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Restoring social deficits in IRSp53-deleted mice: chemogenetic inhibition of ventral dentate gyrus Emx1-expressing cells. 恢复 IRSp53 缺失小鼠的社交障碍:对腹侧齿状回 Emx1 表达细胞的化学抑制。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-07 DOI: 10.1038/s41398-024-03104-6
Su Hyun Kim, Bomee Lee, Seong Mi Lee, Yangsik Kim

IRSp53 is a synaptic scaffold protein reported to be involved in schizophrenia, autism spectrum disorders, and social deficits in knockout mice. Identifying critical brain regions and cells related to IRSp53 deletion is expected to be of great help in the treatment of psychiatric problems. In this study, we performed chemogenetic inhibition within the ventral dentate gyrus (vDG) of mice with IRSp53 deletion in Emx1-expressing cells (Emx1-Cre;IRSp53 flox/flox). We observed the recovery of social deficits after chemogenetic inhibition within vDG of Emx1-Cre;IRSp53 flox/flox mice. Additionally, chemogenetic activation induced social deficits in Emx1-Cre mice. CRHR1 expression increased in the hippocampus of Emx1-Cre;IRSp53 flox/flox mice, and CRHR1 was reduced by chemogenetic inhibition. Htd2, Ccn1, and Atp61l were decreased in bulk RNA sequencing, and Eya1 and Ecrg4 were decreased in single-cell RNA sequencing of the hippocampus in Emx1-Cre;IRSp53 flox/flox mice compared to control mice. This study determined that the vDG is a critical brain region for social deficits caused by IRSp53 deletion. Social deficits in Emx1-Cre;IRSp53 flox/flox mice were recovered through chemogenetic inhibition, providing clues for new treatment methods for psychiatric disorders accompanied by social deficits.

据报道,IRSp53 是一种突触支架蛋白,与精神分裂症、自闭症谱系障碍和基因敲除小鼠的社交障碍有关。识别与IRSp53缺失相关的关键脑区和细胞有望对精神疾病的治疗大有帮助。在这项研究中,我们对表达Emx1细胞(Emx1-Cre;IRSp53 flox/flox)的IRSp53缺失小鼠腹侧齿状回(vDG)进行了化学抑制。我们观察到,在Emx1-Cre;IRSp53 flox/flox小鼠的vDG内进行化学抑制后,社交障碍得到了恢复。此外,化学遗传激活也诱发了Emx1-Cre小鼠的社交障碍。CRHR1在Emx1-Cre;IRSp53 floatx/flox小鼠海马中的表达增加,CRHR1在化学基因抑制下减少。与对照组小鼠相比,Emx1-Cre;IRSp53 flox/flox小鼠海马的大体RNA测序结果显示Htd2、Ccn1和Atp61l减少,单细胞RNA测序结果显示Eya1和Ecrg4减少。这项研究确定,vDG是IRSp53缺失导致社交障碍的关键脑区。Emx1-Cre;IRSp53缺失/flox小鼠的社交障碍可通过化学抑制恢复,这为伴有社交障碍的精神疾病的新治疗方法提供了线索。
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引用次数: 0
Trajectories and predictors of suicidal ideation in clinical characteristics and pharmacological treatments for major depressive disorder: a study based on a national multi-centered prospective cohort. 重度抑郁障碍临床特征和药物治疗中自杀意念的轨迹和预测因素:基于全国多中心前瞻性队列的研究。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-06 DOI: 10.1038/s41398-024-03115-3
Ruoxi Ding, Xuequan Zhu, Lei Feng, Le Xiao, Ling Zhang, Ping He, Gang Wang

Suicidal ideation (SI) is a significant precursor and risk marker for suicide behaviors in major depressive disorder (MDD). Exploration of SI trajectory from a longitudinal framework are essential for treatment guidelines and clinical management of suicide risk. This study sought to explore SI trajectories and its associated clinical, sociodemographic characteristics, and initial treatment among patients with MDD. We used data from a non-interventional, national multi-centered prospective cohort study. 1 461 patients with MDD were included in the growth mixture modeling using SI at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 6 months, 9 months, and 12 months as the indicator. A multinomial regression was employed with SI trajectory as the outcome and anhedonia, depressive symptoms, atypical depressive symptoms, pharmacological treatments, and other covariates as the predictors. Four distinct SI trajectories were identified: a consistently low SI trajectory(50.7%), a persistently mild SI trajectory(20.6%), a fast declined SI trajectory(8.9%), and a slowly declined trajectory(19.8%). Compared to those with a consistently low SI trajectory, a higher score of anhedonia was associated with an increased risk of experiencing persistently mild (RRR = 1.20, 95%CI: 1.05, 1.38) and slowly declined SI (1.54, 95%CI: 1.32, 1.80). Severity of depressive symptom was also positively associated with the risk of experiencing persistently mild (1.15, 95%CI: 1.13, 1.18) and slowly declined SI (1.17, 95%CI: 1.14, 1.21). And the risk of experiencing slowly declined SI was higher for those use SSRI(1.49, 95%CI: 1.02, 2.31), and for those use antidepressant and antipsychotic/mood stabilizer combined therapy (3.78, 95%CI: 1.48, 9.61). The findings of this study are potentially useful for clinical practice as critical indicators of profiles and interventions for prognosis among patients with MDD. Further research is warranted to explore potential modifiable factors and the association between SI trajectories and suicide behavior.

自杀意念(SI)是重度抑郁障碍(MDD)患者自杀行为的重要前兆和风险标志。从纵向框架中探索自杀意念的轨迹对于自杀风险的治疗指南和临床管理至关重要。本研究旨在探索 SI 轨迹及其相关的临床、社会人口学特征以及 MDD 患者的初始治疗。我们使用了一项非干预性、全国性多中心前瞻性队列研究的数据。以基线、2 周、4 周、8 周、12 周、6 个月、9 个月和 12 个月时的 SI 为指标,对 1 461 名 MDD 患者进行了生长混合建模。以 SI 轨迹为结果,以失乐症、抑郁症状、非典型抑郁症状、药物治疗和其他协变量为预测因素,采用多项式回归。结果发现了四种不同的 SI 轨迹:持续低 SI 轨迹(50.7%)、持续轻度 SI 轨迹(20.6%)、快速下降 SI 轨迹(8.9%)和缓慢下降 SI 轨迹(19.8%)。与持续低 SI 轨迹的患者相比,失乐症得分越高,出现持续轻度 SI(RRR = 1.20,95%CI:1.05, 1.38)和缓慢 SI(1.54,95%CI:1.32, 1.80)的风险越高。抑郁症状的严重程度也与出现持续轻度(1.15,95%CI:1.13,1.18)和缓慢下降的 SI(1.17,95%CI:1.14,1.21)的风险呈正相关。而使用 SSRI(1.49,95%CI:1.02,2.31)和抗抑郁药与抗精神病药/情绪稳定剂联合疗法(3.78,95%CI:1.48,9.61)的患者出现 SI 缓慢下降的风险更高。这项研究的结果可能对临床实践很有帮助,因为它是预测 MDD 患者预后的概况和干预措施的关键指标。我们有必要开展进一步研究,探索潜在的可改变因素以及 SI 轨迹与自杀行为之间的关联。
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引用次数: 0
Cacna1c deficiency in forebrain glutamatergic neurons alters behavior and hippocampal plasticity in female mice. 前脑谷氨酸能神经元缺乏 Cacna1c 会改变雌性小鼠的行为和海马可塑性。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-06 DOI: 10.1038/s41398-024-03140-2
Srivaishnavi Loganathan, Danusa Menegaz, Jan Philipp Delling, Matthias Eder, Jan M Deussing

CACNA1C, coding for the α1 subunit of L-type voltage-gated calcium channel (LTCC) Cav1.2, has been associated with multiple psychiatric disorders. Clinical studies have revealed alterations in behavior as well as in brain structure and function in CACNA1C risk allele carriers. These findings are supported by rodent models of Cav1.2 deficiency, which showed increased anxiety, cognitive and social impairments as well as a shift towards active stress-coping strategies. These behavioral alterations were accompanied by functional deficits, such as reduced long-term potentiation (LTP) and an excitation/inhibition (E/I) imbalance. However, these preclinical studies are largely limited to male rodents, with few studies exploring sex-specific effects. Here, we investigated the effects of Cav1.2 deficiency in forebrain glutamatergic neurons in female conditional knockout (CKO) mice. CKO mice exhibited hyperlocomotion in a novel environment, increased anxiety-related behavior, cognitive deficits, and increased active stress-coping behavior. These behavioral alterations were neither influenced by the stage of the estrous cycle nor by the Nex/Neurod6 haploinsufficiency or Cre expression, which are intrinsically tied to the utilization of the Nex-Cre driver line for conditional inactivation of Cacna1c. In the hippocampus, Cav1.2 inactivation enhanced presynaptic paired-pulse facilitation without altering postsynaptic LTP at CA3-CA1 synapses. In addition, CA1 pyramidal neurons of female CKO mice displayed a reduction in dendritic complexity and spine density. Taken together, our findings extend the existing knowledge suggesting Cav1.2-dependent structural and functional alterations as possible mechanisms for the behavioral alterations observed in female Cav1.2-Nex mice.

编码 L 型电压门控钙通道(LTCC)Cav1.2 α1 亚基的 CACNA1C 与多种精神疾病有关。临床研究发现,CACNA1C 风险等位基因携带者的行为以及大脑结构和功能都发生了改变。Cav1.2 缺乏症的啮齿类动物模型也证实了这些研究结果,该模型显示焦虑、认知和社交障碍增加,并转向积极的压力应对策略。这些行为改变伴随着功能缺陷,如长期电位(LTP)降低和兴奋/抑制(E/I)失衡。然而,这些临床前研究主要局限于雄性啮齿动物,很少有研究探讨性别特异性效应。在这里,我们研究了雌性条件性基因敲除(CKO)小鼠前脑谷氨酸能神经元中 Cav1.2 缺失的影响。CKO小鼠在新环境中表现出过度运动、焦虑相关行为增加、认知障碍和主动压力应对行为增加。这些行为改变既不受发情周期阶段的影响,也不受Nex/Neurod6单倍体缺失或Cre表达的影响,这与利用Nex-Cre驱动系条件性失活Cacna1c有内在联系。在海马中,Cav1.2失活增强了突触前的成对脉冲促进,而不会改变CA3-CA1突触的突触后LTP。此外,雌性 CKO 小鼠的 CA1 锥体神经元显示出树突复杂性和棘密度的降低。总之,我们的研究结果扩展了现有的知识,表明依赖于Cav1.2的结构和功能改变是雌性Cav1.2-Nex小鼠行为改变的可能机制。
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引用次数: 0
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。
{"title":"Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum.","authors":"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","doi":"10.1038/s41398-024-03121-5","DOIUrl":"10.1038/s41398-024-03121-5","url":null,"abstract":"<p><p>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/ .</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"420"},"PeriodicalIF":5.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378342","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
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
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
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Translational Psychiatry
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