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Trajectory of depressive symptoms over adolescence in autistic and neurotypical youth 自闭症和神经畸形青少年青春期抑郁症状的变化轨迹
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-05-02 DOI: 10.1186/s13229-024-00600-w
Blythe A. Corbett, Rachael A. Muscatello, Trey McGonigle, Simon Vandekar, Christina Burroughs, Sloane Sparks
Adolescence coincides with a dramatic rise in the onset of psychiatric conditions including depression. Depression symptoms may be particularly prevalent and impairing for youth with autism spectrum disorder (ASD). While prior research suggests adolescence is associated with worsening depression symptoms for typically developing (TD) and autistic youth, it is unclear if they follow a similar course. The study examined the trajectory of depressive symptoms in autistic and neurotypical youth over a 4-year longitudinal study using linear and logistic mixed effects models. In youth with clinically relevant depressive scores (t-score > 65), moderating factors (i.e., diagnosis, age, puberty, sex) were explored. During Year 1, the sample included 244 youth 10-to-13 years: 140 in the ASD group (36 females) and 104 in the TD group (46 females). Autistic youth had elevated depression scores compared to TD peers (p < 0.001) and females were higher than males in both groups (p = 0.001). There was significant diagnosis by age (p < 0.001) and diagnosis by pubertal stage (p < 0.05) interactions. In the ASD group, elevated depressive scores presented in early adolescence and decreased during middle adolescence and puberty, whereas the TD group showed the opposite trend with an increase in depression symptoms with advancing development. Limitations include an unequal sex distribution (fewer females), non-representative autistic sample (e.g., cognition and race/ethnicity), and potential confound of the COVID-19 pandemic. Autistic youth present with higher rates of depressive symptoms early in development; yet, approaching middle adolescence and puberty, the symptom trajectory in the autistic youth declines coinciding with an increase in the TD youth. While group trajectories are divergent, they lead to similar levels of depression in late adolescence with higher symptoms in females. Findings suggest a period of quiescence in depressive symptomology influenced by biopsychosocial factors impacting affective profiles.
青春期是包括抑郁症在内的精神疾病发病率急剧上升的时期。对于患有自闭症谱系障碍(ASD)的青少年来说,抑郁症状可能尤其普遍和严重。虽然先前的研究表明,青春期与典型发育期(TD)和自闭症青少年抑郁症状的恶化有关,但目前还不清楚他们是否会经历类似的过程。这项研究采用线性和逻辑混合效应模型,对自闭症青少年和神经畸形青少年的抑郁症状轨迹进行了为期四年的纵向研究。在具有临床相关抑郁评分(t-score > 65)的青少年中,对调节因素(即诊断、年龄、青春期、性别)进行了探讨。第一年的样本包括 244 名 10-13 岁的青少年:自闭症组 140 人(36 名女性),TD 组 104 人(46 名女性)。与 TD 青少年相比,自闭症青少年的抑郁评分较高(p < 0.001),两组中女性抑郁评分均高于男性(p = 0.001)。诊断与年龄(p < 0.001)和诊断与青春期阶段(p < 0.05)之间存在明显的交互作用。在ASD组中,抑郁评分在青春期早期升高,在青春期中期和青春期降低,而TD组则表现出相反的趋势,抑郁症状随着发育的推进而增加。该研究的局限性包括性别分布不均(女性较少)、自闭症样本不具代表性(如认知能力和种族/族裔)以及 COVID-19 大流行可能造成的混淆。自闭症青少年在发育早期出现抑郁症状的比例较高;然而,在接近青春期中期和青春期时,自闭症青少年的症状轨迹有所下降,而自闭症发育迟缓青少年的症状轨迹则有所上升。虽然各群体的症状轨迹不同,但他们在青春期晚期的抑郁程度相似,女性的症状更高。研究结果表明,受影响情感特征的生物-心理-社会因素的影响,抑郁症状会有一个静止期。
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引用次数: 0
Additive interaction between birth asphyxia and febrile seizures on autism spectrum disorder: a population-based study 出生时窒息和发热性癫痫对自闭症谱系障碍的叠加相互作用:一项基于人群的研究
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-04-10 DOI: 10.1186/s13229-024-00596-3
Yi Mao, Xindi Lin, Yuhan Wu, Jiayi Lu, Jiayao Shen, Shaogen Zhong, Xingming Jin, Jun Ma
Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder that can significantly impact an individual’s ability to socially integrate and adapt. It’s crucial to identify key factors associated with ASD. Recent studies link both birth asphyxia (BA) and febrile seizures (FS) separately to higher ASD prevalence. However, investigations into the interplay of BA and FS and its relationship with ASD are yet to be conducted. The present study mainly focuses on exploring the interactive effect between BA and FS in the context of ASD. Utilizing a multi-stage stratified cluster sampling, we initially recruited 84,934 Shanghai children aged 3–12 years old from June 2014 to June 2015, ultimately including 74,251 post-exclusion criteria. A logistic regression model was conducted to estimate the interaction effect after controlling for pertinent covariates. The attributable proportion (AP), the relative excess risk due to interaction (RERI), the synergy index (SI), and multiplicative-scale interaction were computed to determine the interaction effect. Among a total of 74,251 children, 192 (0.26%) were diagnosed with ASD. The adjusted odds ratio for ASD in children with BA alone was 3.82 (95% confidence interval [CI] 2.42–6.02), for FS alone 3.06 (95%CI 1.48–6.31), and for comorbid BA and FS 21.18 (95%CI 9.10–49.30), versus children without BA or FS. The additive interaction between BA and FS showed statistical significance (P < 0.001), whereas the multiplicative interaction was statistically insignificant (P > 0.05). This study can only demonstrate the relationship between the interaction of BA and FS with ASD but cannot prove causation. Animal brain experimentation is necessary to unravel its neural mechanisms. A larger sample size, ongoing monitoring, and detailed FS classification are needed for confirming BA-FS interaction in ASD. In this extensive cross-sectional study, both BA and FS were significantly linked to ASD. The coexistence of these factors was associated with an additive increase in ASD prevalence, surpassing the cumulative risk of each individual factor.
自闭症谱系障碍(ASD)是一种普遍存在的神经发育障碍,会严重影响个人融入社会和适应社会的能力。识别与 ASD 相关的关键因素至关重要。最近的研究分别将出生窒息(BA)和发热性癫痫发作(FS)与较高的 ASD 患病率联系起来。然而,有关 BA 和 FS 的相互作用及其与 ASD 的关系的研究尚未开展。本研究主要探讨在 ASD 的背景下 BA 和 FS 之间的交互作用。通过多阶段分层整群抽样,我们在2014年6月至2015年6月期间初步招募了84934名3-12岁的上海儿童,最终纳入了74251名排除标准后的儿童。在控制了相关协变量后,我们采用逻辑回归模型估算了交互效应。计算了可归因比例(AP)、交互作用导致的相对超额风险(RERI)、协同指数(SI)和乘法规模交互作用,以确定交互作用效应。在总共 74,251 名儿童中,有 192 人(0.26%)被诊断为 ASD。与没有 BA 或 FS 的儿童相比,仅有 BA 的儿童患 ASD 的调整后几率比为 3.82(95% 置信区间 [CI] 2.42-6.02),仅有 FS 的儿童患 ASD 的调整后几率比为 3.06(95% 置信区间 [CI] 1.48-6.31),合并有 BA 和 FS 的儿童患 ASD 的调整后几率比为 21.18(95% 置信区间 [CI] 9.10-49.30)。BA和FS之间的交互作用具有统计学意义(P 0.05)。这项研究只能证明 BA 和 FS 的交互作用与 ASD 的关系,但不能证明因果关系。要揭示其神经机制,还需要进行动物脑部实验。要证实BA与FS在ASD中的相互作用,还需要更大的样本量、持续的监测和详细的FS分类。在这项广泛的横断面研究中,BA 和 FS 都与 ASD 有显著关联。这些因素的共存与 ASD 患病率的叠加增加有关,超过了每个单独因素的累积风险。
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引用次数: 0
Systematic review and meta-analysis: multimodal functional and anatomical neural alterations in autism spectrum disorder 系统回顾和荟萃分析:自闭症谱系障碍的多模式功能和解剖学神经改变
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-04-04 DOI: 10.1186/s13229-024-00593-6
Zixuan Guo, Xinyue Tang, Shu Xiao, Hong Yan, Shilin Sun, Zibin Yang, Li Huang, Zhuoming Chen, Ying Wang
This meta-analysis aimed to explore the most robust findings across numerous existing resting-state functional imaging and voxel-based morphometry (VBM) studies on the functional and structural brain alterations in individuals with autism spectrum disorder (ASD). A whole-brain voxel-wise meta-analysis was conducted to compare the differences in the intrinsic functional activity and gray matter volume (GMV) between individuals with ASD and typically developing individuals (TDs) using Seed-based d Mapping software. A total of 23 functional imaging studies (786 ASD, 710 TDs) and 52 VBM studies (1728 ASD, 1747 TDs) were included. Compared with TDs, individuals with ASD displayed resting-state functional decreases in the left insula (extending to left superior temporal gyrus [STG]), bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), left angular gyrus and right inferior temporal gyrus, as well as increases in the right supplementary motor area and precuneus. For VBM meta-analysis, individuals with ASD displayed decreased GMV in the ACC/mPFC and left cerebellum, and increased GMV in the left middle temporal gyrus (extending to the left insula and STG), bilateral olfactory cortex, and right precentral gyrus. Further, individuals with ASD displayed decreased resting-state functional activity and increased GMV in the left insula after overlapping the functional and structural differences. The present multimodal meta-analysis demonstrated that ASD exhibited similar alterations in both function and structure of the insula and ACC/mPFC, and functional or structural alterations in the default mode network (DMN), primary motor and sensory regions. These findings contribute to further understanding of the pathophysiology of ASD.
这项荟萃分析旨在探讨现有的众多静息态功能成像和基于体素的形态测量(VBM)研究中关于自闭症谱系障碍(ASD)患者大脑功能和结构改变的最可靠的研究结果。为了比较自闭症谱系障碍(ASD)患者和典型发育患者(TDs)在固有功能活动和灰质体积(GMV)方面的差异,我们使用基于种子的 d Mapping 软件进行了全脑体素荟萃分析。共纳入了 23 项功能成像研究(786 例 ASD,710 例 TD)和 52 项 VBM 研究(1728 例 ASD,1747 例 TD)。与TDs相比,ASD患者的左侧岛叶(延伸至左侧颞上回(STG))、双侧前扣带回皮层/内侧前额叶皮层(ACC/MPFC)、左侧角回和右侧颞下回的静息态功能减弱,而右侧辅助运动区和楔前回的功能增强。在VBM荟萃分析中,ASD患者的ACC/MPFC和左侧小脑的GMV降低,而左侧颞中回(延伸至左侧岛叶和STG)、双侧嗅皮层和右侧前中央回的GMV升高。此外,在重叠功能和结构差异后,ASD 患者的静息态功能活动减少,而左侧脑岛的 GMV 增加。本研究的多模态荟萃分析表明,ASD患者的脑岛和ACC/MPFC在功能和结构上都表现出类似的改变,默认模式网络(DMN)、初级运动区和感觉区也存在功能或结构上的改变。这些发现有助于进一步了解 ASD 的病理生理学。
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引用次数: 0
Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons Shank3 缺乏症通过激活下丘脑 AgRP 神经元中的 p38α 引发自闭症样行为
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-04-03 DOI: 10.1186/s13229-024-00595-4
Shanshan Wu, Jing Wang, Zicheng Zhang, Xinchen Jin, Yang Xu, Youwen Si, Yixiao Liang, Yueping Ge, Huidong Zhan, Li peng, Wenkai Bi, Dandan Luo, Mengzhu Li, Bo Meng, Qingbo Guan, Jiajun Zhao, Ling Gao, Zhao He
SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3−/−) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3−/− mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.
SH3和多杏仁蛋白重复结构域蛋白3(SHANK3)单基因突变或缺乏会导致过度的刻板行为和社交能力受损,这在自闭症病例中经常出现。迄今为止,Shank3突变或缺失导致自闭症的潜在机制以及Shank3突变导致自闭症表型的大脑部位还未得到充分研究。下丘脑与刻板行为和交际能力有关。p38α是大脑炎症反应的介质,被认为是某些自闭症病例的潜在基因。然而,尚不清楚下丘脑和 p38α 是否与 Shank3 突变或缺乏导致的自闭症发病有关。研究人员利用京都基因组百科全书(KEGG)通路分析和免疫印迹法评估了Shank3基因敲除(Shank3-/-)小鼠下丘脑中交替的信号通路。家庭笼实时监测试验用于记录小鼠的刻板行为,三室试验用于监测小鼠的社会性。使用腺相关病毒9(AAV9)在弓状核(ARC)或激动相关肽(AgRP)神经元中表达p38α。D176A 和 F327S 突变表达组成活性 p38α。T180A 和 Y182F 突变表达了非活性 p38α。我们发现,Shank3通过调节AgRP神经元中p38α的活性来控制刻板行为和社会性。Shank3-/-小鼠下丘脑中磷酸化的p38水平显著升高。同样,在ARC或AgRP神经元中过表达p38α会引起野生型(WT)小鼠过度的刻板行为并损害其社交能力。值得注意的是,激活 AgRP 神经元中的 p38α 会增加刻板行为并损害社交能力。相反,AgRP 神经元中的 p38α 失活会显著改善 Shank3-/- 小鼠的自闭症行为。与此相反,激活原绒毛膜促皮质素(POMC)神经元中的 p38α 不会影响小鼠的刻板行为和社会性。我们证实,SHANK3 可调节下丘脑中磷酸化 p38 的水平,而 AgRP 神经元中的 p38α 失活可显著改善 Shank3-/- 小鼠的自闭症行为。然而,我们并未阐明 SHANK3 抑制 AgRP 神经元中 p38α 的生化机制。这些结果表明,Shank3缺陷通过激活AgRP神经元中的p38α信号转导而导致类似自闭症的行为,表明AgRP神经元中的p38α信号转导是Shank3突变相关自闭症的潜在治疗靶点。
{"title":"Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons","authors":"Shanshan Wu, Jing Wang, Zicheng Zhang, Xinchen Jin, Yang Xu, Youwen Si, Yixiao Liang, Yueping Ge, Huidong Zhan, Li peng, Wenkai Bi, Dandan Luo, Mengzhu Li, Bo Meng, Qingbo Guan, Jiajun Zhao, Ling Gao, Zhao He","doi":"10.1186/s13229-024-00595-4","DOIUrl":"https://doi.org/10.1186/s13229-024-00595-4","url":null,"abstract":"SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3−/−) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3−/− mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Detection of autism spectrum disorder-related pathogenic trio variants by a novel structure-based approach 用一种基于结构的新方法检测与自闭症谱系障碍相关的致病三元组变体
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-04-03 DOI: 10.1186/s13229-024-00590-9
Sadhna Rao, Anastasiia Sadybekov, David C. DeWitt, Joanna Lipka, Vsevolod Katritch, Bruce E. Herring
Glutamatergic synapse dysfunction is believed to underlie the development of Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) in many individuals. However, identification of genetic markers that contribute to synaptic dysfunction in these individuals is notoriously difficult. Based on genomic analysis, structural modeling, and functional data, we recently established the involvement of the TRIO-RAC1 pathway in ASD and ID. Furthermore, we identified a pathological de novo missense mutation hotspot in TRIO’s GEF1 domain. ASD/ID-related missense mutations within this domain compromise glutamatergic synapse function and likely contribute to the development of ASD/ID. The number of ASD/ID cases with mutations identified within TRIO’s GEF1 domain is increasing. However, tools for accurately predicting whether such mutations are detrimental to protein function are lacking. Here we deployed advanced protein structural modeling techniques to predict potential de novo pathogenic and benign mutations within TRIO’s GEF1 domain. Mutant TRIO-9 constructs were generated and expressed in CA1 pyramidal neurons of organotypic cultured hippocampal slices. AMPA receptor-mediated postsynaptic currents were examined in these neurons using dual whole-cell patch clamp electrophysiology. We also validated these findings using orthogonal co-immunoprecipitation and fluorescence lifetime imaging (FLIM-FRET) experiments to assay TRIO mutant overexpression effects on TRIO-RAC1 binding and on RAC1 activity in HEK293/T cells. Missense mutations in TRIO’s GEF1 domain that were predicted to disrupt TRIO-RAC1 binding or stability were tested experimentally and found to greatly impair TRIO-9’s influence on glutamatergic synapse function. In contrast, missense mutations in TRIO’s GEF1 domain that were predicted to have minimal effect on TRIO-RAC1 binding or stability did not impair TRIO-9’s influence on glutamatergic synapse function in our experimental assays. In orthogonal assays, we find most of the mutations predicted to disrupt binding display loss of function but mutants predicted to disrupt stability do not reflect our results from neuronal electrophysiological data. We present a method to predict missense mutations in TRIO’s GEF1 domain that may compromise TRIO function and test for effects in a limited number of assays. Possible limitations arising from the model systems employed here can be addressed in future studies. Our method does not provide evidence for whether these mutations confer ASD/ID risk or the likelihood that such mutations will result in the development of ASD/ID. Here we show that a combination of structure-based computational predictions and experimental validation can be employed to reliably predict whether missense mutations in the human TRIO gene impede TRIO protein function and compromise TRIO’s role in glutamatergic synapse regulation. With the growing accessibility of genome sequencing, the use of such tools in the accurate identifica
谷氨酸能突触功能障碍被认为是自闭症谱系障碍(ASD)和智力障碍(ID)在许多人身上发展的基础。然而,鉴定导致这些患者突触功能障碍的遗传标记物却非常困难。基于基因组分析、结构建模和功能数据,我们最近确定了 TRIO-RAC1 通路参与了 ASD 和 ID 的研究。此外,我们还在 TRIO 的 GEF1 结构域中发现了一个病理性的新发错义突变热点。该结构域中与ASD/ID相关的错义突变会损害谷氨酸能突触的功能,并可能导致ASD/ID的发生。在TRIO的GEF1结构域中发现突变的ASD/ID病例数量正在增加。然而,准确预测这种突变是否对蛋白质功能有害的工具却很缺乏。在这里,我们利用先进的蛋白质结构建模技术来预测 TRIO GEF1 结构域中潜在的新致病突变和良性突变。我们生成了突变的 TRIO-9 构建体,并在有机培养的海马切片的 CA1 锥体神经元中进行了表达。我们使用双全细胞膜片钳电生理学方法检测了这些神经元中 AMPA 受体介导的突触后电流。我们还利用正交共免疫沉淀和荧光寿命成像(FLIM-FRET)实验验证了这些发现,并在 HEK293/T 细胞中检测了 TRIO 突变体过表达对 TRIO-RAC1 结合和 RAC1 活性的影响。实验测试了 TRIO 的 GEF1 结构域中被认为会破坏 TRIO-RAC1 结合或稳定性的错义突变,结果发现这些突变极大地削弱了 TRIO-9 对谷氨酸能突触功能的影响。与此相反,在我们的实验测试中,TRIO 的 GEF1 结构域中被认为对 TRIO-RAC1 的结合或稳定性影响最小的错义突变并没有损害 TRIO-9 对谷氨酸能突触功能的影响。在正交试验中,我们发现大多数被预测为破坏结合的突变显示出功能缺失,但被预测为破坏稳定性的突变并未反映出我们从神经元电生理数据中得出的结果。我们提出了一种方法来预测 TRIO GEF1 结构域中可能损害 TRIO 功能的错义突变,并在有限的实验中测试其影响。本文所采用的模型系统可能存在的局限性可在今后的研究中加以解决。我们的方法并不能证明这些突变是否会带来 ASD/ID 风险,也不能证明这些突变会导致 ASD/ID 发病的可能性。我们在此表明,基于结构的计算预测和实验验证相结合,可以可靠地预测人类 TRIO 基因中的错义突变是否会阻碍 TRIO 蛋白的功能并损害 TRIO 在谷氨酸能突触调控中的作用。随着基因组测序技术的日益普及,利用此类工具准确鉴定病理突变将有助于诊断 ASD/ID。
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引用次数: 0
Clinical correlates of diagnostic certainty in children and youths with Autistic Disorder 自闭症儿童和青少年诊断确定性的临床相关性
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-04-03 DOI: 10.1186/s13229-024-00592-7
Eya-Mist Rødgaard, Borja Rodríguez-Herreros, Abderrahim Zeribi, Kristian Jensen, Valérie Courchesne, Elise Douard, David Gagnon, Guillaume Huguet, Sebastien Jacquemont, Laurent Mottron
Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians’ understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference. Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed. In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2. The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians. Some ADOS items may better capture the signs that are most associated with clinicians’ implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.
诊断自闭症的临床医生依赖于诊断标准和工具,以及基于临床专业知识的与自闭症相关的特殊体征和表现的隐性知识。这种隐性知识会影响诊断标准的解释,但无法直接观察到。相反,通过调查临床医生对自闭症诊断的确定性,可以深入了解他们对自闭症的理解。之前有报道称,自闭症诊断的确定性与症状负荷之间存在一定的相关性。在此,我们研究了诊断确定性与 ADOS 的特定项目以及包括头围在内的其他临床特征之间的关联。我们利用西蒙斯简易样本库(Simons Simplex Collection)中的表型数据调查了被诊断为自闭症患者(n = 1511,年龄在 4 至 18 岁之间)的诊断确定性的临床相关性。我们根据评估自闭症的 ADOS 模块对参与者进行了分层。我们研究了诊断确定性与 ADOS 总分、年龄和 ADOS 模块之间的关系。我们计算了在ADOS评估过程中出现或不出现不同体征时被诊断为最高确定性的几率比率。我们还评估了诊断确定性与其他认知和临床变量之间的关联。在 ADOS 的每个模块中,某些项目与诊断确定性的关系比其他项目更大。在所有三个 ADOS 模块中,确定性评级最高的个体的头围明显较高。反过来,头围与一些与诊断确定性相关的 ADOS 项目呈正相关,而在 ADOS 模块 2 的评估对象中,头围与言语/非言语智商比呈负相关。所调查的人群在年龄、智商、语言水平和 ADOS 总分等方面都是异质性的,这可能会妨碍识别仅存在于人口中某一亚群的关联。样本中确定性评分的变异性较低,这限制了识别与其他变量潜在关联的能力。此外,不同临床医生对诊断确定性的评分可能会有所不同。某些 ADOS 项目可能能更好地捕捉到与临床医生对自闭症的隐性认知最相关的体征。如果在未来的研究中得到验证,可能需要新的诊断工具对体征进行不同的加权,以更好地反映这一点,从而提高标准化评估的特异性。
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引用次数: 0
Neuroligin-2 shapes individual slow waves during slow-wave sleep and the response to sleep deprivation in mice 神经胶质蛋白-2塑造小鼠慢波睡眠期间的单个慢波以及对睡眠剥夺的反应
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-04-03 DOI: 10.1186/s13229-024-00594-5
Tanya Leduc, Hiba El Alami, Khadija Bougadir, Erika Bélanger-Nelson, Valérie Mongrain
Sleep disturbances are a common comorbidity to most neurodevelopmental disorders and tend to worsen disease symptomatology. It is thus crucial to understand mechanisms underlying sleep disturbances to improve patients’ quality of life. Neuroligin-2 (NLGN2) is a synaptic adhesion protein regulating GABAergic transmission. It has been linked to autism spectrum disorders and schizophrenia in humans, and deregulations of its expression were shown to cause epileptic-like hypersynchronized cerebral activity in rodents. Importantly, the absence of Nlgn2 (knockout: KO) was previously shown to alter sleep-wake duration and quality in mice, notably increasing slow-wave sleep (SWS) delta activity (1–4 Hz) and altering its 24-h dynamics. This type of brain oscillation is involved in memory consolidation, and is also a marker of homeostatic sleep pressure. Sleep deprivation (SD) is notably known to impair cognition and the physiological response to sleep loss involves GABAergic transmission. Using electrocorticographic (ECoG) recordings, we here first aimed to verify how individual slow wave (SW; 0.5-4 Hz) density and properties (e.g., amplitude, slope, frequency) contribute to the higher SWS delta activity and altered 24-h dynamics observed in Nlgn2 KO mice. We further investigated the response of these animals to SD. Finally, we tested whether sleep loss affects the gene expression of Nlgn2 and related GABAergic transcripts in the cerebral cortex of wild-type mice using RNA sequencing. Our results show that Nlgn2 KO mice have both greater SW amplitude and density, and that SW density is the main property contributing to the altered 24-h dynamics. We also found the absence of Nlgn2 to accelerate paradoxical sleep recovery following SD, together with profound alterations in ECoG activity across vigilance states. Sleep loss, however, did not modify the 24-h distribution of the hypersynchronized ECoG events observed in these mice. Finally, RNA sequencing confirmed an overall decrease in cortical expression of Nlgn2 and related GABAergic transcripts following SD in wild-type mice. This work brings further insight into potential mechanisms of sleep duration and quality deregulation in neurodevelopmental disorders, notably involving NLGN2 and GABAergic neurotransmission.
睡眠障碍是大多数神经发育障碍的常见合并症,往往会加重疾病症状。因此,了解睡眠障碍的内在机制对改善患者的生活质量至关重要。神经胶质蛋白-2(NLGN2)是一种调节 GABA 能传导的突触粘附蛋白。它与人类自闭症谱系障碍和精神分裂症有关,其表达的失调已被证明会导致啮齿类动物癫痫样超同步化脑活动。重要的是,Nlgn2的缺失(基因敲除:KO)先前已被证明会改变小鼠的睡眠-觉醒持续时间和质量,特别是会增加慢波睡眠(SWS)的δ活动(1-4赫兹)并改变其24小时的动态变化。这种类型的大脑振荡参与记忆巩固,同时也是平衡睡眠压力的标志。众所周知,睡眠不足(SD)会损害认知能力,而对睡眠不足的生理反应涉及 GABA 能传递。在此,我们首先利用皮层电图(ECoG)记录来验证 Nlgn2 KO 小鼠的慢波(SW;0.5-4 Hz)密度和特性(如振幅、斜率、频率)是如何导致较高的 SWS 三角活动和 24 小时动态变化的。我们进一步研究了这些动物对 SD 的反应。最后,我们使用 RNA 测序法检测了睡眠丧失是否会影响野生型小鼠大脑皮层中 Nlgn2 及相关 GABA 能转录物的基因表达。我们的结果表明,Nlgn2 KO小鼠的SW振幅和密度都更大,SW密度是导致24小时动态变化的主要特性。我们还发现,缺失 Nlgn2 会加速自毁性睡眠后的矛盾性睡眠恢复,同时在各种警觉状态下的心电图活动也会发生深刻变化。然而,失眠并没有改变在这些小鼠身上观察到的超同步心电图事件的 24 小时分布。最后,RNA 测序证实,野生型小鼠在自毁睡眠后,大脑皮层中 Nlgn2 和相关 GABA 能转录物的表达量总体下降。这项研究进一步揭示了神经发育障碍中睡眠时间和质量失调的潜在机制,特别是涉及NLGN2和GABA能神经传递的机制。
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引用次数: 0
Fetal brain growth and infant autistic traits. 胎儿大脑发育与婴儿自闭症特征。
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-02-28 DOI: 10.1186/s13229-024-00586-5
Ezra Aydin, Alex Tsompanidis, Daren Chaplin, Rebecca Hawkes, Carrie Allison, Gerald Hackett, Topun Austin, Eglė Padaigaitė, Lidia V Gabis, John Sucking, Rosemary Holt, Simon Baron-Cohen

Background: Structural differences exist in the brains of autistic individuals. To date only a few studies have explored the relationship between fetal brain growth and later infant autistic traits, and some have used fetal head circumference (HC) as a proxy for brain development. These findings have been inconsistent. Here we investigate whether fetal subregional brain measurements correlate with autistic traits in toddlers.

Methods: A total of 219 singleton pregnancies (104 males and 115 females) were recruited at the Rosie Hospital, Cambridge, UK. 2D ultrasound was performed at 12-, 20- and between 26 and 30 weeks of pregnancy, measuring head circumference (HC), ventricular atrium (VA) and transcerebellar diameter (TCD). A total of 179 infants were followed up at 18-20 months of age and completed the quantitative checklist for autism in toddlers (Q-CHAT) to measure autistic traits.

Results: Q-CHAT scores at 18-20 months of age were positively associated with TCD size at 20 weeks and with HC at 28 weeks, in univariate analyses, and in multiple regression models which controlled for sex, maternal age and birth weight.

Limitations: Due to the nature and location of the study, ascertainment bias could also have contributed to the recruitment of volunteer mothers with a higher than typical range of autistic traits and/or with a significant interest in the neurodevelopment of their children.

Conclusion: Prenatal brain growth is associated with toddler autistic traits and this can be ascertained via ultrasound starting at 20 weeks gestation.

背景:自闭症患者的大脑存在结构性差异。迄今为止,只有少数研究探讨了胎儿大脑发育与婴儿日后自闭症特征之间的关系,其中一些研究使用胎儿头围(HC)作为大脑发育的替代指标。这些研究结果并不一致。在此,我们研究了胎儿亚区域脑部测量是否与幼儿的自闭症特征相关:方法:英国剑桥罗西医院共招募了 219 名单胎孕妇(104 名男性和 115 名女性)。在怀孕 12 周、20 周和 26-30 周时进行二维超声波检查,测量头围 (HC)、心室心房 (VA) 和跨小脑直径 (TCD)。共有 179 名婴儿在 18-20 个月大时接受了随访,并填写了幼儿自闭症定量检查表(Q-CHAT)以测量自闭症特征:在单变量分析和控制性别、母亲年龄和出生体重的多元回归模型中,18-20个月大时的Q-CHAT得分与20周时的TCD大小和28周时的HC呈正相关:由于研究的性质和地点,招募的志愿者母亲中自闭症特质和/或对其子女的神经发育有浓厚兴趣的比例高于典型范围,这也可能导致确认偏差:结论:产前脑部发育与幼儿的自闭症特征有关,这可以通过从妊娠 20 周开始的超声波检查来确定。
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引用次数: 0
Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines 粒细胞巨噬细胞集落刺激因子诱导的自闭症谱系障碍患者巨噬细胞通过分泌促炎细胞因子对神经元树突产生不利影响
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-02-21 DOI: 10.1186/s13229-024-00589-2
Ryohei Takada, Michihiro Toritsuka, Takahira Yamauchi, Rio Ishida, Yoshinori Kayashima, Yuki Nishi, Mitsuru Ishikawa, Kazuhiko Yamamuro, Minobu Ikehara, Takashi Komori, Yuki Noriyama, Kohei Kamikawa, Yasuhiko Saito, Hideyuki Okano, Manabu Makinodan
A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.
越来越多的证据表明,外周组织和中枢神经系统的免疫功能障碍和炎症与自闭症谱系障碍(ASD)的神经发育缺陷有关。据报道,自闭症谱系障碍患者的血浆、血清和外周血单核细胞中促炎细胞因子的表达水平升高。这些细胞因子的表达水平与 ASD 行为障碍和症状的严重程度有关。在之前的一项研究中,我们小组报告了粒细胞-巨噬细胞集落刺激因子诱导的巨噬细胞(GM-CSF MΦ)中肿瘤坏死因子-α(TNF-α)的表达以及GM-CSF MΦ/M-CSF MΦ(巨噬细胞集落刺激因子诱导的巨噬细胞)中TNF-α的表达比率,ASD患者明显高于典型发育(TD)患者。然而,巨噬细胞和高表达细胞因子如何影响神经元的机制仍有待研究。为了阐明巨噬细胞对人类神经元的影响,我们使用了一种人类诱导多能干细胞衍生神经元与从五名TD患者和五名ASD患者外周血单核细胞中获得的分化巨噬细胞的共培养系统。所有参与者均为男性,日裔。我们的共培养实验结果表明,GM-CSF MΦ通过分泌促炎细胞因子(白细胞介素-1α和TNF-α)影响神经元树突的生长。来自ASD患者的巨噬细胞比来自TD患者的巨噬细胞产生的影响更严重。我们研究的主要局限性在于样本量较小,且性别偏向男性;使用了人工极化的巨噬细胞;无法直接观察来自同一个体的神经元和巨噬细胞之间的相互作用。我们的共培养系统揭示了在白细胞介素-1α和TNF-α的介导下,GM-CSF MΦ对ASD患者神经元的非细胞自主不良影响。这些结果可能支持了ASD的免疫功能紊乱假说,为了解其病理提供了新的视角。
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引用次数: 0
Naturally occurring low sociality in female rhesus monkeys: A tractable model for autism or not? 雌性恒河猴天生社交能力低下:自闭症的可控模型?
IF 6.2 1区 医学 Q1 Neuroscience Pub Date : 2024-01-31 DOI: 10.1186/s13229-024-00588-3
Ozge Oztan, Laura A Del Rosso, Sierra M Simmons, Duyen K K Nguyen, Catherine F Talbot, John P Capitanio, Joseph P Garner, Karen J Parker

Background: Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD.

Methods: Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models.

Results: Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found.

Limitations: This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores.

Conclusions: Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.

背景:自闭症谱系障碍(ASD)的特点是持续的社会交往障碍,并且男性偏多。我们已在雄性恒河猴中建立了自然发生的低社交性模型,作为自闭症社交特征的模型。社会性低的雄性恒河猴表现出社会交往减少和自闭症样特征负荷增加,这两种测量结果高度相关,并与脑脊液(CSF)精氨酸加压素(AVP)浓度低密切相关。然而,人们对雌性恒河猴的行为和神经化学特征知之甚少,也不知道雌性恒河猴的低社会性是否是自闭症的一个可控模型:方法:在非繁殖季节对N = 88只室外饲养的雌性恒河猴进行了社会行为评估(伦理观察;反向翻译的自闭症特质测量量表--猕猴社会反应性量表-修订版[mSRS-R])。从N = 16只猴子的非社会行为频率分布中收集了脑脊液和血液样本,并对AVP和催产素(OXT)的浓度进行了量化。数据采用一般线性模型进行分析:结果:非社会行为频率和 mSRS-R 评分在整个雌猴群体中呈连续分布,这与之前在雄猴群体中发现的情况相同。然而,雌猴的优势等级能显著预测mSRS-R得分,等级越高的个体表现出的类似自闭症的特征越少,这种关系以前在该猴群的雄猴身上没有观察到。雌猴在其他几个方面也与雄猴不同:社会行为频率与 mSRS-R 评分无关,AVP 浓度与任何社会行为测量值无关。雌性动物血液和脑脊液中的 AVP 浓度呈正相关,但没有发现任何与 OXT 测量相关的显著关系:该研究样本较小,且未考虑可能与女性 mSRS-R 评分相关的遗传、环境或其他神经化学指标:优势等级是预测雌性恒河猴自闭症样特征的最重要因素,而 CSF 神经肽浓度与雌性社会功能测量无关(这与之前在雄性恒河猴和男女自闭症儿童中发现的 CSF AVP 形成鲜明对比)。尽管是初步研究,但这些证据表明,该物种强大的母系组织可能会限制雌性恒河猴的低社会性作为自闭症模型的有用性。
{"title":"Naturally occurring low sociality in female rhesus monkeys: A tractable model for autism or not?","authors":"Ozge Oztan, Laura A Del Rosso, Sierra M Simmons, Duyen K K Nguyen, Catherine F Talbot, John P Capitanio, Joseph P Garner, Karen J Parker","doi":"10.1186/s13229-024-00588-3","DOIUrl":"10.1186/s13229-024-00588-3","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD.</p><p><strong>Methods: </strong>Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models.</p><p><strong>Results: </strong>Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found.</p><p><strong>Limitations: </strong>This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores.</p><p><strong>Conclusions: </strong>Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10829375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642504","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}
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Molecular Autism
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