小细胞催产素神经元在社会功能障碍中的选择性脆弱性-动脉网

Selective vulnerability of parvocellular oxytocin neurons in social dysfunction

Nature 等信源发布 2024-10-06 21:47

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AbstractSelective vulnerability offers a conceptual framework for understanding neurodegenerative disorders such as Parkinson’s disease, where specific neuronal types are selectively affected and adjacent ones are spared. However, the applicability of this framework to neurodevelopmental disorders, particularly those characterized by atypical social behaviors, such as autism spectrum disorder, remains uncertain.

摘要选择性脆弱性为理解帕金森氏病等神经退行性疾病提供了一个概念框架，其中特定的神经元类型被选择性地影响，而相邻的神经元则不受影响。然而，该框架对神经发育障碍的适用性，特别是那些以非典型社会行为为特征的疾病，如自闭症谱系障碍，仍然不确定。

Here we show that an embryonic disturbance, known to induce social dysfunction in male mice, preferentially impaired the gene expression crucial for neural functions in parvocellular oxytocin (OT) neurons—a subtype linked to social rewards—while neighboring cell types experienced a lesser impact. Chemogenetic stimulation of OT neurons at the neonatal stage ameliorated social deficits in early adulthood, concurrent with cell-type-specific sustained recovery of pivotal gene expression within parvocellular OT neurons.

在这里，我们表明，已知会诱发雄性小鼠社交功能障碍的胚胎障碍，优先损害了对小细胞催产素（OT）神经元神经功能至关重要的基因表达，这是一种与社会奖励相关的亚型，而邻近细胞类型的影响较小。新生儿期OT神经元的化学遗传刺激改善了成年早期的社会缺陷，同时细胞类型特异性持续恢复了小细胞OT神经元内关键基因的表达。

Collectively, our data shed light on the transcriptomic selective vulnerability within the hypothalamic social behavioral center and provide a potential therapeutic target through specific neonatal neurostimulation..

总的来说，我们的数据揭示了下丘脑社会行为中心内的转录组选择性脆弱性，并通过特定的新生儿神经刺激提供了潜在的治疗靶点。。

IntroductionThe applicability of the selective vulnerability framework1 to neurodevelopmental disorders (NDDs) remains uncertain. The pathogenesis of NDDs is closely associated with fetal genetic factors and maternal/environmental influences, such as maternal immune activation, gut microbiota, and medications administered during fetal brain development2,3,4,5.

引言选择性脆弱性框架1对神经发育障碍（NDD）的适用性仍不确定。NDDs的发病机制与胎儿遗传因素和母体/环境影响密切相关，例如母体免疫激活，肠道微生物群以及胎儿大脑发育过程中服用的药物2,3,4,5。

As these factors exert systemic effects on the entire nervous system, the precise mechanisms underlying the pathogenesis of NDDs remain largely elusive. For example, despite rapid advancements in our understanding of the neural circuits that regulate social behaviors in rodents6,7, it remains unclear whether specific neural cell types are selectively affected in pathological conditions that model NDDs.

由于这些因素对整个神经系统产生系统性影响，因此NDD发病机制的确切机制仍然难以捉摸。例如，尽管我们对调节啮齿动物社交行为的神经回路的理解取得了快速进展[6,7]，但尚不清楚特定的神经细胞类型是否在模拟NDD的病理条件下受到选择性影响。

To fill this knowledge gap, in this study, we focus on the OT neurons in the paraventricular hypothalamus (PVHOT neurons) in mouse models that exhibit social dysfunction.Decades of rodent studies have highlighted the significance of the OT system in the typical development of social behaviors, bond formation, and parental behaviors6,8,9.

为了填补这一知识空白，在这项研究中，我们专注于表现出社交功能障碍的小鼠模型中室旁下丘脑（PVHOT神经元）中的OT神经元。数十年的啮齿动物研究强调了OT系统在社会行为，债券形成和父母行为的典型发展中的重要性6,8,9。

Numerous brain regions express OT receptors10, emphasizing their widespread functions throughout the brain. Among the population of OT neurons, magnocellular PVHOT neurons exhibit bifurcated axonal projections to the posterior pituitary and various forebrain structures11. By contrast, parvocellular PVHOT neurons selectively project to the central brain, including the ventral tegmental area and substantia nigra, thereby modulating the dopamine system and contributing to social reward12,13,14.

。在OT神经元群体中，大细胞PVHOT神经元表现出对垂体后叶和各种前脑结构的分叉轴突投射11。相比之下，小细胞PVHOT神经元选择性地投射到中枢大脑，包括腹侧被盖区和黑质，从而调节多巴胺系统并促进社会回报12,13,14。

Additionally, parvocellular PVHOT neurons innervate the hindbrain and spinal cord, exerting diverse neuromodulatory effects on emotions, appetite, and pain11,15.Impairment of the OT system has b.

此外，小细胞PVHOT神经元支配后脑和脊髓，对情绪，食欲和疼痛产生多种神经调节作用11,15。OT系统的损伤有b。

Data availability

数据可用性

The snRNaseq data generated in this study have been deposited in the Gene Expression Omnibus database under accession code GSE245555. Source data are provided with this paper.

本研究中产生的snRNaseq数据已保存在Gene Expression Omnibus数据库中，登录号为GSE245555。本文提供了源数据。

Code availability

代码可用性

This paper does not report the original code. All Python and R scripts used in this manuscript are provided with this paper.

本文不报告原始代码。。

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Download referencesAcknowledgementsWe thank Kota Tamada and Toru Takumi (Kobe University), Teruhiro Okuyama (the Univ. of Tokyo), and members of the Miyamichi Lab for the critical reading of the manuscript, Ritsuko Morita and Hironobu Fujiwara for sharing the Sony SH800 cell sorter, Quan Wu and the DNA Analysis Facility at the Laboratory for Phyloinformatics for the advice on the snRNA-seq analysis, Masato Kinoshita and Hideki Enomoto for the advice on the MHFD, Takeshi Sakurai for sharing stop-hM3Dq mice, Addgene for the AAV productions, and the animal facility of RIKEN BDR for taking care of the animals.

下载参考文献致谢我们感谢Kota Tamada和Toru Takumi（神户大学），Teruhiro Okuyama（东京大学）以及宫城实验室成员对手稿的批判性阅读，Ritsuko Morita和Hironobu Fujiwara分享了Sony SH800细胞分选仪，Quan Wu和系统信息学实验室的DNA分析设施提供了snRNA-seq分析的建议，Masato Kinoshita和Hideki Enomoto提供了关于MHFD的建议，Takeshi Sakurai分享了stop-hM3Dq小鼠，Addgene用于AAV生产，以及RIKEN BDR照顾动物。

AAV OTp-mCherry was produced by the Viral Vector Core of Gunma University Initiative for Advanced Research (GIAR) under the support of the Brain/MINDS program from AMED JP20dm0207057 and JP21dm0207111 to Hirokazu Hirai. This work was supported by a RIKEN Junior Research Associate Program to M.T., JSPS KAKENHI (20K20589, 21H02587), and a RIKEN Center Project Grant to K.M.Author informationAuthors and AffiliationsLaboratory for Comparative Connectomics, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, JapanMasafumi Tsurutani, Teppei Goto, Mitsue Hagihara, Satsuki Irie & Kazunari MiyamichiGraduate School of Biostudies, Kyoto University, Kyoto, Kyoto, JapanMasafumi TsurutaniAuthorsMasafumi TsurutaniView author publicationsYou can also search for this author in.

AAV-OTp-mCherry由群马大学高级研究计划（GIAR）的病毒载体核心在AMED JP20dm0207057和JP21dm0207111向Hirokazu Hirai提供的Brain/MINDS计划的支持下生产。这项工作得到了麻省理工学院理研初级研究助理项目、JSPS KAKENHI（20K2058921H02587）以及理研中心项目对K.M.作者信息作者和附属机构比较连接组学实验室、理研生物系统动力学研究中心、神户、兵库、日本马萨富米·津鲁塔尼、Teppei Goto、Mitsue Hagihara、Satsuki Irie&Kazunari Miyamichi生物研究生院、京都大学、京都、日本马萨富米·津鲁塔尼作者出版物的支持也可以在中搜索此作者。

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PubMed Google ScholarTeppei GotoView作者出版物您也可以在

PubMed Google ScholarMitsue HagiharaView author publicationsYou can also search for this author in

PubMed Google Scholaramitsue HagiharaView作者出版物您也可以在

PubMed Google ScholarSatsuki IrieView author publicationsYou can also search for this author in

PubMed Google ScholarSatsuki IrieView作者出版物您也可以在

PubMed Google ScholarKazunari MiyamichiView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsM.T. and K.M. conceived the experiments. M.T. performed all the experiments and analyzed the data, with technical support from T.G., M.H., and S.I. M.T. and K.M. wrote the paper with help from all the authors.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献。T、 K.M.构思了这些实验。M、 T.在T.G.，M.H。和S.I.M.T.的技术支持下进行了所有实验并分析了数据，K.M.在所有作者的帮助下撰写了这篇论文。对应作者对应。

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Nature Communications thanks Dayu Lin, Takuya Osakada and the other, anonymous, reviewer for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleTsurutani, M., Goto, T., Hagihara, M. et al. Selective vulnerability of parvocellular oxytocin neurons in social dysfunction.

转载和许可本文引用本文Tsurutani，M.，Goto，T.，Hagihara，M。等人。小细胞催产素神经元在社交功能障碍中的选择性脆弱性。

Nat Commun 15, 8661 (2024). https://doi.org/10.1038/s41467-024-53092-wDownload citationReceived: 19 November 2023Accepted: 30 September 2024Published: 06 October 2024DOI: https://doi.org/10.1038/s41467-024-53092-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》158661（2024）。https://doi.org/10.1038/s41467-024-53092-wDownload引文接收日期：2023年11月19日接收日期：2024年9月30日发布日期：2024年10月6日OI：https://doi.org/10.1038/s41467-024-53092-wShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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