采用随机对照设计,研究低频经颅磁刺激对精神分裂症患者刺激部位(尤其是左侧颞顶叶交界处(TPJ))神经连接的影响。本研究采用动态因果模型(DCM)评估了定向连接模式的变化及其与临床症状的相关性。结果表明,AVH 有了明显改善。值得注意的是,研究人员观察到连通性发生了重大变化,包括异常功能连通性和多个脑区之间的有效连通性。特别是,从左侧中央前回和左侧内侧额上回到左侧 TPJ 的抑制作用与 AVH 的改善密切相关。这些发现强调了经颅磁刺激可以有效调节与精神分裂症幻觉有关的神经通路,从而为其治疗效果提供了神经生物学基础。
{"title":"Targeting auditory verbal hallucinations in schizophrenia: effective connectivity changes induced by low-frequency rTMS.","authors":"Xie Yuanjun, Muzhen Guan, Tian Zhang, Chaozong Ma, Lingling Wang, Xinxin Lin, Chenxi Li, Zhongheng Wang, Ma Zhujing, Huaning Wang, Fang Peng","doi":"10.1038/s41398-024-03106-4","DOIUrl":"https://doi.org/10.1038/s41398-024-03106-4","url":null,"abstract":"<p><p>Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as an effective intervention for alleviating symptoms of psychiatric disorders, particularly schizophrenia characterized by persistent auditory verbal hallucinations (AVH). However, the underlying mechanism of its action remain elusive. This study employed a randomized controlled design to investigate the impact of low-frequency rTMS on the neural connectivity at the stimulate site, specifically left temporoparietal junction (TPJ), in schizophrenia patients with suffering from AVH. Using Dynamic Causal Modeling (DCM), this study assessed changes in directed connectivity patterns and their correlations with clinical symptomatology. The results demonstrated significant improvements in AVH. Notably, significant changes in connectivity were observed, including both abnormal functional connectivity and effective connectivity among multiple brain regions. Particularly, the inhibition effects from the left precentral gyrus and left medial superior frontal gyrus to the left TPJ were closely associated with improvements in AVH. These findings underscore the potential of rTMS to effectively modulate neural pathways implicated in hallucinations in schizophrenia, thereby providing a neurobiological foundation for its therapeutic effects.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation. 失调的miR-124介导父亲早期社会隔离导致的社会记忆行为受损
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-28 DOI: 10.1038/s41398-024-03109-1
Sijia Chen, Shixin Ding, Yingting Pang, Yuxi Jin, Peng Sun, Yue Li, Min Cao, Yimiao Wang, Ze Wang, Tianqi Wang, Ying Zou, Yanli Zhang, Ming Xiao

Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.

早期社会隔离(SI)会导致成年后情绪和行为的各种异常。然而,社会隔离对后代的负面影响仍不清楚。这项研究发现,父系早期社会隔离会导致 F1 年轻成年小鼠的社会记忆缺陷和焦虑样行为,并改变内侧前额叶皮层(mPFC)的髓鞘和突触。对 F1 后代进行 2 周的 SI 会加剧 mPFC 中的社会记忆障碍和髓鞘化不足。此外,在F1小鼠的mPFC中下调miR-124(一种髓鞘生成的关键抑制因子)或过度表达其靶基因Nr4a1可改善社交互动能力,并促进少突胶质细胞的成熟和髓鞘的形成。从机理上讲,父系 SI 小鼠精子中 miR-124 水平的升高会通过表观遗传传递给子代,从而改变 mPFC 少突胶质细胞中 miR-124/Nr4a1/ 糖皮质激素受体的表达水平。这反过来又阻碍了依赖髓鞘生成的社会行为的建立。这项研究揭示了一种新的机制,通过这种机制,miR-124介导了早期隔离应激的代际效应,最终损害了社会行为和神经发育的建立。
{"title":"Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation.","authors":"Sijia Chen, Shixin Ding, Yingting Pang, Yuxi Jin, Peng Sun, Yue Li, Min Cao, Yimiao Wang, Ze Wang, Tianqi Wang, Ying Zou, Yanli Zhang, Ming Xiao","doi":"10.1038/s41398-024-03109-1","DOIUrl":"10.1038/s41398-024-03109-1","url":null,"abstract":"<p><p>Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Translational Psychiatry
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1