AbstractDecades of research into the function of the medial temporal lobe has driven curiosity around clinical outcomes associated with hippocampal dysfunction, including psychosis. Post-mortem analyses of brain tissue from human schizophrenia brain show decreased expression of the NMDAR subunit GluN1 confined to the dentate gyrus with evidence of downstream hippocampal hyperactivity in CA3 and CA1.

摘要数十年来对内侧颞叶功能的研究引起了人们对与海马功能障碍（包括精神病）相关的临床结果的好奇。对人类精神分裂症大脑脑组织的尸检分析显示，局限于齿状回的NMDAR亚基GluN1的表达降低，并有证据表明CA3和CA1下游海马过度活跃。

Little is known about the mechanisms of the emergence of hippocampal hyperactivity as a putative psychosis biomarker. We have developed a reverse-translation mouse to study critical neural features. We had previously studied a dentate gyrus (DG)-specific GluN1 KO, which displays hippocampal hyperactivity and a psychosis-relevant behavioral phenotype.

关于海马过度活跃作为假定的精神病生物标志物出现的机制知之甚少。我们开发了一种反向翻译鼠标来研究关键的神经功能。我们之前曾研究过齿状回（DG）特异性GluN1 KO，它表现出海马活动过度和与精神病相关的行为表型。

Here, we expressed an inhibitory DREADD (pAAV-CaMKIIa-hM4D(Gi)-mCherry) in granule cells of the mouse dentate gyrus, and continuously inhibited the region for 21 days in adolescent (6 weeks) and adult (10 weeks) C57BL/6 J mice with DREADD agonist Compound 21 (C21). Following this period, we quantified activity in the hippocampal subfields by assessing cFos expression, hippocampally mediated behaviors, and hippocampal local field potential with an intracerebral probe with continual monitoring over time.

在这里，我们在小鼠齿状回的颗粒细胞中表达了抑制性DREADD（pAAV-CaMKIIa-hM4D（Gi）-mCherry），并在青少年（6周）和成人（10周）C57BL/6J小鼠中连续抑制该区域21天DREADD激动剂化合物21（C21）。在此期间，我们通过使用脑内探针评估cFos表达，海马介导的行为和海马局部场电位来量化海马亚区的活动，并随着时间的推移进行持续监测。

DG inhibition during adolescence generates an increase in hippocampal activity in CA3 and CA1, impairs social cognition and spatial working memory, as well as shows evidence of increased activity in local field potentials as spontaneous synchronous bursts of activity, which we term hyper-synchronous events (HSEs) in hippocampus.

青春期的DG抑制会导致CA3和CA1的海马活动增加，损害社会认知和空间工作记忆，并显示出局部场电位活动增加的证据，即自发同步爆发的活动，我们称之为超同步事件（HSEs）海马。

The same DG inhibition delivered during adulthood in the mouse lacks these outcomes. These results suggest a sensitive period in development in which the hippocampus is susceptible to DG inhibition resulti.

小鼠成年期间产生的相同DG抑制缺乏这些结果。这些结果表明海马对DG抑制结果敏感的发育敏感期。

IntroductionThe hippocampus is a brain region specialized for learning and memory functions, with a well-described anatomy, molecular functions, and circuit connectivity. Seminal observations regarding human memory have been generated through decades of research into the functions of the medial temporal lobe.

简介海马是一个专门用于学习和记忆功能的大脑区域，具有良好的解剖学，分子功能和电路连通性。通过对内侧颞叶功能的数十年研究，已经产生了关于人类记忆的开创性观察结果。

These data have driven curiosity around clinical conditions associated with hippocampal dysfunction. Learning and memory disorders are associated with hippocampal pathology. Among these are age-related memory loss and dementias [1, 2], anxiety with PTSD [3, 4], depression [5], and, of particular emphasis here, psychotic disorders [6, 7].Increased resting state neural activity in hippocampus, (i.e.

这些数据引起了人们对与海马功能障碍相关的临床状况的好奇。学习和记忆障碍与海马病理有关。其中包括与年龄有关的记忆丧失和痴呆[1，2]，PTSD焦虑[3，4]，抑郁症[5]，以及这里特别强调的精神病[6，7]。海马静息状态神经活动增加（即。

hippocampal hyperactivity) has been consistently observed in young people with schizophrenia, ascertained in vivo with brain imaging techniques [8,9,10], and localized to CA1 using high resolution MR methods [10,11,12,13]. In human post-mortem tissue analyses, in schizophrenia vs healthy control, we sought potential mechanisms for this hyperactivity [14], and reported reduced expression of GluN1 in dentate gyrus (DG), accompanied by increased markers of excitatory activity in CA3 and CA1.

海马活动过度）在精神分裂症年轻人中一直被观察到，通过脑成像技术在体内确定[8，9，10]，并使用高分辨率MR方法定位于CA1[10，11，12，13]。。

Further, subfield-selective transcriptome analysis of this human hippocampal tissue showed an increase in transcription of excitatory genes in CA3 in schizophrenia, while the transcriptome in CA1 was characterized by a compensatory alteration in the expression of genes involved in the excitatory/inhibitory balance [15].

此外，对这种人类海马组织的亚区选择性转录组分析显示，精神分裂症患者CA3中兴奋性基因的转录增加，而CA1中的转录组的特征是参与兴奋性/抑制性平衡的基因表达的补偿性改变〔15〕。

Recent DG transcriptome analysis in schizophrenia, specifically targeting granule cells, further confirms a decrease in genes related to neurotransmission in schizophrenia cases [16]. While there is some evidence that hippocampal hyperactivity in schizophrenia may be asso.

。虽然有证据表明精神分裂症患者的海马活动过度可能是相关的。

(1)

(1)

where \(Y\) is the dependent variable, E(Y) is the expected value, and g(Y) is the logistic link function that connects the expected value to the predictor variables. The terms f1(x1), …, fp(xp) denote smooth, non-parametric functions.The initial predictor in our analysis was the averaged amplitude of the time series raw data (LFP) across 32 channels.

其中\（Y \）是因变量，E（Y）是期望值，g（Y）是将期望值连接到预测变量的逻辑链接函数。术语f1（x1），…，fp（xp）表示平滑的非参数函数。我们分析中的初始预测因子是32个通道中时间序列原始数据（LFP）的平均幅度。

Additionally, animal position data recorded from the head was also used as a predictor. This positional data specifically focused on quiet and stable periods serving as a distinctive factor to discern from artifacts. Within GAMs, it is possible to adjust the influence of each predictor as needed; however, for our analysis, we presumed equal weight for both LFP amplitude and position.

此外，从头部记录的动物位置数据也被用作预测因子。。在GAMs中，可以根据需要调整每个预测变量的影响；但是，对于我们的分析，我们假设LFP振幅和位置的权重相等。

We randomly chose about 100 min of data (time series of varying duration 1–60 min) with fast spikes where we marked HSEs and artifacts in LFP recorded from CA1 and the corresponding position. We used this labeled data from two DG (−) Adolescent mice across 6 days as the training dataset for the GAM (L1).

我们随机选择了大约100分钟的数据（持续时间变化为1-60分钟的时间序列），这些数据具有快速峰值，我们在CA1和相应位置记录的LFP中标记了HSE和伪影。我们使用来自两只DG（-）青春期小鼠的6天标记数据作为GAM（L1）的训练数据集。

While this GAM layer cleaned up the data, we included another layer to further differentiate between HSEs and high amplitude control events. We randomly chose two single channel time series data from each of the 13 animals, specifically from CA1 and DG consisting of amplitude and normalized amplitude but excluding position data.

虽然这个GAM层清理了数据，但我们包括了另一层，以进一步区分HSE和高振幅控制事件。我们从13只动物中随机选择了两个单通道时间序列数据，特别是来自CA1和DG的数据，包括振幅和归一化振幅，但不包括位置数据。

This exclusion was possible because the HSE labels were already preserved from the first layer (L1) (Supplementary Fig. S3a, b). The model consisted of a two-layer processing approach: initially to eliminate artifacts, followed by determining the accurate count of HSEs/h.ResultsDentate gyrus inhibitionTo assess the effectiveness of DREADD-mediated DG inhibition, we first verified the regional specificit.

这种排除是可能的，因为HSE标签已经从第一层（L1）保留下来（补充图S3a，b）。该模型由两层处理方法组成：首先消除伪影，然后确定HSE/h的准确计数。结果齿状回抑制为了评估DREADD介导的DG抑制的有效性，我们首先验证了区域特异性。

Data availability

数据可用性

The data supporting this study are available from the corresponding authors upon reasonable request.

支持这项研究的数据可以根据合理的要求从通讯作者那里获得。

Code availability

代码可用性

The code for analyzing the data is available from the corresponding authors upon reasonable request.

根据合理的要求，通讯作者可以提供分析数据的代码。

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Download referencesAcknowledgementsThe authors acknowledge support from Dr. Wei Li for assistance in the execution of the immunohistochemistry, Mr. Paolo Chio for support in the behavioral analyses, and Dr. Pietro Scaduto for assistance in the collection of in vivo electrophysiological data.FundingThese studies were funded by NIMH R01 grants (5R01MH123479, CT; R01MH120135, JY), NARSAD Young Investigator Grant (27821, JY), and funding from the Sumitomo Foundation (170456, JY), and the Whitehall Foundation (20190851, JY).Author informationAuthors and AffiliationsDepartment of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USADaniel S.

。资助这些研究由NIMH R01拨款（5R01MH123479，CT；R01MH120135，JY），NARSAD青年研究者拨款（27821，JY）以及住友基金会（170456，JY）和白厅基金会（20190851，JY）资助。作者信息作者和附属机构美国德克萨斯州达拉斯德克萨斯大学西南医学中心精神病学系Daniel S。

Scott, Muthumeenakshi Subramanian, Jun Yamamoto & Carol A. TammingaO’Donnell Brain Institute, The University of Texas Southwestern Medical Center, Dallas, TX, USADaniel S. Scott, Jun Yamamoto & Carol A. TammingaDepartment of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX, USAJun YamamotoAuthorsDaniel S.

Scott，Muthumeenakshi Subramanian，Jun Yamamoto＆Carol A.TammingaO'Donnell Brain Institute，德克萨斯大学西南医学中心，德克萨斯州达拉斯，美国Daniel S.Scott，Jun Yamamoto＆Carol A.Tamminga Department of Neuroscience，德克萨斯大学西南医学中心，德克萨斯州达拉斯，美国Jun Yamamoto作者Daniel S。

ScottView author publicationsYou can also search for this author in.

ScottView作者出版物您也可以在中搜索此作者。

PubMed Google ScholarMuthumeenakshi SubramanianView author publicationsYou can also search for this author in

PubMed Google Scholarmauthumenakshi SubramanianView作者出版物您也可以在

PubMed Google ScholarJun YamamotoView author publicationsYou can also search for this author in

PubMed Google ScholarJun YamamotoView作者出版物您也可以在

PubMed Google ScholarCarol A. TammingaView author publicationsYou can also search for this author in

PubMed Google ScholarContributionsThe conception and design of the study, as well as acquisition, analysis, and interpretation of data were performed by DSS, in addition to the drafting of the article JY performed the acquisition and analysis of the in vivo electrophysiology.

PubMed谷歌学术贡献这项研究的概念和设计，以及数据的获取，分析和解释都是由DSS进行的，除了起草文章之外，JY还进行了体内电生理学的获取和分析。

MS developed and analyzed the large data set from the in vivo electrophysiology using the machine learning algorithm. CAT participated in the conceptual basis and design of the study and assisted in the analysis and interpretation of data, revision of the article, and final approval of the version to be submitted.

MS使用机器学习算法开发并分析了来自体内电生理学的大量数据集。CAT参与了该研究的概念基础和设计，并协助分析和解释数据，修订文章以及最终批准提交的版本。

All authors have no conflict of interest to report.Corresponding authorsCorrespondence to.

。通讯作者通讯。

Jun Yamamoto or Carol A. Tamminga.Ethics declarations

山本郡或卡罗尔·A·塔明加。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

。

Ethics approval and consent to participate

All experiments were performed with the relevant guidelines and regulations in accordance with protocols approved by the UT Southwestern Animal Resource Center (APN 2015-100852) and Institutional Animal Care and Use Committee.

所有实验均按照UT西南动物资源中心（APN 2015-100852）和机构动物护理和使用委员会批准的方案，按照相关指南和法规进行。

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Reprints and permissionsAbout this articleCite this articleScott, D.S., Subramanian, M., Yamamoto, J. et al. Schizophrenia pathology reverse-translated into mouse shows hippocampal hyperactivity, psychosis behaviors and hyper-synchronous events.

转载和许可本文引用本文Scott，D.S.，Subramanian，M.，Yamamoto，J。等人。精神分裂症病理学反向翻译为小鼠显示海马活动过度，精神病行为和超同步事件。

Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02781-5Download citationReceived: 20 December 2023Revised: 27 September 2024Accepted: 01 October 2024Published: 16 October 2024DOI: https://doi.org/10.1038/s41380-024-02781-5Share 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.

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