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The phenomenology of postpartum psychosis: preliminary findings from the Massachusetts General Hospital Postpartum Psychosis Project 产后精神病的现象学:马萨诸塞州总医院产后精神病项目的初步发现
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-06 DOI: 10.1038/s41380-024-02856-3
Lee S. Cohen, Miranda Arakelian, Taylor R. Church, Madison M. Dunk, Margaret L. Gaw, Hannah E. Yoon, Lauren A. Kobylski, Rachel Vanderkruik, Marlene P. Freeman

Postpartum psychosis (PP) is a severe psychiatric disorder–with limited data or consensus on diagnostic criteria and clinical presentation–that affects thousands of people each year. The Massachusetts General Hospital Postpartum Psychosis Project (MGHP3) was established to: 1) describe the phenomenology of PP, and 2) identify genomic and clinical predictors in a large cohort. Results thus far point to a richer understanding of the heterogeneity and complexity of this often-misunderstood illness and its nature over time. Data are collected from those who experienced PP within 6 months of delivery and within the 10 years prior to the MGHP3 interview. Participants provide information via the Mini International Neuropsychiatric Interview for Psychotic Disorders Studies (MINI-PDS), MGHP3© Questionnaire (including assessment of episode onset, duration, symptoms, and treatment received), and other relevant history. This retrospective study uses validated diagnostic tools to evaluate psychiatric history across participants’ lifetimes. Descriptive statistics (e.g., median values, frequencies) were conducted to describe the phenomenology of PP. As of November 3, 2022, 248 participants with histories of at least one episode of PP completed the MGHP3 interview. Most participants met criteria for Bipolar I Disorder with psychotic features (71.8%). During PP episode(s), participants reported odd beliefs or delusions (87.6%), persecutory delusions (75.2%), ideas of reference (55.8%), and visual (52.3%) and/or auditory (48.1%) hallucinations. The median time between delivery and symptom onset was 10 days (SD = 43.72). Most participants reported receiving medication (93.0%) and/or psychotherapy (65.9%). This report describes findings regarding the phenomenology of postpartum psychosis among the MGHP3 cohort, the largest cohort with validated PP studied to date. This ongoing effort to refine the phenotype of PP and to delineate underlying genetic determinants of the disorder will contribute to an enhanced understanding of this serious illness. It also underscores areas for further rigorous assessment using other research methods and sets the stage for translational reproductive neuroscience – including ongoing analyses of neuroimaging and genetic data from the MGHP3 cohort.

产后精神病(PP)是一种严重的精神疾病,在诊断标准和临床表现上的数据或共识有限,每年影响数千人。马萨诸塞州总医院产后精神病项目(MGHP3)的建立是为了:1)描述产后精神病的现象学,2)在一个大队列中确定基因组和临床预测因子。迄今为止的结果表明,人们对这种经常被误解的疾病的异质性和复杂性及其随时间推移的性质有了更丰富的了解。数据收集自分娩后6个月内和MGHP3访谈前10年内经历过PP的患者。参与者通过精神障碍研究迷你国际神经精神病学访谈(Mini - pds)、MGHP3©问卷(包括对发作、持续时间、症状和接受治疗的评估)和其他相关病史提供信息。本回顾性研究使用经过验证的诊断工具来评估参与者一生的精神病史。描述性统计(例如,中位数,频率)用于描述PP的现象学。截至2022年11月3日,248名至少有一次PP病史的参与者完成了MGHP3访谈。大多数参与者符合伴有精神病特征的双相I型障碍的标准(71.8%)。在PP发作期间,参与者报告了奇怪的信念或妄想(87.6%),受迫害的妄想(75.2%),参照的想法(55.8%),视觉(52.3%)和/或听觉(48.1%)幻觉。分娩至出现症状的中位时间为10 d (SD = 43.72)。大多数参与者报告接受药物治疗(93.0%)和/或心理治疗(65.9%)。本报告描述了MGHP3队列中产后精神病现象学的研究结果,MGHP3队列是迄今为止研究的最大的验证PP队列。这项正在进行的努力,旨在完善PP的表型,并描述该疾病的潜在遗传决定因素,将有助于加强对这种严重疾病的了解。它还强调了使用其他研究方法进行进一步严格评估的领域,并为转化生殖神经科学奠定了基础——包括对来自MGHP3队列的神经成像和遗传数据的持续分析。
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引用次数: 0
Delta opioid receptor agonists activate PI3K–mTORC1 signaling in parvalbumin-positive interneurons in mouse infralimbic prefrontal cortex to exert acute antidepressant-lie effects 阿片受体激动剂激活小鼠边缘下前额叶皮层细小蛋白阳性中间神经元PI3K-mTORC1信号,发挥急性抗抑郁作用
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-06 DOI: 10.1038/s41380-024-02814-z
Toshinori Yoshioka, Daisuke Yamada, Akari Hagiwara, Keita Kajino, Keita Iio, Tsuyoshi Saitoh, Hiroshi Nagase, Akiyoshi Saitoh

The delta opioid receptor (DOP) is a promising target for novel antidepressants due to its potential for rapid action with minimal adverse effects; however, the functional mechanism underlying acute antidepressant actions remains elusive. We report that subcutaneous injection of the selective DOP agonist KNT-127 reduced immobility in the forced swimming test, and that this antidepressant-like response was reversed by intracerebroventricular injection of the selective mechanistic (or mammalian) target of rapamycin (mTOR) inhibitor rapamycin or the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. KNT-127 also alleviated social avoidance and reduced sucrose consumption (anhedonia) among chronic vicarious social defeat stress model mice, which were similarly reversed by PI3K and mTOR inhibitors. In addition, KNT-127 increased phosphorylation levels of the mTOR signaling-related proteins Akt and p70S6 kinase in medial prefrontal cortex as revealed by immunoblotting. In the forced swimming test, a microinfusion of KNT-127 and another DOP agonist SNC80 in the infralimbic prefrontal cortex (IL-PFC) attenuated the immobility, which were blocked by rapamycin and LY294002. Perfusion of KNT-127 onto IL-PFC slices increased miniature excitatory postsynaptic current frequency and reduced miniature inhibitory postsynaptic current frequency in pyramidal neurons as measured by whole-cell patch-clamping, and both responses were reversed by rapamycin. Imaging of brain slices from transgenic mice with DOP-promoter-driven green fluorescent protein revealed that most DOPs were expressed in parvalbumin-positive interneurons in the IL-PFC. These findings suggest that DOP agonists exert antidepressant-like actions by suppressing GABA release from parvalbumin-positive interneurons via the PI3K–Akt–mTORC1–p70S6 kinase pathway, thereby enhancing IL-PFC pyramidal neuron excitation.

delta阿片受体(DOP)是一种很有希望的新型抗抑郁药靶点,因为它具有快速作用和最小的不良反应的潜力;然而,急性抗抑郁作用的功能机制仍然难以捉摸。我们报道,皮下注射选择性DOP激动剂KNT-127减少了强迫游泳试验中的不动,并且这种抗抑郁样反应被脑室内注射雷帕霉素(mTOR)抑制剂雷帕霉素或磷脂酰肌醇-3激酶(PI3K)抑制剂LY294002的选择性机制(或哺乳动物)靶点逆转。在慢性替代性社会失败应激模型小鼠中,KNT-127还能缓解社交回避和减少蔗糖消耗(快感缺乏),类似地,PI3K和mTOR抑制剂也能逆转这种情况。此外,免疫印迹显示,KNT-127增加内侧前额叶皮层mTOR信号相关蛋白Akt和p70S6激酶的磷酸化水平。在强迫游泳试验中,在边缘下前额叶皮层(IL-PFC)微量注射KNT-127和另一种DOP激动剂SNC80,可以减轻雷帕霉素和LY294002阻断的不动。在IL-PFC切片上灌注KNT-127后,锥体神经元的兴奋性突触后电流频率增加,抑制性突触后电流频率降低,这两种反应被雷帕霉素逆转。DOPs启动子驱动的绿色荧光蛋白转基因小鼠的脑切片成像显示,大多数DOPs在IL-PFC的小白蛋白阳性中间神经元中表达。这些发现表明,DOP激动剂通过PI3K-Akt-mTORC1-p70S6激酶途径抑制小白蛋白阳性中间神经元的GABA释放,从而增强IL-PFC锥体神经元的兴奋,从而发挥抗抑郁样作用。
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引用次数: 0
Brain volumes in genetic syndromes associated with mTOR dysregulation: a systematic review and meta-analysis 与mTOR失调相关的遗传综合征的脑容量:系统回顾和荟萃分析
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41380-024-02863-4
Jonathan M. Payne, Kristina M. Haebich, Rebecca Mitchell, Kiymet Bozaoglu, Emma Giliberto, Paul J. Lockhart, Alice Maier, Silvia Velasco, Gareth Ball, Kathryn N. North, Darren R. Hocking

Background/objectives

Dysregulation of molecular pathways associated with mechanistic target of rapamycin (mTOR) and elevated rates of neurodevelopmental disorders are implicated in the genetic syndromes neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Noonan syndrome (NS). Given shared molecular and clinical features, understanding convergent and divergent implications of these syndromes on brain development may offer unique insights into disease mechanisms. While an increasing number of studies have examined brain volumes in these syndromes, the effects of each syndrome on global and subcortical brain volumes are unclear. Therefore, the aim of the current study was to conduct a systematic review and meta-analysis to synthesize existing literature on volumetric brain changes across TSC, FXS, NF1, and NS. Study outcomes were the effect sizes of the genetic syndromes on whole brain, gray and white matter, and subcortical volumes compared to typically developing controls.

Subjects/methods

We performed a series of meta-analyses synthesizing data from 23 studies in NF1, TSC, FXS, and NS (pooled N = 1556) reporting whole brain volume, gray and white matter volumes, and volumes of subcortical structures compared to controls.

Results

Meta-analyses revealed significantly larger whole brain volume, gray and white matter volumes, and subcortical volumes in NF1 compared to controls. FXS was associated with increased whole brain, and gray and white matter volumes relative to controls, but effect sizes were smaller than those seen in NF1. In contrast, studies in NS indicated smaller whole brain and gray matter volumes, and reduced subcortical volumes compared to controls. For individuals with TSC, there were no significant differences in whole brain, gray matter, and white volumes compared to controls. Volumetric effect sizes were not moderated by age, sex, or full-scale IQ.

Conclusions

This meta-analysis revealed that dysregulation of mTOR signaling across pre- and post-natal periods of development can result in convergent and divergent consequences for brain volume among genetic syndromes. Further research employing advanced disease modeling techniques with human pluripotent stem cell-derived in vitro models is needed to further refine our understanding of between and within syndrome variability on early brain development and identify shared molecular mechanisms for the development of pharmaceutical interventions.

背景/目的1型神经纤维瘤病(NF1)、结节性硬化症(TSC)、脆性X综合征(FXS)和努南综合征(NS)与雷帕霉素机制靶点(mTOR)相关的分子通路失调和神经发育障碍发生率升高有关。鉴于共同的分子和临床特征,了解这些综合征对大脑发育的趋同和不同影响可能为疾病机制提供独特的见解。虽然越来越多的研究检查了这些综合征的脑容量,但每种综合征对整体和皮层下脑容量的影响尚不清楚。因此,本研究的目的是进行系统回顾和荟萃分析,综合现有关于TSC、FXS、NF1和NS脑容量变化的文献。研究结果是遗传综合征对全脑、灰质和白质以及皮质下体积的影响大小,与典型发育对照组相比。研究对象/方法我们进行了一系列荟萃分析,综合了来自NF1、TSC、FXS和NS的23项研究的数据(汇总N = 1556),报告了与对照组相比的全脑体积、灰质和白质体积以及皮质下结构体积。结果荟萃分析显示,与对照组相比,NF1组的全脑体积、灰质和白质体积以及皮质下体积显著增大。与对照组相比,FXS与全脑、灰质和白质体积的增加有关,但效应值小于NF1。相比之下,NS组的研究表明,与对照组相比,全脑和灰质体积更小,皮质下体积也更小。对于患有TSC的个体,与对照组相比,全脑、灰质和白质体积没有显著差异。体积效应大小不受年龄、性别或全面智商的影响。本荟萃分析显示,mTOR信号在产前和产后发育期间的失调可能导致遗传综合征脑容量的趋同和分化后果。需要采用先进的疾病建模技术和人类多能干细胞衍生的体外模型进行进一步的研究,以进一步完善我们对早期大脑发育之间和内部综合征变异性的理解,并确定开发药物干预的共同分子机制。
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引用次数: 0
Cortical hypometabolism in Parkinson’s disease is linked to cholinergic basal forebrain atrophy 帕金森病的皮质代谢降低与胆碱能性基底前脑萎缩有关
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41380-024-02842-9
Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez, Niels Okkels, Laura Muñoz-Delgado, Jacob Horsager, Sandra Castro-Labrador, Pablo Franco-Rosado, Ana María Castellano-Guerrero, Elena Iglesias-Camacho, Manuela San-Eufrasio, Daniel Macías-García, Silvia Jesús, Astrid Adarmes-Gómez, Elena Ojeda-Lepe, Fátima Carrillo, Juan Francisco Martín-Rodríguez, Florinda Roldan Lora, David García-Solís, Per Borghammer, Pablo Mir, Michel J. Grothe

Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson’s disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [18F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [18F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R2 = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R2 = 0.16, p = 0.01). Topographic correspondence analysis with the [18F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman’s ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.

FDG-PET的皮质代谢低下是帕金森病(PD)认知障碍的一种公认的神经成像生物标志物,但其病理生理起源尚不完全清楚。基底前脑胆碱能变性(cBF)是pd相关认知障碍的一个重要病理特征,可能通过皮质投射区胆碱能失神经支配导致皮质代谢降低。在这里,我们研究了95名患有不同程度认知障碍的PD参与者在3T-MRI上的分区域cBF体积、[18F]FDG-PET上的皮质低代谢和认知缺陷之间的体内关联。我们在第二组队列中通过[18F]FEOBV-PET突触前胆碱能末端密度成像进一步评估了脑血流相关低代谢的皮质模式与PD中胆碱能失神经控制模式的空间对应关系。脑后皮质突出区体积较低与广泛的新皮质低代谢显著相关[p(FDR) < 0.05],这介导了脑后皮质萎缩和认知障碍之间的关联(介导比例:43%,p < 0.001)。在联合模型中,脑皮质后部萎缩比皮质局部萎缩更能解释皮质代谢低下(R2 = 0.26, p < 0.001)的差异(R2 = 0.16, p = 0.01)。与[18F]FEOBV-PET模式的地形对应分析显示,在PD中表现出最明显的cbf相关低代谢的皮质区域与表现出最严重的胆碱能失神经支配的皮质区域相对应(Spearman 's ρ = 0.57, p < 0.001)。综上所述,PD后脑皮质萎缩与失神经皮质靶区代谢降低选择性相关,从而介导脑皮质萎缩对认知功能障碍的影响。这些数据首次提供了体内证据,证明胆碱能变性是帕金森病患者认知障碍基础上皮层代谢低下的主要病理关联。
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引用次数: 0
Glial cell deficits are a key feature of schizophrenia: implications for neuronal circuit maintenance and histological differentiation from classical neurodegeneration 神经胶质细胞缺陷是精神分裂症的一个关键特征:对神经回路维持和经典神经变性的组织学分化的影响
IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41380-024-02861-6
Hans-Gert Bernstein, Madeleine Nussbaumer, Veronika Vasilevska, Henrik Dobrowolny, Thomas Nickl-Jockschat, Paul C. Guest, Johann Steiner
Dysfunctional glial cells play a pre-eminent role in schizophrenia pathophysiology. Post-mortem studies have provided evidence for significantly decreased glial cell numbers in different brain regions of individuals with schizophrenia. Reduced glial cell numbers are most pronounced in oligodendroglia, but reduced astrocyte cell densities have also been reported. This review highlights that oligo- and astroglial deficits are a key histopathological feature in schizophrenia, distinct from typical changes seen in neurodegenerative disorders. Significant deficits of oligodendrocytes in schizophrenia may arise in two ways: (i) demise of mature functionally compromised oligodendrocytes; and (ii) lack of mature oligodendrocytes due to failed maturation of progenitor cells. We also analyse in detail the controversy regarding deficits of astrocytes. Regardless of their origin, glial cell deficits have several pathophysiological consequences. Among these, myelination deficits due to a reduced number of oligodendrocytes may be the most important factor, resulting in the disconnectivity between neurons and different brain regions observed in schizophrenia. When glial cells die, it appears to be through degeneration, a process which is basically reversible. Thus, therapeutic interventions that (i) help rescue glial cells (ii) or improve their maturation might be a viable option. Since antipsychotic treatment alone does not seem to prevent glial cell loss or maturation deficits, there is intense search for new therapeutic options. Current proposals range from the application of antidepressants and other chemical agents as well as physical exercise to engrafting healthy glial cells into brains of schizophrenia patients.
功能失调的神经胶质细胞在精神分裂症病理生理中起着重要作用。死后研究提供了证据,证明精神分裂症患者大脑不同区域的神经胶质细胞数量显著减少。胶质细胞数量减少在少突胶质细胞中最为明显,但星形胶质细胞密度也有减少的报道。这篇综述强调了寡聚和星形胶质细胞缺陷是精神分裂症的一个关键的组织病理学特征,不同于神经退行性疾病的典型变化。精神分裂症患者少突胶质细胞的显著缺陷可能以两种方式出现:(i)成熟功能受损的少突胶质细胞死亡;(ii)由于祖细胞未成熟而缺乏成熟的少突胶质细胞。我们还详细分析了关于星形胶质细胞缺陷的争议。无论其来源如何,神经胶质细胞缺陷有几个病理生理后果。其中,由于少突胶质细胞数量减少而导致的髓鞘形成缺陷可能是最重要的因素,导致精神分裂症中观察到的神经元与大脑不同区域之间的连接断开。当神经胶质细胞死亡时,它似乎是通过退化,这一过程基本上是可逆的。因此,治疗干预(i)帮助拯救神经胶质细胞(ii)或促进其成熟可能是一个可行的选择。由于单靠抗精神病药物治疗似乎并不能预防神经胶质细胞的丧失或成熟缺陷,因此人们正在积极寻找新的治疗方案。目前的建议包括抗抑郁药和其他化学制剂的应用以及体育锻炼,以及将健康的神经胶质细胞植入精神分裂症患者的大脑。
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引用次数: 0
From placenta to the foetus: a systematic review of in vitro models of stress- and inflammation-induced depression in pregnancy 从胎盘到胎儿:妊娠期应激和炎症诱导的抑郁体外模型的系统综述
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41380-024-02866-1
Madeline Kirkpatrick, Gargi Mandal, Ismail Elhadidy, Nicole Mariani, Kristi Priestley, Carmine M. Pariante, Alessandra Borsini

Background

Depression in pregnancy can increase vulnerability for psychiatric disorders in the offspring, likely via the transfer of heightened maternal cortisol and cytokines to the in-utero environment. However, the precise cellular and molecular mechanisms, are largely unclear. Animal studies can represent this complex pathophysiology at a systemic level but are expensive and ethically challenging. While simpler, in vitro models offer high-throughput opportunities. Therefore, this systematic review integrates findings of in vitro models relevant to depression in pregnancy, to generate novel hypotheses and targets for intervention.

Methods

The systematic analysis covered studies investigating glucocorticoid or cytokine challenges on placental or foetal neural progenitor cells (NPCs), with or without co-treatment with sex hormones.

Results

Of the 50 included studies, 11 used placental cells and 39 NPCs; surprisingly, only one used a combination of oestrogen and cortisol, and no study combined placental cells and NPCs. In placental cells, cortisol or cytokines decreased nutrient transporter expression and steroidogenic enzyme activity, and increased cytokine production. NPCs exhibited decreases in proliferation and differentiation, via specific molecular pathways, namely, inhibition of hedgehog signalling and activation of kynurenine pathway. In these cells, studies also highlighted epigenetic priming of stress and inflammatory pathways.

Conclusions

Overall, results suggest that stress and inflammation not only detrimentally impact placental regulation of nutrients and hormones to the foetus, but also activate downstream pathways through increased inflammation in the placenta, ultimately eliciting adverse effects on foetal neurogenesis. Future research should investigate how sex hormones regulate these mechanisms, with the aim of developing targeted therapeutic approaches for depression in pregnancy.

背景怀孕期间的抑郁可能通过母体皮质醇和细胞因子向子宫内环境的转移而增加后代患精神疾病的脆弱性。然而,精确的细胞和分子机制在很大程度上是不清楚的。动物研究可以在系统水平上代表这种复杂的病理生理,但成本高昂,而且在伦理上具有挑战性。虽然更简单,但体外模型提供了高通量的机会。因此,本系统综述整合了与妊娠期抑郁相关的体外模型的发现,以产生新的假设和干预目标。方法系统分析研究糖皮质激素或细胞因子对胎盘或胎儿神经祖细胞(npc)的影响,并与性激素联合或不联合处理。结果纳入的50项研究中,11项使用胎盘细胞,39项使用npc;令人惊讶的是,只有一项研究将雌激素和皮质醇结合使用,没有一项研究将胎盘细胞和npc结合使用。在胎盘细胞中,皮质醇或细胞因子降低了营养转运蛋白的表达和类固醇生成酶的活性,并增加了细胞因子的产生。npc表现出增殖和分化的减少,通过特定的分子途径,即抑制刺猬信号传导和激活犬尿氨酸途径。在这些细胞中,研究还强调了应激和炎症途径的表观遗传启动。综上所述,应激和炎症不仅会影响胎盘对胎儿的营养和激素的调节,还会通过胎盘炎症的增加激活下游通路,最终对胎儿神经发生产生不利影响。未来的研究应该探究性激素如何调节这些机制,以开发针对妊娠抑郁症的靶向治疗方法。
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引用次数: 0
Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice 锂可以使dyrk1a敲入小鼠的asd相关神经元、突触和行为表型正常化
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41380-024-02865-2
Junyeop Daniel Roh, Mihyun Bae, Hyosang Kim, Yeji Yang, Yeunkeum Lee, Yisul Cho, Suho Lee, Yan Li, Esther Yang, Hyunjee Jang, Hyeonji Kim, Hyun Kim, Hyojin Kang, Jacob Ellegood, Jason P. Lerch, Yong Chul Bae, Jin Young Kim, Eunjoon Kim

Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.

Dyrk1A缺陷与多种神经发育障碍有关,包括发育迟缓、智力残疾(ID)和自闭症谱系障碍(ASD)。据报道,小鼠中Dyrk1a的单倍性不足会导致asd相关表型。然而,关键的病理机制尚不清楚,人类DYRK1A突变在小鼠中仍未表征。在这里,我们产生并研究了携带人类ASD患者突变(Ile48LysfsX2;Dyrk1a-I48K老鼠)。这些小鼠表现出严重的小头畸形、社交和认知缺陷、树突萎缩、兴奋性突触缺陷,以及富含多种信号通路和突触蛋白的磷酸化蛋白质组学模式改变。早期慢性锂治疗新生突变小鼠在幼年和成年阶段恢复了脑容量、行为、树突、突触和信号/突触磷酸化蛋白质组表型。这些结果表明,信号/突触改变有助于Dyrk1a-I48K小鼠的表型改变,并且通过锂处理对这些改变的早期纠正在预防幼年期和成年期表型方面具有持久的作用。
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引用次数: 0
X‐chromosome-wide association study for Alzheimer’s disease 阿尔茨海默病的X染色体全相关性研究
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 10.1038/s41380-024-02838-5
Julie Le Borgne, Lissette Gomez, Sami Heikkinen, Najaf Amin, Shahzad Ahmad, Seung Hoan Choi, Joshua Bis, Benjamin Grenier-Boley, Omar Garcia Rodriguez, Luca Kleineidam, Juan Young, Kumar Parijat Tripathi, Lily Wang, Achintya Varma, Rafael Campos-Martin, Sven van der Lee, Vincent Damotte, Itziar de Rojas, Sagnik Palmal, Richard Lipton, Eric Reiman, Ann McKee, Philip De Jager, William Bush, Scott Small, Allan Levey, Andrew Saykin, Tatiana Foroud, Marilyn Albert, Bradley Hyman, Ronald Petersen, Steven Younkin, Mary Sano, Thomas Wisniewski, Robert Vassar, Julie Schneider, Victor Henderson, Erik Roberson, Charles DeCarli, Frank LaFerla, James Brewer, Russell Swerdlow, Linda Van Eldik, Kara Hamilton-Nelson, Henry Paulson, Adam Naj, Oscar Lopez, Helena Chui, Paul Crane, Thomas Grabowski, Walter Kukull, Sanjay Asthana, Suzanne Craft, Stephen Strittmatter, Carlos Cruchaga, James Leverenz, Alison Goate, M. Ilyas Kamboh, Peter St George-Hyslop, Otto Valladares, Amanda Kuzma, Laura Cantwell, Matthias Riemenschneider, John Morris, Susan Slifer, Carolina Dalmasso, Atahualpa Castillo, Fahri Küçükali, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J. Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M. Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Jose Luís Royo, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Alexandre de Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnalek, Jesper Qvist Thomassen, Yolande A. L. Pijnenburg, Henne Holstege, John van Swieten, Inez Ramakers, Frans Verhey, Philip Scheltens, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Anne Boland, Jean-François Deleuze, Gael Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Benedetta Nacmias, Marco Spallazzi, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Paola Bossù, Carlo Masullo, Giacomina Rossi, Frank Jessen, Victoria Fernandez, Patrick Gavin Kehoe, Ruth Frikke-Schmidt, Magda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Jonathan Haines, Lindsay Farrer, Richard Mayeux, Li-San Wang, Rebecca Sims, Anita DeStefano, Gerard D. Schellenberg, Sudha Seshadri, Philippe Amouyel, Julie Williams, Wiesje van der Flier, Alfredo Ramirez, Margaret Pericak-Vance, Ole A. Andreassen, Cornelia Van Duijn, Mikko Hiltunen, Agustín Ruiz, Josée Dupuis, Eden Martin, Jean-Charles Lambert, Brian Kunkle, Céline Bellenguez

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 108) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 106). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

由于方法学上的原因,x染色体在阿尔茨海默病(AD)的主要全基因组关联研究中没有被纳入。为了解决这个问题并更好地描述AD的遗传景观,我们对115,841例AD病例或AD代理病例进行了深入的x染色体全关联研究(XWAS),其中包括52,214例临床诊断的AD病例和613,671例对照。我们考虑了三种方法来解释女性不同的x染色体失活(XCI)状态,即随机XCI,偏态XCI和逃逸XCI。我们没有检测到任何全基因组显著信号(P≤5 × 10−8),但鉴定出7个x染色体显著位点(P≤1.6 × 10−6)。索引变异在Xp22.32、FRMPD4、DMD和Xq25基因座中很常见,而在WNK3、PJA1和DACH2基因座中很少见。总的来说,这个功能强大的XWAS在x染色体的非假常染色体区域没有发现AD的遗传风险因素,但它发现了值得进一步研究的暗示信号。
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引用次数: 0
Deciphering white matter microstructural alterations in catatonia according to ICD-11: replication and machine learning analysis 根据ICD-11解读紧张症的白质微观结构变化:复制和机器学习分析
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-02 DOI: 10.1038/s41380-024-02821-0
Robin Peretzke, Peter F. Neher, Geva A. Brandt, Stefan Fritze, Sebastian Volkmer, Jonas Daub, Georg Northoff, Jonas Bohn, Yannick Kirchhoff, Saikat Roy, Klaus H. Maier-Hein, Andreas Meyer-Lindenberg, Dusan Hirjak

Catatonia is a severe psychomotor disorder characterized by motor, affective and cognitive-behavioral abnormalities. Although previous magnetic resonance imaging (MRI) studies suggested white matter (WM) dysconnectivity in the pathogenesis of catatonia, it is unclear whether microstructural alterations of WM tracts connecting psychomotor regions might contribute to a better classification of catatonia patients. Here, diffusion-weighted MRI data were collected from two independent cohorts (whiteCAT/replication cohort) of patients with (n = 45/n = 13) and without (n = 56/n = 26) catatonia according to ICD-11 criteria. Catatonia severity was examined using the Northoff (NCRS) and Bush-Francis (BFCRS) Catatonia Rating Scales. We used tract-based spatial statistics (TBSS), tractometry (TractSeg) and machine-learning (ML) to classify catatonia patients from tractometry values as well as tractomics features generated by the newly developed tool RadTract. Catatonia patients showed fractional anisotropy (FA) alterations measured via TractSeg in different corpus callosum segments (CC_1, CC_3, CC_4, CC_5 and CC_6) compared to non-catatonia patients across both cohorts. Our classification results indicated a higher level of performance when trained on tractomics as opposed to traditional tractometry values. Moreover, in the CC_6, we successfully trained two classifiers using the tractomics features identified in the whiteCAT data. These classifiers were applied separately to the whiteCAT and replication cohorts, demonstrating comparable performance with Area Under the Receiver Operating Characteristics (AUROC) values of 0.79 for the whiteCAT cohort and 0.76 for the replication cohort. In contrast, training on FA tractometry resulted in lower AUROC values of 0.66 for the whiteCAT cohort and 0.51 for the replication cohort. In conclusion, these findings underscore the significance of CC WM microstructural alterations in the pathophysiology of catatonia. The successful use of an ML based classification model to identify catatonia patients has the potential to improve diagnostic precision.

紧张症是一种严重的精神运动障碍,以运动、情感和认知行为异常为特征。尽管先前的磁共振成像(MRI)研究表明,白质(WM)连接障碍在紧张症的发病机制中起着重要作用,但目前尚不清楚连接精神运动区域的白质束的微结构改变是否有助于更好地对紧张症患者进行分类。在这里,根据ICD-11标准,从两个独立的队列(whiteCAT/复制队列)中收集弥散加权MRI数据,这些队列中有(n = 45/n = 13)和没有(n = 56/n = 26)紧张症患者。使用Northoff (NCRS)和Bush-Francis (BFCRS)紧张症评定量表检查紧张症严重程度。我们使用基于束的空间统计(TBSS),束测(tractsig)和机器学习(ML)根据束测值以及新开发的工具RadTract生成的束测特征对紧张症患者进行分类。与非紧张症患者相比,紧张症患者在不同胼胝体节段(CC_1, CC_3, CC_4, CC_5和CC_6)的TractSeg测量显示分数各向异性(FA)改变。我们的分类结果表明,与传统的肌束测量值相比,接受肌束切开术训练的患者表现更高。此外,在CC_6中,我们利用whiteCAT数据中识别的tractomics特征成功训练了两个分类器。这些分类器分别应用于白色ecat和复制队列,显示出与白色ecat队列的接受者工作特征下面积(AUROC)值(0.79)和复制队列的0.76相当的性能。相比之下,FA量测法训练导致白色ecat组的AUROC值较低,为0.66,复制组为0.51。总之,这些发现强调了CC - WM微结构改变在紧张症病理生理中的意义。成功地使用基于ML的分类模型来识别紧张症患者有可能提高诊断精度。
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引用次数: 0
Tempering an interpretation based on quality of data to make causal conclusions about race, inequities, and brain differences 根据数据质量调整解释,得出关于种族、不平等和大脑差异的因果结论
IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-30 DOI: 10.1038/s41380-024-02859-0
Michael S. Scheeringa
In volume 28 of this journal, Harnett et al. [1] reported their effort to understand how structural inequities partially explain differences between racial groups on neurophysiology and brain connectivity [1]. The authors’ interpretation was that inequities are a form of chronic stress of structural racism which acts on human development to cause enduring brain differences. Given the strong interest in unequal treatment of races and government’s history of intervening with a strong hand when justified by science, I believe this paper merits additional comment on how the findings were interpreted.
在该杂志的第28卷中,Harnett et al. b[1]报道了他们为理解结构不平等如何部分解释种族群体在神经生理学和大脑连通性方面的差异所做的努力b[1]。作者的解释是,不平等是结构性种族主义的一种慢性压力形式,它对人类的发展起作用,导致持久的大脑差异。考虑到人们对种族不平等待遇的强烈兴趣,以及政府在有科学依据的情况下以强硬手段进行干预的历史,我认为这篇论文值得对这些发现的解释进行额外的评论。
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引用次数: 0
期刊
Molecular Psychiatry
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