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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
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
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
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
Dietary habits and genetic susceptibility: correlations between nutritional intake and genetic risks for schizophrenia and bipolar disorder. 饮食习惯与遗传易感性:营养摄入与精神分裂症和躁狂症遗传风险之间的相关性。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-02 DOI: 10.1038/s41398-024-03105-5
Kazutaka Ohi, Daisuke Nishizawa, Taiga Saito, Taichi Goto, Itsuki Kubota, Tomoya Shinoda, Daisuke Fujikane, Junko Hasegawa, Naomi Sato, Fumihiko Tanioka, Haruhiko Sugimura, Kazutaka Ikeda, Toshiki Shioiri

Dietary habits may impact the prevention and management of schizophrenia (SCZ) and bipolar disorder (BD), and genetic and environmental factors can influence both these habits and these disorders. This study investigated the effects of genetic predispositions to SCZ and BD on current dietary habits among older adults with lifestyle-related diseases, potentially offering insights for preventive mental health strategies. A cohort of 730 older patients who were diagnosed with or suspected of having lifestyle-related diseases was assessed for eight current dietary categories: miso soup, Japanese tea, green and yellow vegetables, light-colored vegetables, fruits, pickles, meats, and soybeans. Polygenic risk scores (PRSs) for the risk of SCZ and BD, including BD types I and II, the shared risk of SCZ and BD, and the differentiation of SCZ from BD, were calculated utilizing data from large-scale genome-wide association studies (GWASs). Our findings revealed that PRSs for SCZ and BD risk significantly influenced specific dietary habits, particularly decreased consumption of nutrient-rich foods such as light-colored vegetables (SCZ, R2 = 0.0096, p = 3.54 × 10-3; BD, R2 = 0.0074, p = 9.09 × 10-3) and soybeans (SCZ, R2 = 0.0061, p = 0.019; BD, R2 = 0.014, p = 8.38 × 10-4). Notable differences in dietary effects were observed between PRSs for BD I and BD II, with a more pronounced impact associated with BD I (e.g., light-colored vegetables, BD I, R2 = 0.015, p = 3.11 × 10-4; BD II, p > 0.05). Moreover, shared genetic factors for SCZ and BD were correlated with lower intakes of miso soup (R2 = 0.013, p = 1.21 × 10-3), Japanese tea (R2 = 0.0092, p = 5.59 × 10-3), light-colored vegetables (R2 = 0.010, p = 2.92 × 10-3), and soybeans (R2 = 0.014, p = 3.13 × 10-4). No significant correlations were found between PRSs for differentiating SCZ from BD and any dietary patterns (p > 6.25 × 10-3). Genetic risks shared by individuals with SCZ and BD may influence dietary choices in older adults, emphasizing the potential for dietary modifications as part of comprehensive strategies for the prevention of the SCZ and BD onset, as well as for the treatment of individuals at risk of or diagnosed with SCZ and BD.

饮食习惯可能会影响精神分裂症(SCZ)和双相情感障碍(BD)的预防和管理,而遗传和环境因素会影响这些习惯和这些疾病。本研究调查了精神分裂症和双相情感障碍的遗传倾向对患有生活方式相关疾病的老年人当前饮食习惯的影响,从而为精神健康预防策略提供潜在的启示。研究人员对 730 名确诊或疑似患有生活方式相关疾病的老年患者进行了当前饮食习惯的八项评估:味噌汤、日本茶、绿色和黄色蔬菜、浅色蔬菜、水果、腌菜、肉类和大豆。利用大规模全基因组关联研究(GWAS)的数据,计算了SCZ和BD(包括BD I型和II型)的多基因风险评分(PRSs)、SCZ和BD的共同风险以及SCZ与BD的区别。我们的研究结果表明,SCZ 和 BD 风险的 PRSs 显著影响特定的饮食习惯,尤其是减少食用富含营养的食物,如浅色蔬菜(SCZ,R2 = 0.0096,p = 3.54 × 10-3;BD,R2 = 0.0074,p = 9.09 × 10-3)和大豆(SCZ,R2 = 0.0061,p = 0.019;BD,R2 = 0.014,p = 8.38 × 10-4)。在 BD I 和 BD II 的 PRS 之间观察到饮食影响的显著差异,BD I 的影响更为明显(如浅色蔬菜,BD I,R2 = 0.015,p = 3.11 × 10-4;BD II,p > 0.05)。此外,SCZ 和 BD 的共同遗传因子与味噌汤(R2 = 0.013,p = 1.21 × 10-3)、日本茶(R2 = 0.0092,p = 5.59 × 10-3)、浅色蔬菜(R2 = 0.010,p = 2.92 × 10-3)和大豆(R2 = 0.014,p = 3.13 × 10-4)的较低摄入量相关。区分 SCZ 和 BD 的 PRS 与任何饮食模式之间均未发现明显的相关性(p > 6.25 × 10-3)。SCZ和BD患者共有的遗传风险可能会影响老年人的饮食选择,这强调了饮食调整作为预防SCZ和BD发病的综合策略的一部分,以及治疗有SCZ和BD风险或确诊为SCZ和BD的患者的潜力。
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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
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。
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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。
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引用次数: 0
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Translational Psychiatry
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