首页 > 最新文献

Translational Psychiatry最新文献

英文 中文
Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder. 纹状体磷酸二酯酶10 A的变化及其与双相情感障碍I复发率的关系
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03107-3
Yasunori Sano, Yasuharu Yamamoto, Manabu Kubota, Sho Moriguchi, Kiwamu Matsuoka, Shin Kurose, Kenji Tagai, Hironobu Endo, Bun Yamagata, Hisaomi Suzuki, Ryosuke Tarumi, Kie Nomoto, Yuhei Takado, Kazunori Kawamura, Ming-Rong Zhang, Hajime Tabuchi, Masaru Mimura, Hiroyuki Uchida, Makoto Higuchi, Keisuke Takahata

Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [18F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.

磷酸二酯酶10 A(PDE10A)是多巴胺受体刺激下游第二信使信号转导的关键因素,被认为是双相情感障碍(BD-I)情绪不稳定的主要诱因或多巴胺能调节失调的反应。我们旨在确定 BD-I 患者纹状体 PDE10A 的可用性是否发生改变,并评估其与 BD-I 临床特征的关系。这项病例对照研究采用了正电子发射断层扫描(PET)技术,检测 2-(2-(3-(4-(2-[18F]氟乙氧基)苯基)-7-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙基)-4-异丙氧基异吲哚啉-1,3-二酮([18F]MNI-659)、MNI-659 是一种能与 PDE10A 结合的放射性配体,用于研究 BD-I 患者活体大脑纹状体 PDE10A 供应的改变及其与 BD-I 临床特征的关系。[18F]MNI-659正电子发射计算机断层扫描数据来自25名BD-Ⅰ患者和27名年龄和性别匹配的健康对照者。在纹状体的执行(F = 8.86; P = 0.005)和感觉运动(F = 6.13; P = 0.017)亚区,BD-Ⅰ患者的PDE10A可用性明显低于对照组。执行亚区较低的 PDE10A 可用性与 BD-I 患者较高的情绪发作频率显著相关(r = -0.546;P = 0.007)。这项研究首次提供了 BD-I 患者 PDE10A 可利用率发生改变的证据。纹状体执行亚区较低的 PDE10A 可用性与复发风险的增加有关,这表明 PDE10A 可预防 BD-I 复发。要阐明 PDE10A 在 BD-I 病理生理学中的作用并探索其作为治疗靶点的潜力,还需要进一步的研究。
{"title":"Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder.","authors":"Yasunori Sano, Yasuharu Yamamoto, Manabu Kubota, Sho Moriguchi, Kiwamu Matsuoka, Shin Kurose, Kenji Tagai, Hironobu Endo, Bun Yamagata, Hisaomi Suzuki, Ryosuke Tarumi, Kie Nomoto, Yuhei Takado, Kazunori Kawamura, Ming-Rong Zhang, Hajime Tabuchi, Masaru Mimura, Hiroyuki Uchida, Makoto Higuchi, Keisuke Takahata","doi":"10.1038/s41398-024-03107-3","DOIUrl":"10.1038/s41398-024-03107-3","url":null,"abstract":"<p><p>Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[<sup>18</sup>F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([<sup>18</sup>F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [<sup>18</sup>F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"403"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366603","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
COVID-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study. 意大利青少年中与 COVID-19 相关的认知、大脑结构和功能变化:一项多模式纵向病例对照研究。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03108-2
Azzurra Invernizzi, Stefano Renzetti, Christoph van Thriel, Elza Rechtman, Alessandra Patrono, Claudia Ambrosi, Lorella Mascaro, Daniele Corbo, Giuseppa Cagna, Roberto Gasparotti, Abraham Reichenberg, Cheuk Y Tang, Roberto G Lucchini, Robert O Wright, Donatella Placidi, Megan K Horton

Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in ECdelta (i.e., the difference in EC values pre- and post-COVID-19) and Volumetricdelta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that ECdelta significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetricdelta between groups (p = 0.041). The reduced ECdelta in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.

冠状病毒病 2019(COVID-19)与感染数月后持续存在的大脑功能、结构和认知变化有关。与 COVID-19 相关的神经系统结果研究大多集中在严重感染和老龄人群。在此,我们在一项病例对照研究中调查了 COVID-19 相关结果的神经活动,研究对象是在 COVID-19 全球热点地区意大利伦巴第参加纵向研究的轻度感染青年。所有参与者(13 例病例,27 例对照,平均年龄 24 岁)均在基线(COVID 前)和随访(COVID 后)期间完成了静息态功能(fMRI)、结构性 MRI 和认知评估(CANTAB 空间工作记忆)。利用图论特征向量中心性(EC)和数据驱动统计方法,我们研究了 COVID-19 病例和对照组之间 ECdelta(即 COVID-19 前后 EC 值的差异)和 Volumetricdelta(即 COVID 前后皮质和皮质下区域皮质体积的差异)的差异。我们发现,COVID-19 和健康参与者在五个脑区的 ECdelta 显著不同:右侧颅内皮质、右侧舌回、左侧海马、左侧杏仁核、左侧额眶皮质。左侧海马的 Volumetricdelta 值在不同组间显著下降(p = 0.041)。与 COVID-19 状态相关的左侧杏仁核 ECdelta 的减少介导了 COVID-19 与空间工作记忆紊乱之间的关联。我们的研究结果表明,与嗅觉和认知相关的关键脑区在结构、功能和认知方面发生了持续性变化。这些结果可以指导治疗工作,以评估 COVID-19 后观察到的大脑和认知变化的持久性、可逆性和影响。
{"title":"COVID-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study.","authors":"Azzurra Invernizzi, Stefano Renzetti, Christoph van Thriel, Elza Rechtman, Alessandra Patrono, Claudia Ambrosi, Lorella Mascaro, Daniele Corbo, Giuseppa Cagna, Roberto Gasparotti, Abraham Reichenberg, Cheuk Y Tang, Roberto G Lucchini, Robert O Wright, Donatella Placidi, Megan K Horton","doi":"10.1038/s41398-024-03108-2","DOIUrl":"10.1038/s41398-024-03108-2","url":null,"abstract":"<p><p>Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in EC<sub>delta</sub> (i.e., the difference in EC values pre- and post-COVID-19) and Volumetric<sub>delta</sub> (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that EC<sub>delta</sub> significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetric<sub>delta</sub> between groups (p = 0.041). The reduced EC<sub>delta</sub> in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"402"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366605","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
Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-related intellectual disability. SYNGAP1相关智障临床前小鼠模型的过度兴奋和转化表型。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03077-6
Timothy A Fenton, Olivia Y Haouchine, Elizabeth B Hallam, Emily M Smith, Kiya C Jackson, Darlene Rahbarian, Cesar P Canales, Anna Adhikari, Alex S Nord, Roy Ben-Shalom, Jill L Silverman

Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability (ID), motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicating the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered, identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of SYNGAP1/Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the original mouse model from the Huganir laboratory, corroborated behaviors including robust hyperactivity and deficits in learning and memory in young adults. Furthermore, we described impairments in the domain of sleep, characterized using neurophysiological data that was collected with wireless, telemetric electroencephalography (EEG). Syngap1+/- mice exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta power frequency. For the first time, we illustrated that primary neurons from Syngap1+/- mice displayed: 1) increased network firing activity, 2) greater bursts, 3) and shorter inter-burst intervals between peaks, by utilizing high density microelectrode arrays (HD-MEA). Our work bridges in vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development and efficacy assessment of targeted treatments for SRID.

SYNGAP1中断会直接导致一种可遗传识别的神经发育障碍(NDD),即SYNGAP1相关智力障碍(SRID)。如果没有功能性的 SynGAP1 蛋白,患者就会发育迟缓,并具有智力障碍 (ID)、运动障碍和癫痫等显著特征。在过去二十年中,有许多发现表明了Syngap1的关键作用。目前已设计出多个缺失 Syngap1 的啮齿类动物模型,确定了其在神经元结构和功能中的精确作用,以及突触完整性的关键生化途径。SYNGAP1/Syngap1的同基因缺失是致命的。Syngap1的杂合突变会导致多种行为表型。我们使用 Huganir 实验室的原始小鼠模型所获得的体内功能数据证实了这些行为,包括年轻成人的过度活跃和学习与记忆缺陷。此外,我们还利用无线遥测脑电图(EEG)收集的神经生理学数据描述了睡眠障碍。Syngap1+/-小鼠表现出尖峰事件和尖峰序列的升高,此外还有功率的升高,最明显的是δ功率频率的升高。我们首次证明了 Syngap1+/- 小鼠的初级神经元表现出以下特征:通过使用高密度微电极阵列(HD-MEA),我们首次证明了 Syngap1+/- 小鼠的初级神经元显示出:1)更高的网络发射活动;2)更大的爆发;3)更短的峰值间爆发间隔。我们的工作将体外神经元电生理活动和功能与体内大脑神经生理活动和功能联系起来。这些数据阐明了体内和体外的定量转化生物标志物,可用于SRID靶向治疗的开发和疗效评估。
{"title":"Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-related intellectual disability.","authors":"Timothy A Fenton, Olivia Y Haouchine, Elizabeth B Hallam, Emily M Smith, Kiya C Jackson, Darlene Rahbarian, Cesar P Canales, Anna Adhikari, Alex S Nord, Roy Ben-Shalom, Jill L Silverman","doi":"10.1038/s41398-024-03077-6","DOIUrl":"10.1038/s41398-024-03077-6","url":null,"abstract":"<p><p>Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability (ID), motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicating the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered, identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of SYNGAP1/Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the original mouse model from the Huganir laboratory, corroborated behaviors including robust hyperactivity and deficits in learning and memory in young adults. Furthermore, we described impairments in the domain of sleep, characterized using neurophysiological data that was collected with wireless, telemetric electroencephalography (EEG). Syngap1<sup>+/-</sup> mice exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta power frequency. For the first time, we illustrated that primary neurons from Syngap1<sup>+/-</sup> mice displayed: 1) increased network firing activity, 2) greater bursts, 3) and shorter inter-burst intervals between peaks, by utilizing high density microelectrode arrays (HD-MEA). Our work bridges in vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development and efficacy assessment of targeted treatments for SRID.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"405"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366634","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
Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects. 定量蛋白质组学结合独立的 PRM 分析揭示了去甲异博定抗抑郁作用的线粒体和突触机制。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03127-z
Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du

Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NORCSDS groups and NORIMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NORCSDS and NORIMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.

重度抑郁症(MDD)是一种常见疾病,影响着全球 3 亿人。现有药物对大约 30% 的患者无效,因此开发具有新机制的新型抗抑郁药物迫在眉睫。在这里,我们发现诺异波定(NOR)在慢性社会挫败应激(CSDS)抑郁模型的尾悬、强迫游泳和蔗糖消耗试验中显示出抗抑郁疗效。然后,我们利用药物治疗 CSDS 小鼠范例,从前额叶皮层分离并获得了 CSDS 与 CON(CSDSCON)、丙咪嗪(IMI)治疗与 CSDS(IMICSDS)以及 NOR 治疗与 CSDS(NORCSDS)的不同蛋白质组。这些蛋白质表达的变化首先通过方差分析进行了分析,CSDS 组和 NORIMI 组的 p 支持方差分析的结果。我们采用蛋白质-蛋白质相互作用(PPI)分析来研究 NORCSDS 和 NORIMI 的蛋白质,结果显示与线粒体核糖体和突触功能相关的蛋白质得到了富集。利用平行反应监测(PRM)进行的进一步独立分析表明,Cox7c、Mrp142、Naa30、Ighm、Apoa4、Ssu72、Mrps30、Apoh、Acbd5 和 Cdv3 在 NOR 处理组中表现出调节作用,以支持线粒体功能的平衡。此外,还观察到 Dcx、Arid1b、Rnf112 和 Fam3c 也在 NOR 处理组中受到调节,以支持突触的形成和功能。这些发现表明,参与抑郁治疗的蛋白质具有增强小鼠前脑功能区线粒体和突触功能的作用。Western印迹分析表明,CSDS小鼠体内Mrpl42、Cox7c、Naa30、Rnf112、Dcx Apoa4、Apoh和Fam3c的水平发生了改变,而NOR治疗可以挽救这些改变,这支持了PRM数据。NOR 治疗还能缓解 CSDS 小鼠 NLRP3 炎性体的激活。总之,目前对前额叶皮层进行的蛋白质组学研究为CSDS诱导的抑郁症的病理生理学和治疗提供了有价值的见解,揭示了诺力索波定的治疗效果。
{"title":"Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.","authors":"Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du","doi":"10.1038/s41398-024-03127-z","DOIUrl":"10.1038/s41398-024-03127-z","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS<sub>CON</sub>), imipramine (IMI)-treated versus CSDS (IMI<sub>CSDS</sub>), and NOR-treated versus CSDS (NOR<sub>CSDS</sub>) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR<sub>CSDS</sub> groups and NOR<sub>IMI</sub> groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR<sub>CSDS</sub> and NOR<sub>IMI,</sub> revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"400"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366637","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
LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents. 胰高血糖素受体反向激动剂 LEAP2 及其对啮齿动物酒精相关反应的影响。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03136-y
Maximilian Tufvesson-Alm, Cajsa Aranäs, Sebastian Blid Sköldheden, Jesper Vestlund, Christian E Edvardsson, Elisabet Jerlhag

The underlying neurobiology of alcohol use disorder (AUD) is complex and needs further unraveling, with one of the key mechanisms being the gut-brain peptide ghrelin and its receptor (GHSR). However, additional substrates of the ghrelin pathway, such as liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR inverse agonist, may contribute to this neurobiological framework. While LEAP2 modulates feeding and reward through central mechanisms, its effects on alcohol responses are unknown. The aim of the present study was therefore to identify the impact of central LEAP2 on the ability of alcohol to activate the mesolimbic dopamine system and to define its ability to control alcohol intake. These experiments revealed that central LEAP2 (i.e. into the third ventricle) prevented the ability of alcohol to cause locomotor stimulation in male mice, suppressed the memory of alcohol reward and attenuated the dopamine release in the nucleus accumbens caused by alcohol. Moreover, central LEAP2 reduced alcohol consumption in both male and female rats exposed to alcohol for 6 weeks before treatment. However, the serum levels of LEAP2 were similar between high- and low- alcohol-consuming (male) rats. Furthermore, central LEAP2 lowered the food intake in the alcohol-consuming male rats and reduced the body weight in the females. Collectively, the present study revealed that central LEAP2 mitigates alcohol-related responses in rodents, contributing to our understanding of the ghrelin pathway's role in alcohol effects.

酒精使用障碍(AUD)的潜在神经生物学非常复杂,需要进一步研究,其中一个关键机制是肠脑肽胃泌素及其受体(GHSR)。然而,胃泌素通路的其他底物,如肝表达抗菌肽 2(LEAP2),一种内源性 GHSR 反向激动剂,也可能有助于这一神经生物学框架。虽然 LEAP2 通过中枢机制调节进食和奖赏,但其对酒精反应的影响尚不清楚。因此,本研究旨在确定中枢 LEAP2 对酒精激活间叶多巴胺系统能力的影响,并确定其控制酒精摄入量的能力。这些实验表明,中枢LEAP2(即进入第三脑室)可阻止酒精对雄性小鼠运动能力的刺激,抑制对酒精奖赏的记忆,并减弱酒精在伏隔核中引起的多巴胺释放。此外,中枢 LEAP2 还能减少接触酒精 6 周的雄性和雌性大鼠的酒精消耗量。然而,高酒精消耗量和低酒精消耗量(雄性)大鼠血清中的LEAP2水平相似。此外,中枢 LEAP2 降低了饮酒雄性大鼠的食物摄入量,减轻了雌性大鼠的体重。总之,本研究揭示了中枢 LEAP2 可减轻啮齿类动物与酒精相关的反应,有助于我们了解胃泌素途径在酒精效应中的作用。
{"title":"LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents.","authors":"Maximilian Tufvesson-Alm, Cajsa Aranäs, Sebastian Blid Sköldheden, Jesper Vestlund, Christian E Edvardsson, Elisabet Jerlhag","doi":"10.1038/s41398-024-03136-y","DOIUrl":"10.1038/s41398-024-03136-y","url":null,"abstract":"<p><p>The underlying neurobiology of alcohol use disorder (AUD) is complex and needs further unraveling, with one of the key mechanisms being the gut-brain peptide ghrelin and its receptor (GHSR). However, additional substrates of the ghrelin pathway, such as liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR inverse agonist, may contribute to this neurobiological framework. While LEAP2 modulates feeding and reward through central mechanisms, its effects on alcohol responses are unknown. The aim of the present study was therefore to identify the impact of central LEAP2 on the ability of alcohol to activate the mesolimbic dopamine system and to define its ability to control alcohol intake. These experiments revealed that central LEAP2 (i.e. into the third ventricle) prevented the ability of alcohol to cause locomotor stimulation in male mice, suppressed the memory of alcohol reward and attenuated the dopamine release in the nucleus accumbens caused by alcohol. Moreover, central LEAP2 reduced alcohol consumption in both male and female rats exposed to alcohol for 6 weeks before treatment. However, the serum levels of LEAP2 were similar between high- and low- alcohol-consuming (male) rats. Furthermore, central LEAP2 lowered the food intake in the alcohol-consuming male rats and reduced the body weight in the females. Collectively, the present study revealed that central LEAP2 mitigates alcohol-related responses in rodents, contributing to our understanding of the ghrelin pathway's role in alcohol effects.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"401"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366635","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
Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease. 达伍内肽能提高前驱阿尔茨海默氏症患者的记忆力,但这与性别有关。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03118-0
Illana Gozes, Jason Blatt, Alexandra Lobyntseva

Background: The tauopathy inhibitor, davunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy. Extending these findings to prodromal Alzheimer's disease, we submitted a double-blind, placebo-controlled, 12 weeks/16 weeks follow-up, davunetide clinical trial results in amnestic mild cognitive impairment (ClinicalTrials.gov ID NCT00422981), to a sex-dependent analysis.

Methods: One hundred forty-four individuals, separated into eight groups (1:2 placebo-and 2 doses, 5 mg davunetide/daily or 15 mg davunetide/twice-daily, with matching placebo intranasal volumes), were evaluated.

Results: Significant dose-dependent cognitive increases were observed in men compared to women with a test of delayed (12 ss) visual matching to the sample. In a test of semantic working memory and attention (digit span), women showed a significant low-dose placebo effect, ensuing in a high dose significant davunetide improvement, over the matched placebo. Correlating anxiety with cognition showed sex-opposing results, with women depicting significant anxiety correlations with delayed matching to sample.

Discussion: In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role.

背景:tauopathy抑制剂达呋奈肽对患有进行性核上性麻痹的女性具有性别依赖性疗效。为了将这些发现推广到阿尔茨海默病的前驱期,我们提交了一项双盲、安慰剂对照、12周/16周随访、达武内肽治疗失忆性轻度认知障碍的临床试验结果(ClinicalTrials.gov ID NCT00422981),并进行了性别依赖性分析:方法:将144人分为8组(1:2安慰剂和2个剂量,5毫克达武尼肽/天或15毫克达武尼肽/天两次,同时配合安慰剂鼻内用量)进行评估:在对样本进行延迟(12 秒)视觉匹配测试时,男性的认知能力明显高于女性。在语义工作记忆和注意力(数字跨度)测试中,女性表现出显著的低剂量安慰剂效应,而高剂量达芙尼肽则比匹配的安慰剂有显著改善。将焦虑与认知相关联的结果与性别相反,女性在延迟与样本匹配的情况下表现出显著的焦虑相关性:总之,我们鼓励开发针对不同性别的阿尔茨海默氏症前驱期药物,其中达呋奈肽将发挥主导作用。
{"title":"Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease.","authors":"Illana Gozes, Jason Blatt, Alexandra Lobyntseva","doi":"10.1038/s41398-024-03118-0","DOIUrl":"10.1038/s41398-024-03118-0","url":null,"abstract":"<p><strong>Background: </strong>The tauopathy inhibitor, davunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy. Extending these findings to prodromal Alzheimer's disease, we submitted a double-blind, placebo-controlled, 12 weeks/16 weeks follow-up, davunetide clinical trial results in amnestic mild cognitive impairment (ClinicalTrials.gov ID NCT00422981), to a sex-dependent analysis.</p><p><strong>Methods: </strong>One hundred forty-four individuals, separated into eight groups (1:2 placebo-and 2 doses, 5 mg davunetide/daily or 15 mg davunetide/twice-daily, with matching placebo intranasal volumes), were evaluated.</p><p><strong>Results: </strong>Significant dose-dependent cognitive increases were observed in men compared to women with a test of delayed (12 ss) visual matching to the sample. In a test of semantic working memory and attention (digit span), women showed a significant low-dose placebo effect, ensuing in a high dose significant davunetide improvement, over the matched placebo. Correlating anxiety with cognition showed sex-opposing results, with women depicting significant anxiety correlations with delayed matching to sample.</p><p><strong>Discussion: </strong>In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"412"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366606","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
The involvement of K+ channels in depression and pharmacological effects of antidepressants on these channels. K+ 通道与抑郁症的关系以及抗抑郁药对这些通道的药理作用。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03069-6
Xian-Tao Li

Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the "monoamine hypothesis", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K+ channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K+ channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K+ channels, such as Kv, Kir and K2P, meaning the functioning of these drug via a "multi-target" manner. On the other hand, the scenario of antidepressants impinging K+ channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a "druggable target" to develop novel therapeutic compound to antagonize this psychiatry.

抑郁症是一种常见而复杂的精神疾病,具有多种临床症状,甚至会导致残疾和自杀。由于对抑郁样障碍的发病机理认识不足,现有的药物治疗策略主要基于 "单胺类假说",结果在临床实践中疗效有限,并产生了许多不良反应。多重致病因素的概念有助于明确抑郁症的病因并开发抗抑郁药物。有资料表明,K+通道在调节大脑神经元兴奋性和神经递质释放方面起着至关重要的作用,这些通道的异常参与了癫痫发作和阿尔茨海默病(AD)等多种中枢神经系统(CNS)病症的致病过程。临床和前临床证据还表明,几种类型的 K+ 通道参与抑郁样行为似乎是显而易见的,这表明这些通道是导致这种衰弱性疾病的多种病因之一。新出现的数据表明,不同的抗抑郁药物会影响不同的 K+ 通道,如 Kv、Kir 和 K2P,这意味着这些药物通过 "多靶点 "方式发挥作用。另一方面,抗抑郁药影响 K+ 通道的情况可以为临床试验中的药理作用和众多副作用提供另一种解释。此外,这些通道可被视为 "可药物靶点",以开发新型治疗化合物来拮抗这种精神疾病。
{"title":"The involvement of K<sup>+</sup> channels in depression and pharmacological effects of antidepressants on these channels.","authors":"Xian-Tao Li","doi":"10.1038/s41398-024-03069-6","DOIUrl":"10.1038/s41398-024-03069-6","url":null,"abstract":"<p><p>Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the \"monoamine hypothesis\", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K<sup>+</sup> channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K<sup>+</sup> channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K<sup>+</sup> channels, such as Kv, Kir and K<sub>2P</sub>, meaning the functioning of these drug via a \"multi-target\" manner. On the other hand, the scenario of antidepressants impinging K<sup>+</sup> channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a \"druggable target\" to develop novel therapeutic compound to antagonize this psychiatry.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"411"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366638","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
Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology. 研究前额叶皮质-丘脑-纹状体回路白质结构的 NODDI 指数与强迫症症状之间的关系。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03101-9
João Paulo Lima Santos, Amelia Versace, Manan Arora, Michele A Bertocci, Henry W Chase, Alex Skeba, Simona Graur, Lisa Bonar, Chiara Maffei, Anastasia Yendiki, Steven A Rasmussen, Suzanne N Haber, Mary L Phillips

Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.

强迫症是一种以侵入性思维和重复行为为特征的精神障碍。它有两个显著特征:伤害回避(HA)和不完整性(INC)。之前的静息态研究报告称,强迫症患者的前额叶皮质(PFC)和皮质下区域(丘脑、纹状体)之间的连接异常升高。然而,人们对这些连接中的白质(WM)结构异常却知之甚少。我们利用脑分割和分块、全脑束成像和神经元定向弥散和密度成像(NODDI)技术,旨在描述强迫症患者与健康对照组患者的白质结构异常,并确定这些连接的 NODDI 指数与所有参与者的阈下 HA、INC 和总体强迫症症状严重程度的相关程度。对四个 PFC 区域进行了分割:腹内侧 (vmPFC)、腹外侧 (vlPFC)、背内侧 (dmPFC) 和背外侧 (dlPFC)。从这些PFC区域与丘脑(42名强迫症患者,44名健康对照者,平均年龄[SD]=23.65[4.25]岁,女性占63.9%)和纹状体(38名强迫症患者,41名健康对照者,平均年龄[SD]=23.59[4.27]岁,女性占64.5%)之间的连接中提取了WM结构的NODDI神经元密度(NDI)和定向分散(ODI)指数。多变量协方差分析表明,这些指数没有组间差异。多变量回归模型显示,vmPFC-丘脑中更大的NDI、vmPFC-纹状体中更大的NDI和ODI以及dmPFC-丘脑连接中更大的NDI与更严重的INC相关(Q≤0.032)。这些发现凸显了NODDI在检查强迫症患者WM结构中的作用,为了解维度INC背后的特定WM改变提供了宝贵的见解,并有助于为具有耐药性症状的强迫症患者开发定制化治疗方法。
{"title":"Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology.","authors":"João Paulo Lima Santos, Amelia Versace, Manan Arora, Michele A Bertocci, Henry W Chase, Alex Skeba, Simona Graur, Lisa Bonar, Chiara Maffei, Anastasia Yendiki, Steven A Rasmussen, Suzanne N Haber, Mary L Phillips","doi":"10.1038/s41398-024-03101-9","DOIUrl":"10.1038/s41398-024-03101-9","url":null,"abstract":"<p><p>Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"410"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366610","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
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":"14 1","pages":"407"},"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
The relationship between COMT, proline, and negative symptoms in clinical high risk and recent psychosis onset. COMT、脯氨酸与临床高危人群和近期精神病患者的阴性症状之间的关系。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03099-0
James D Clelland, Hannah Hesson, Krista Ramiah, Julia Anderson, Abraham Thengampallil, Ragy R Girgis, Catherine L Clelland

Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) Val158Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total (n = 50, β = 0.066, adjusted p = 0.007) and global severity scores (n = 50, coefficient = 0.026, adjusted p = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores (n = 50, β-coefficient = 0.035, adjusted p = 0.044), although this result did not reach the Benjamini-Hochberg's threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = -0.005, adjusted p = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.

罹患精神病的临床高危人群(CHR)以及近期发病的精神病患者(RO)都会出现严重的负面症状,这些症状会对日常生活功能产生不利影响,并与不良预后有关,即使是那些没有转为精神病的患者也是如此。因此,针对消极症状的治疗可能会为治疗新近精神病发作(CHR)和新近精神病发作(RO)患者带来希望。在之前研究结果的基础上,我们研究了儿茶酚-O-甲基转移酶(COMT)Val158Met功能多态性和空腹外周脯氨酸浓度是否能预测CHR青少年和年轻成人或RO患者所经历的消极症状的严重程度。正如假设的那样,空腹血浆脯氨酸和 COMT 之间的相互作用可预测消极症状,通过消极症状评估量表(SANS)总分(n = 50,β = 0.066,调整后 p = 0.007)和总体严重性得分(n = 50,系数 = 0.026,调整后 p = 0.003)来衡量:较高的脯氨酸对 Val/Val 受试者有利,但对 Met 等位基因受试者不利。在一项辅助分析中,COMT x 脯氨酸交互作用也能预测通过消极症状临床评估访谈(CAINS)总分测量的症状(n = 50,β系数 = 0.035,调整后 p = 0.044),尽管这一结果未达到本杰明-霍奇伯格的显著性阈值。此外,与社交和人际交往功能(社交整体功能,系数 = -0.005,调整后 p = 0.055)的相关性也有显著性趋势。阴性症状很顽固,目前的药物基本上无法解决。这项研究进一步证实了外周脯氨酸与 COMT 之间的关系,这种关系会影响年轻 CHR 患者和 RO 患者的消极症状,如失乐症。较高的脯氨酸通过 COMT 对症状产生反向影响,这可能对开发早期干预和专门针对相互作用途径的治疗药物具有重要意义。
{"title":"The relationship between COMT, proline, and negative symptoms in clinical high risk and recent psychosis onset.","authors":"James D Clelland, Hannah Hesson, Krista Ramiah, Julia Anderson, Abraham Thengampallil, Ragy R Girgis, Catherine L Clelland","doi":"10.1038/s41398-024-03099-0","DOIUrl":"10.1038/s41398-024-03099-0","url":null,"abstract":"<p><p>Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) Val<sup>158</sup>Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total (n = 50, β = 0.066, adjusted p = 0.007) and global severity scores (n = 50, coefficient = 0.026, adjusted p = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores (n = 50, β-coefficient = 0.035, adjusted p = 0.044), although this result did not reach the Benjamini-Hochberg's threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = -0.005, adjusted p = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"409"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366639","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