AbstractResistance to stress is a key determinant for mammalian functioning. While many studies have revealed neural circuits and substrates responsible for initiating and mediating stress responses, little is known about how the brain resists to stress and prevents overreactions. Here, we identified a previously uncharacterized neuropeptide Y (NPY) neuronal population in the dorsal raphe nucleus and ventrolateral periaqueductal gray region (DRN/vlPAG) with anxiolytic effects in male mice.

摘要抗压力是哺乳动物功能的关键决定因素。虽然许多研究揭示了负责启动和介导压力反应的神经回路和底物，但对大脑如何抵抗压力和防止过度反应知之甚少。在这里，我们在中缝背核和中脑导水管周围灰质腹外侧区（DRN/vlPAG）中发现了一个以前未表征的神经肽Y（NPY）神经元群，对雄性小鼠具有抗焦虑作用。

NPYDRN/vlPAG neurons are rapidly activated by various stressful stimuli. Inhibiting these neurons exacerbated hypophagic and anxiety responses during stress, while activation significantly ameliorates acute stress-induced hypophagia and anxiety levels and transmits positive valence. Furthermore, NPYDRN/vlPAG neurons exert differential but synergic anxiolytic effects via inhibitory projections to the paraventricular thalamic nucleus (PVT) and the lateral hypothalamic area (LH).

NPYDRN/vlPAG神经元被各种压力刺激迅速激活。抑制这些神经元会加剧应激期间的吞咽和焦虑反应，而激活会显着改善急性应激诱导的吞咽和焦虑水平，并传递正价。此外，NPYDRN/vlPAG神经元通过对脑室旁丘脑核（PVT）和下丘脑外侧区（LH）的抑制性投射发挥不同但协同的抗焦虑作用。

Together, our findings reveal a feedforward inhibition neural mechanism underlying stress resistance and suggest NPYDRN/vlPAG neurons as a potential therapeutic target for stress-related disorders..

总之，我们的研究结果揭示了应激抵抗的前馈抑制神经机制，并提示NPYDRN/vlPAG神经元是应激相关疾病的潜在治疗靶点。。

IntroductionStress affects the physiological functions and behaviors of individuals, yielding both positive and negative outcomes. On the positive side, stressors trigger the fight and flight response that is crucial to the performance and survival under threats1. On the negative side, impaired adaptation and resistance to stressful events can precipitate the onset or relapse of symptoms in a range of psychiatric and behavioral disorders, including anxiety2, depression3, hyperphagia4 or hypophagia5, and even posttraumatic stress disorder (PTSD)6.

引言压力影响个体的生理功能和行为，产生积极和消极的结果。从积极的方面来看，压力源引发了对威胁下的表现和生存至关重要的战斗和逃跑反应1。从消极的方面来看，对压力事件的适应和抵抗力受损可能会导致一系列精神和行为障碍的症状发作或复发，包括焦虑2，抑郁3，食欲亢进4或吞咽不足5，甚至创伤后应激障碍（PTSD）6。

A balance between two opposing stress and anti-stress mechanisms determines the overall impact of stress. The former renders organisms more sensitive and vulnerable to stress-related disorders, while the later imparts resilience and resistance. Thus, identifying mechanisms that make individuals resistant or less vulnerable to stressful stimuli is an important approach for the prevention of stress-related disorders.

两种相反的压力和抗压力机制之间的平衡决定了压力的整体影响。。因此，确定使个体抵抗或不易受到压力刺激的机制是预防压力相关疾病的重要方法。

Recent studies showed that many brain areas (such as the amygdala4, hypothalamus7 and hippocampus8) are implicated in initiating or mediating stress-induced changes in emotion and behavior. However, relatively little is known about the neuronal mechanisms of anti-stress, especially at the neural circuit level.Neuropeptide Y (NPY) is a 36-amino-acid peptide that plays important roles in the control of many basic physiological functions and behaviors, including vasoconstriction9, energy metabolism10, and feeding behavior11.

最近的研究表明，许多大脑区域（如杏仁核4，下丘脑7和海马8）与引发或介导压力引起的情绪和行为变化有关。然而，关于抗应激的神经元机制知之甚少，特别是在神经回路水平。神经肽Y（NPY）是一种36个氨基酸的肽，在控制许多基本生理功能和行为中起着重要作用，包括血管收缩9，能量代谢10和摄食行为11。

In addition, a number of reports indicate that NPY has anti-stress properties12. Direct administration of NPY into the brain ventricle or multiple brain areas reduces anxiety13,14, and high cerebral levels of NPY can prevent the development of stress-induced behavior disruption and freezing15. Consi.

此外，许多报告表明NPY具有抗压力特性12。将NPY直接给予脑室或多个大脑区域可减少焦虑13,14，大脑中高水平的NPY可防止压力引起的行为破坏和释放15的发展。Consi公司。

Data availability

数据可用性

All data generated in this study are provided within the article, Supplementary Information and Source Data file. Further information regarding to the findings in the present study are available from the corresponding authors upon request. Source data are provided with this paper.

本研究中产生的所有数据均在文章，补充信息和源数据文件中提供。有关本研究结果的更多信息，可应要求从通讯作者处获得。本文提供了源数据。

Code availability

代码可用性

Custom made codes for photometry data export and animal route tracking are available from the corresponding authors upon request.

可根据要求从通讯作者处获得用于光度数据输出和动物路线跟踪的定制代码。

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Download referencesAcknowledgementsThis work is supported by grants from the STI2030-Major Projects (2021ZD0203900 to C.Z.), the National Key R&D Program of China (2019YFA0801900 to T.L.), the National Natural Science Foundation of China (32271063, 31822026, 31500860 to C.Z.), Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYPY20220018 to C.Z.), the National Natural Science Foundation of China (92357304, 92249302 to T.L.), the Shanghai Municipal Science and Technology Major Project, International Human Phenome Project II (2023SHZDZX02 to T.L.), Faculty Resources Project of College of Life Sciences, Inner Mongolia University (2022-102 to T.L.), Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, the National Natural Science Foundation of China (32171144 to Z.Z.) and Shanghai Pujiang Program (22PJD007 to Z.Z.).Author informationAuthor notesThese authors contributed equally: Yan Zhang, Jiayi Shen.Authors and AffiliationsState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, ChinaYan Zhang, Famin Xie, Zhi Zhang & Tiemin LiuHuman Phenome Institute, Fudan University, Shanghai, ChinaYan Zhang & Tiemin LiuHefei National Research center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, ChinaYan Zhang, Meiting Cai & Cheng ZhanCenter for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaJiayi Shen, Zhiwei Liu, Liang Wang & Cheng ZhanInstitute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, ChinaFangfang Yin & Ping WuNational Institute of Biological Sciences, Beijing, ChinaMingxi.

下载参考文献致谢这项工作得到了STI2030重大项目（2021ZD0203900授予C.Z.），国家重点研发计划（2019YFA0801900授予T.L.），国家自然科学基金（3227106313263150860授予C.Z.），IHM高级跨学科科学与生物医学中心研究基金（QYPY20220018授予C.Z.），国家自然科学基金（9235730492249302授予T.L.），上海市科学技术重大项目，国际人类表型项目II（2023SHZDZX02）的资助。内蒙古大学生命科学学院教师资源项目（2022-102至T.L.），上海运动与代谢健康前沿科学研究基地，国家自然科学基金（32171144至Z.Z.）和上海浦江计划（22PJD007至Z.Z.）。作者信息作者注意到这些作者做出了同样的贡献：张燕，沈佳怡。作者和单位复旦大学生命科学学院基因工程国家重点实验室，上海，中国张燕，谢法敏，张志敏和刘铁敏，复旦大学人类现象研究所，上海，张燕和刘铁敏中国科学技术大学合肥国家微尺度物理科学研究中心，合肥，张燕，蔡美婷和程湛中国科学技术大学生命科学与医学系IHM高级跨学科科学与生物医学中心Wu国家生物科学研究所，北京，中国明溪。

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PubMed Google ScholarContributionsT.L. and C.Z. conceived the study. Y.Z. and C.Z. wrote the manuscript. Y.Z., J.S., F.X., Z.L., M.C., and M.C. conducted the experiments. F.Y. and L.W. built behavioral test apparatuses and the fiber photometry system. H.H., P.W. and Z.Z. provided intellectual expertise, assisted in interpreting the experimental findings and contributed to the manuscript revisions.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献者。五十、 C.Z.构思了这项研究。Y、 Z.和C.Z.写了手稿。Y、 Z.，J.S.，F.X.，Z.L.，M.C。和M.C.进行了实验。F、 Y.和L.W.建造了行为测试装置和光纤测光系统。H、 H.，P.W.和Z.Z.提供了知识专长，协助解释了实验结果，并为稿件修订做出了贡献。。

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Reprints and permissionsAbout this articleCite this articleZhang, Y., Shen, J., Xie, F. et al. Feedforward inhibition of stress by brainstem neuropeptide Y neurons.

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