{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:12:24Z","timestamp":1788667944170,"version":"build-2803163510"},"reference-count":70,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81530061"],"award-info":[{"award-number":["81530061"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471829"],"award-info":[{"award-number":["81471829"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81273350"],"award-info":[{"award-number":["81273350"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Stress\u2010induced neuroepigenetic programming gains growing more and more interest in the studies of the etiology of posttraumatic stress disorder (PTSD). However, seldom attention is focused on DNA demethylation in fear memory generalization, which is the core characteristic of PTSD. Here, we show that ten\u2010eleven translocation protein 3 (TET3), the most abundant DNA demethylation enzyme of the TET family in neurons, senses environmental stress and bridges neuroplasticity with behavioral adaptation during fear generalization. Foot shock strength dependently induces fear generalization and TET3 expression in nucleus accumbens (NAc) in mice. Inhibition of DNA demethylation by infusing demethyltransferase inhibitors or AAV\u2010Tet3\u2010shRNA virus in NAc enhances the fear generalization and anxiety\u2010like behavior. Furthermore, TET3 knockdown impairs the dendritic spine density, PSD length, and thickness of neurons, decreases DNA hydroxymethylation (5hmC), reduces the expression of synaptic plasticity\u2010related genes including\n                    <jats:italic>Homer1<\/jats:italic>\n                    ,\n                    <jats:italic>Cdkn1a<\/jats:italic>\n                    ,\n                    <jats:italic>Cdh8<\/jats:italic>\n                    ,\n                    <jats:italic>Vamp8<\/jats:italic>\n                    ,\n                    <jats:italic>Reln<\/jats:italic>\n                    ,\n                    <jats:italic>Bdnf<\/jats:italic>\n                    , while surprisingly increases immune\u2010related genes\n                    <jats:italic>Stat1<\/jats:italic>\n                    ,\n                    <jats:italic>B2m<\/jats:italic>\n                    ,\n                    <jats:italic>H2\u2010Q7<\/jats:italic>\n                    ,\n                    <jats:italic>H2\u2010M2<\/jats:italic>\n                    ,\n                    <jats:italic>C3<\/jats:italic>\n                    ,\n                    <jats:italic>Cd68<\/jats:italic>\n                    shown by RNA\u2010seq. Notably, knockdown of TET3 in NAc activates microglia and CD39\u2010P2Y12R signaling pathway, and inhibition of CD39 reverses the effects of TET3 knockdown on the fear memory generalization and anxiety. Overexpression of TET3 by Crispr\u2010dSaCas9 virus delivery to activate endogenous Tet3 in NAc increases dendritic spine density of neurons in NAc and reverses fear memory generalization and anxiety\u2010like behavior in mice. These results suggest that TET3 modulates fear generalization and anxiety via regulating synaptic plasticity and CD39 signaling pathway.\n                  <\/jats:p>","DOI":"10.1111\/bpa.13080","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T11:50:35Z","timestamp":1653479435000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety\u2010like behaviors in mice"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5349-9947","authenticated-orcid":false,"given":"Bu\u2010Fang","family":"Fan","sequence":"first","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3410-2967","authenticated-orcid":false,"given":"Bo","family":"Hao","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Da","family":"Dai","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9939-9047","authenticated-orcid":false,"given":"Li","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Psychology, School of Public Medicine Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5910-4822","authenticated-orcid":false,"given":"Yan\u2010Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7772-0610","authenticated-orcid":false,"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5216-3758","authenticated-orcid":false,"given":"Shou\u2010Min","family":"Xuan","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5756-8893","authenticated-orcid":false,"given":"Ning","family":"Yang","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7598-1902","authenticated-orcid":false,"given":"Xiao\u2010Guang","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7971-0942","authenticated-orcid":false,"given":"Hu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2015.04.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.01.023"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/da.22353"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.janxdis.2015.02.003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordhb\/9780195399066.013.0007"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.149.3.337"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010818-021701"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.79"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1169786"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1090842"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx272"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1210597"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2959"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2017.6"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201601340RR"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.001"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10443"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep15876"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.12.007"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-018-1928-6"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4008"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19806-z"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318906111"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-psych-010213-115159"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3888"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-019-00422-4"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.09.018"},{"key":"e_1_2_9_29_1","first-page":"e3769","article-title":"The tail suspension test","volume":"59","author":"Can A","year":"2012","journal-title":"J Vis Exp"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-017-0750-9"},{"key":"e_1_2_9_31_1","volume-title":"The mouse brain in streotaxic coordinates","author":"Franklin K","year":"2012"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201947857"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpns.69"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.20022"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3125"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2018.07.004"},{"key":"e_1_2_9_37_1","volume-title":"The fine structure of the nervous system: neurons and their supporting cells","author":"Peters A","year":"1991"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09665-1"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.11.014"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.047555.118"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.11.030"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.14098"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2013.03.005"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175012"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0740-8"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55342"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11436"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn2061"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01178-y"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1170116"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03335-7"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2016.10.036"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/jts.20490"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0695-7"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01074-7"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2016.09.007"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/texcom\/tgab029"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0347-16.2016"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.58"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11725"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1786-08.2008"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2017.09.013"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2020.104921"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2016.08.011"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.050"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb9888"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz2288"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12540"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0169-7"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.11.016"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2019.1649528"}],"container-title":["Brain Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bpa.13080","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bpa.13080","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bpa.13080","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T11:23:32Z","timestamp":1692357812000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bpa.13080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,25]]},"references-count":70,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1111\/bpa.13080"],"URL":"https:\/\/doi.org\/10.1111\/bpa.13080","archive":["Portico"],"relation":{},"ISSN":["1015-6305","1750-3639"],"issn-type":[{"value":"1015-6305","type":"print"},{"value":"1750-3639","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,25]]},"assertion":[{"value":"2021-12-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13080"}}