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Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum. 阿尔茨海默病连续体中两个神经解剖学 AI 维度的遗传和临床相关性。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-05 DOI: 10.1038/s41398-024-03121-5
Junhao Wen, Zhijian Yang, Ilya M Nasrallah, Yuhan Cui, Guray Erus, Dhivya Srinivasan, Ahmed Abdulkadir, Elizabeth Mamourian, Gyujoon Hwang, Ashish Singh, Mark Bergman, Jingxuan Bao, Erdem Varol, Zhen Zhou, Aleix Boquet-Pujadas, Jiong Chen, Arthur W Toga, Andrew J Saykin, Timothy J Hohman, Paul M Thompson, Sylvia Villeneuve, Randy Gollub, Aristeidis Sotiras, Katharina Wittfeld, Hans J Grabe, Duygu Tosun, Murat Bilgel, Yang An, Daniel S Marcus, Pamela LaMontagne, Tammie L Benzinger, Susan R Heckbert, Thomas R Austin, Lenore J Launer, Mark Espeland, Colin L Masters, Paul Maruff, Jurgen Fripp, Sterling C Johnson, John C Morris, Marilyn S Albert, R Nick Bryan, Susan M Resnick, Luigi Ferrucci, Yong Fan, Mohamad Habes, David Wolk, Li Shen, Haochang Shou, Christos Davatzikos

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

阿尔茨海默病(AD)与不同的萎缩模式有关。我们采用了一种名为 "超现实表征学习(Surreal-GAN)"的半监督表征学习技术,通过这种技术,我们确定了有症状的轻度认知障碍(MCI)和阿氏痴呆症患者脑萎缩的两个潜在维度表征:"弥漫-阿氏痴呆症"(R1)维度显示广泛的脑萎缩,而 "MTL-阿氏痴呆症"(R2)维度显示局灶性内侧颞叶(MTL)萎缩。重要的是,只有 R2 与 MCI 和 AD 患者基线时广为人知的散发性 AD 遗传风险因素(如 APOE ε4)相关。然后,我们将训练有素的模型应用于普通人群和两组无症状的认知障碍人群中,独立地检测了这两个维度在早期阶段的存在。在普通人群中,全基因组关联研究发现 77 个与 APOE 无关的基因与 R1 和 R2 有不同的关联。功能分析显示,这些基因在大脑(R1 和 R2)以外的器官(包括心脏(R1)和脑垂体、肌肉和肾脏(R2))的差异表达基因集中的代表性过高。这些基因富集在与树突状细胞(R2)、巨噬细胞功能(R1)和癌症(R1 和 R2)有关的生物通路中。其中几个基因是癌症(R1)、炎症(R1)、心血管疾病(R1)和神经系统疾病(R2)的 "可药用基因"。纵向进展显示,APOE ε4、淀粉样蛋白和 tau 在早期无症状阶段与 R2 相关,但这种纵向关联只出现在 R1 的晚期无症状阶段。我们的研究结果加深了我们对脑外多发性注意力缺失症发病机制的理解。在早期无症状阶段,这两个维度与不同的病理机制有关,包括心血管疾病、炎症和激素功能障碍,这些都是由不同于APOE的基因驱动的,它们可能共同促成了AD的早期发病机制。所有结果均可在 https://labs-laboratory.com/medicine/ 网站上公开获取。
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引用次数: 0
Probing the oral-brain connection: oral microbiome patterns in a large community cohort with anxiety, depression, and trauma symptoms, and periodontal outcomes. 探究口腔与大脑的联系:具有焦虑、抑郁和创伤症状的大型社区队列中的口腔微生物组模式以及牙周结果。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-05 DOI: 10.1038/s41398-024-03122-4
Stefanie Malan-Müller, Rebeca Vidal, Esther O'Shea, Eduardo Montero, Elena Figuero, Iñaki Zorrilla, Javier de Diego-Adeliño, Marta Cano, Maria Paz García-Portilla, Ana González-Pinto, Juan C Leza

The role of the oral microbiome in mental health has recently been appreciated within the proposed oral-brain axis. This study examined the structure and composition of the salivary microbiome in a large-scale population-based cohort of individuals reporting mental health symptoms (n = 306) compared to mentally healthy controls (n = 164) using 16S rRNA sequencing. Mental health symptoms were evaluated using validated questionnaires and included depression, anxiety, and posttraumatic stress disorder (PTSD), with accompanying periodontal outcomes. Participants also indicated current or previous diagnoses of anxiety, depression, periodontitis, and gingivitis. Mental and periodontal health variables influenced the overall composition of the oral microbiome. PTSD symptoms correlated with a lower clr-transformed relative abundance of Haemophilus sputorum and a higher clr-transformed relative abundance of Prevotella histicola. The clr-transformed relative abundance of P. histicola was also positively associated with depressive scores and negatively associated with psychological quality of life. Anxiety disorder diagnosis was associated with a lower clr-transformed relative abundance of Neisseria elongate and a higher clr-transformed relative abundance of Oribacterium asaccharolyticum. A higher clr-transformed relative abundance of Shuttleworthia and lower clr-transformed relative abundance of Capnocytophaga were evident in those who reported a clinical periodontitis diagnosis. Higher Eggerthia and lower Haemophilus parainfluenzae clr-transformed relative abundances were associated with reported clinical periodontitis diagnoses and psychotherapeutic efficacy. Functional prediction analysis revealed a potential role for tryptophan metabolism/degradation in the oral-brain axis, which was confirmed by lower plasma serotonin levels across symptomatic groups. This study sheds light on the intricate interplay between oral microbiota, periodontal and mental health outcomes, and a potential role for tryptophan metabolism in the proposed oral-brain axis, emphasizing the need for further exploration to pave the way for novel therapeutic interventions and predicting therapeutic response.

口腔微生物组在心理健康中的作用最近在拟议的口腔-大脑轴中得到了重视。本研究利用 16S rRNA 测序技术,对一个大规模人群队列中的唾液微生物组的结构和组成进行了研究,该人群队列中报告有精神健康症状的人(n = 306)与精神健康的对照组(n = 164)进行了比较。心理健康症状通过有效问卷进行评估,包括抑郁症、焦虑症和创伤后应激障碍(PTSD),以及相应的牙周症状。受试者还表示目前或以前曾被诊断患有焦虑症、抑郁症、牙周炎和牙龈炎。精神和牙周健康变量影响着口腔微生物组的整体组成。创伤后应激障碍症状与较低的唾液嗜血杆菌clr转换相对丰度和较高的组织前孢子菌clr转换相对丰度相关。组织胞浆菌的clr转换相对丰度也与抑郁评分呈正相关,与心理生活质量呈负相关。焦虑症诊断与较低的细长奈瑟氏菌clr转化相对丰度和较高的asaccharolyticum变形杆菌clr转化相对丰度有关。在报告临床牙周炎诊断的人群中,Shuttleworthia 的 clr 转化相对丰度较高,Capnocytophaga 的 clr 转化相对丰度较低。较高的Eggerthia和较低的副流感嗜血杆菌clr-转化相对丰度与报告的临床牙周炎诊断和心理治疗效果有关。功能预测分析揭示了色氨酸代谢/降解在口腔-大脑轴中的潜在作用,症状组血浆血清素水平较低也证实了这一点。这项研究揭示了口腔微生物群、牙周和心理健康结果之间错综复杂的相互作用,以及色氨酸代谢在拟议的口腔-大脑轴中的潜在作用,强调了进一步探索的必要性,以便为新型治疗干预和预测治疗反应铺平道路。
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引用次数: 0
Basolateral amygdala parvalbumin and cholecystokinin-expressing GABAergic neurons modulate depressive and anxiety-like behaviors. 杏仁核基底外侧副缬氨酸和胆囊收缩素表达的GABA能神经元调节抑郁和焦虑样行为
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-05 DOI: 10.1038/s41398-024-03135-z
Muhammad Asim, Huajie Wang, Abdul Waris, Jufang He

The basolateral amygdala (BLA) is increasingly recognized as a key regulator of depression and anxiety-like behaviors. However, the specific contribution of individual BLA neurons to these behaviors remains poorly understood. Building on our previous study, which demonstrated increased activity in glutamatergic BLA neurons in response to aversive stimuli and that enhancing inhibition in the BLA can alleviate depressive-like behaviors, we investigated the role of individual BLA GABAergic neurons (BLAGABA) in depressive and anxiety-like phenotypes. To address this question, we employed a comprehensive array of techniques, including c-fos staining, fiber photometry recording, optogenetic and chemogenetic manipulation, and behavior analysis. Our findings indicate that BLAGABA neurons show decreased activity during tail suspension and after chronic social defeat stress (CSDS) during social interaction. High-frequency activation of BLAGABA neurons attenuated depressive and anxiety-like behaviors, while low-frequency activation had no effect. Fiber photometry recordings revealed increased activity in BLA GABAergic neurons expressing somatostatin (SST), parvalbumin (PV), and cholecystokinin (CCK) during footshock aversive stimuli. Moreover, we found increased activity in PV and SST neurons and decreased activity in CCK-GABA neurons in the BLA during tail suspension stress. However, after CSDS, BLAPV neurons displayed decreased activity, while SST and CCK neurons showed no changes during the social interaction test. Behavioral analysis demonstrated that chemogenetic inhibition of PV and CCK-GABA neurons induced depressive and anxiety-like behaviors. whereas SST neuron inhibition had no effect. Conversely, chemogenetic activation of BLAPV neurons alleviated depressive behaviors, and activation of BLACCK-GABA neurons alleviated at least partly both depressive and anxiety-like behaviors. This study provides compelling evidence that BLAPV neurons play a critical role in regulating depressive-like behaviors, and that BLACCK-GABA neurons are involved, at least in part, in modulating both depressive-like and anxiety-like behaviors in mice.

人们越来越认识到,杏仁基底外侧(BLA)是抑郁和焦虑样行为的关键调节器。然而,人们对单个杏仁基底外侧神经元对这些行为的具体贡献仍然知之甚少。我们之前的研究表明,谷氨酸能BLA神经元对厌恶刺激的反应活动增加,而且增强BLA的抑制作用可以减轻抑郁样行为,在此基础上,我们研究了单个BLA GABA能神经元(BLAGABA)在抑郁和焦虑样表型中的作用。为了解决这个问题,我们采用了一系列综合技术,包括 c-fos 染色、纤维光度记录、光遗传和化学遗传操作以及行为分析。我们的研究结果表明,BLAGABA神经元在社会交往过程中的尾部悬吊和慢性社会挫败应激(CSDS)后活动减少。高频激活BLAGABA神经元可减轻抑郁和焦虑行为,而低频激活则没有影响。纤维光度记录显示,在脚震厌恶刺激时,BLA GABA能神经元表达躯体促肾上腺皮质素(SST)、副缬氨酸(PV)和胆囊收缩素(CCK)的活动增加。此外,我们还发现在尾部悬吊应激时,BLA中PV和SST神经元的活动增加,而CCK-GABA神经元的活动减少。然而,在 CSDS 后,BLAPV 神经元的活性降低了,而 SST 和 CCK 神经元在社会互动测试中的活性没有变化。行为分析表明,抑制PV和CCK-GABA神经元会诱发抑郁和焦虑行为,而抑制SST神经元则没有影响。相反,BLAPV神经元的化学激活可减轻抑郁行为,而BLACCK-GABA神经元的激活至少可部分减轻抑郁和焦虑行为。这项研究提供了令人信服的证据,证明 BLAPV 神经元在调节小鼠的抑郁样行为中起着关键作用,而 BLACCK-GABA 神经元至少部分参与调节小鼠的抑郁样行为和焦虑样行为。
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引用次数: 0
Deciphering autism heterogeneity: a molecular stratification approach in four mouse models. 解读自闭症的异质性:四种小鼠模型的分子分层方法。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-04 DOI: 10.1038/s41398-024-03113-5
Caroline Gora, Ana Dudas, Océane Vaugrente, Lucile Drobecq, Emmanuel Pecnard, Gaëlle Lefort, Lucie P Pellissier

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.

自闭症谱系障碍(ASD)是一种复杂的神经发育疾病,其特点是社交互动和沟通障碍,以及抑制或刻板行为。自闭症谱系中固有的异质性为开发针对核心特征的有效药物治疗带来了挑战。成功的临床试验需要确定可靠的标记物,以便对患者进行分层。在这项研究中,我们在社交回路的五个相互关联的大脑结构中鉴定了催产素和即刻早期基因家族中的分子标记物。我们使用了野生型小鼠和四种异质性小鼠模型,每种模型都表现出独特的自闭症谱系中的自闭症样行为。催产素家族的失调具有模型特异性,而即时早期基因则表现出广泛的改变,反映了四个模型的整体变化。通过综合分析,我们确定了 Egr1、Foxp1、Homer1a、Oxt 和 Oxtr 这五个稳健且具有鉴别性的分子标记,从而成功地对这四种模型进行了分层。重要的是,在挑战第五个小鼠模型或确定可能对催产素治疗有反应的小鼠亚群时,我们的分层显示出了预测价值。除了提供催产素和即刻早期基因 mRNA 动态的见解外,这项概念验证研究还向可能对 ASD 患者进行分层迈出了重要一步。这项工作对自闭症临床试验的成功和个性化药物的开发具有重要意义。
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引用次数: 0
Cortical kappa opioid receptors integrate negative affect and sleep disturbance. 皮层卡巴阿片受体整合了负性情绪和睡眠障碍。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-04 DOI: 10.1038/s41398-024-03123-3
Robson C Lillo Vizin, Hisakatsu Ito, Caroline M Kopruszinski, Megumi Ikegami, Daigo Ikegami, Xu Yue, Edita Navratilova, Aubin Moutal, Stephen L Cowen, Frank Porreca

Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.

睡眠障碍和消极情绪是许多精神和神经疾病的伴随特征,这些疾病往往同时存在,包括重度抑郁症、广泛性焦虑症和慢性疼痛。负面情绪与睡眠紊乱之间是否存在因果关系,目前仍不清楚。因此,我们想知道促进负面情绪的机制是否会扰乱睡眠,以及抑制病理性负面情绪是否能使扰乱的睡眠恢复正常。卡巴阿片受体(KOR)的信号在人类和动物中都会引起幻觉。我们测试了以下可能性:(a) 前扣带回皮层(ACC)是一个与负面情绪相关的脑区,KOR信号的增加足以促进厌恶情绪和睡眠紊乱;(b) KOR信号的抑制将使慢性疼痛引起的病理性负面情绪和睡眠紊乱恢复正常。化学遗传 Gi- 介导的对表达 KOR 的 ACC 神经元的抑制会产生条件性场所厌恶(CPA),并使天真小鼠的睡眠破碎化。CRISPR/Cas9 编辑 ACC KOR 使病理性慢性疼痛引起的负面情绪和睡眠中断正常化,同时保持了生理上关键的疼痛感觉特征。这些发现表明,KOR拮抗剂可用于治疗与负面情绪和睡眠障碍相关的疾病。
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引用次数: 0
Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography. 通过双谱脑电图发现治疗感染相关谵妄的新型保护剂。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-03 DOI: 10.1038/s41398-024-03130-4
Tsuyoshi Nishiguchi, Kyosuke Yamanishi, Shivani Patel, Johnny R Malicoat, Nathan James Phuong, Tomoteru Seki, Takaya Ishii, Bun Aoyama, Akiyoshi Shimura, Nipun Gorantla, Takehiko Yamanashi, Masaaki Iwata, Andrew A Pieper, Gen Shinozaki

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

谵妄是一种多因素的医学症状,随着时间的推移,精神功能的各个领域都会出现损伤。重要的是,谵妄也是导致长期住院、发病和死亡的最大风险因素之一。由于难以对患者进行客观诊断,也难以对实验室模型进行验证,因此研究这一重要病症极具挑战性。因此,目前还缺乏针对谵妄的保护性治疗方法。我们最近的研究报告显示,双谱脑电图(BSEEG)在诊断患者谵妄和预测患者预后方面具有疗效,从而推进了这一简单测量可代表患者额外生命体征的概念。在这里,我们应用 BSEEG 鉴定和验证了一种新型感染相关谵妄脂多糖(LPS)小鼠模型。然后,我们应用该模型评估了三种假定治疗药物的保护效力:传统抗精神病药物氟哌啶醇、神经保护化合物 P7C3-A20 和抗生素米诺环素。老年小鼠比年轻小鼠更容易受到LPS诱导的BSEEG畸变的影响,这让人联想到老年人更容易出现谵妄。无论是年轻小鼠还是老年小鼠,服用 P7C3-A20 和米诺环素都能防止 LPS 诱导的 BSEEG 异常。与此相反,氟哌啶醇却不能。P7C3-A20 和米诺环素已被证明能从不同方面限制 LPS 的毒性,我们的数据证明了这些药物可能有助于保护患者免于发生与感染相关的谵妄。因此,在感染相关谵妄的小鼠模型中利用 BSEEG 可以确定可应用于患者临床试验的治疗药物。
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引用次数: 0
Serum cytokines and inflammatory proteins in individuals with heroin use disorder: potential mechanistically based biomarkers for diagnosis. 海洛因使用障碍患者的血清细胞因子和炎症蛋白:用于诊断的潜在机理生物标志物。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-03 DOI: 10.1038/s41398-024-03119-z
Eduardo R Butelman, Yuefeng Huang, Flurin Cathomas, Pierre-Olivier Gaudreault, Panos Roussos, Scott J Russo, Rita Z Goldstein, Nelly Alia-Klein

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in the blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially considered as a multi-target biomarker. We used a validated proximity extension assay for the relative quantification of 92 cytokines and inflammatory proteins in the serum of iHUD on medication-assisted therapy (MAT; n = 21), compared to HC (n = 24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison corrections (p = 0.05). These targets included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, with PC1 scores showing significant group differences (iHUD > HC; p < 0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC = 91.7% (p < 0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, that included select demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, providing a multi-target "cytokine biomarker score" for potential diagnostic purposes, and future examination of disease severity.

阿片类药物使用障碍会导致严重的发病率和死亡率,因此迫切需要新的机理靶点和生物标志物来进行诊断和预后。接触μ阿片受体(MOR)激动剂会导致外周血细胞因子和炎症蛋白网络以及大脑胶质细胞和神经元发生变化。海洛因使用障碍(iHUD)患者血液中多种细胞因子水平失调。然而,有关 iHUD 与健康对照(HC)中此类标记物的综合数据有限,尤其是作为多目标生物标记物。我们使用了一种经过验证的近距离延伸测定法,对接受药物辅助治疗的 iHUD(MAT;n = 21)与健康对照组(n = 24)血清中的 92 种细胞因子和炎症蛋白进行了相对定量。经多重比较校正(P = 0.05),29 个靶标显示出明显的组间差异(主要是 iHUD>HC)。这些靶标包括 19 个典型细胞因子家族成员,包括特异性趋化因子、白细胞介素、生长因子和肿瘤坏死因子 (TNF) 相关蛋白。为了降维,将这 19 种细胞因子的数据输入主成分(PC)分析,PC1 分数显示出显著的组间差异(iHUD > HC; p
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引用次数: 0
Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes. 口服抗氧化剂依达拉奉可防止高海拔地区长期低压缺氧引起的认知障碍。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-03 DOI: 10.1038/s41398-024-03133-1
Yuan-Yuan Ma, Xin Li, Zhong-Yuan Yu, Tong Luo, Cheng-Rong Tan, Yu-Di Bai, Gang Xu, Bin-Da Sun, Xian-Le Bu, Yu-Hui Liu, Wang-Sheng Jin, Yu-Qi Gao, Xin-Fu Zhou, Juan Liu, Yan-Jiang Wang

Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.

高海拔地区的长期低压缺氧会损害认知功能,尤其是造成学习和记忆障碍,需要进行治疗干预。在这里,我们发现小鼠在一个月的低压缺氧(模拟海拔 5000 米)环境中会出现明显的认知功能障碍,同时大脑和血液中的氧化应激生物标志物水平也会升高。依达拉奉是一种被批准用于治疗缺血性中风和肌萎缩性脊髓侧索硬化症的自由基清除剂,口服依达拉奉的新型制剂可显著缓解氧化应激和慢性低压缺氧引起的认知障碍。此外,口服依达拉奉还能减轻神经炎症,恢复海马神经干细胞的衰竭。此外,骨膜蛋白(Postn)在慢性低压缺氧导致的认知障碍中起着至关重要的作用,可能是依达拉奉的一个分子靶点。总之,我们的研究结果表明,氧化应激在慢性低压缺氧导致的认知障碍中起着至关重要的作用,而口服依达拉奉是防止高海拔地区慢性低压缺氧导致的认知障碍的一种潜在药物。
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引用次数: 0
Dorsal raphe dopaminergic neurons target CaMKII+ neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors. 背侧剑突多巴胺能神经元以纹状体末端背侧床核的 CaMKII+ 神经元为靶点,介导抑郁相关行为。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03093-6
Wentao Wang, Dan Wang, Di Zhao, Lihong Xu, Shujun Jiang, Yu Zhang, Minghu Cui, Jing Liu, Fantao Meng, Cuilan Liu, Dunjiang Liu, Wei Li, Chen Li

Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II+ (CaMKII+) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRNDA → dBNSTCaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.

多巴胺(DA)神经元在抑郁症的发展和表现以及对抗抑郁治疗的反应中起着至关重要的作用。虽然主要分布在腹侧被盖区(VTA)的多巴胺神经元的功能已得到证实,但背侧剑突核(DRN)中的一小部分多巴胺神经元在抑郁症中的贡献仍不清楚。在这项研究中,我们发现慢性不可预知应激(CUS)会诱发抑郁相关行为,并降低DRN中DA神经元的自发发射率、兴奋性和抑制性突触后电流,这与雌雄小鼠兴奋性突触传递的减少有关。化学抑制 DRN 中的 DA 神经元会产生抑郁表型。相反,激活这些神经元则可完全逆转 CUS 所诱发的厌世和绝望行为。此外,我们还发现,投射到纹状体末端背侧床核(dBNST)的DRN多巴胺能通过调节dBNST中的多巴胺神经递质和多巴胺受体2(DR2),影响钙/钙调蛋白依赖性蛋白激酶II+(CaMKII+)靶神经元的神经活动和N-甲基-D-天冬氨酸受体(NMDAR)介导的EPSC,从而选择性地控制抑郁行为。总之,这些发现凸显了 DRNDA → dBNSTCaMKII+ 神经回路在双向介导应激诱导的抑郁相关行为中的重要作用。我们的研究结果表明,DRN DA神经元是参与调节抑郁相关行为的神经回路的关键组成部分,使其成为抑郁症的潜在治疗靶点。
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引用次数: 0
Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure. 神经精神疾病的拮抗 SNP 与人类大脑结构之间的关联。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03098-1
Lydia M Federmann, Friederike S David, Christiane Jockwitz, Thomas W Mühleisen, Dominique I Pelzer, Markus M Nöthen, Svenja Caspers, Katrin Amunts, Janik Goltermann, Till F M Andlauer, Frederike Stein, Katharina Brosch, Tilo Kircher, Sven Cichon, Udo Dannlowski, Lisa Sindermann, Andreas J Forstner

A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.

此前发表的一项全基因组关联研究(GWAS)荟萃分析发现,在八个神经精神疾病的十一个基因组位点上存在拮抗性单核苷酸多态性(SNPs),其中相同的等位基因对一种神经精神疾病具有保护作用,而对另一种神经精神疾病则会增加患病风险。迄今为止,这些拮抗 SNPs 与大脑结构表型的联系尚未得到进一步研究。在此,我们利用大规模脑结构表型 GWAS 的汇总统计,探讨了它们与皮质表面积和皮质厚度(分别在 34 个脑区和一个总体测量中)以及 8 个皮质下结构体积的关联。我们评估了在 ENIGMA 联盟进行的大规模病例对照成像研究中,与大脑结构表型明显相关的疾病是否与主要神经精神疾病有关。我们进一步确定了拮抗 SNP 对脑组织基因表达的影响及其与其他认知和行为表型的关联,并在 FOR2107 研究(n = 754 例重度抑郁障碍患者和 n = 847 例对照)中进行了基于体素的全脑探索性分析。我们发现,8 个拮抗 SNP 与扣带皮层前部、岛叶和颞上回等区域的大脑结构表型有显著关联。以前曾有报道称,在双相情感障碍、重度抑郁障碍和精神分裂症中,病例对照与大脑结构表型存在相关性差异。此外,拮抗 SNP 与脑组织中的基因表达变化有关,并与几种认知行为特征相关。在我们的探索性全脑分析中,我们观察到左上颞极和左上顶叶区的灰质体积分别与变异 rs301805 和 rs1933802 显著相关。我们的研究结果表明,神经精神疾病的多个拮抗 SNP 与大脑结构表型有关。然而,要进一步阐明这些发现,还需要未来的病例对照基因组成像研究。
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引用次数: 0
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Translational Psychiatry
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