{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:05:30Z","timestamp":1791245130430,"version":"4.1.0"},"reference-count":92,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM131765"],"award-info":[{"award-number":["GM131765"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Major depressive disorder (MDD) is associated with dysfunction in prefrontal cortex (PFC) circuits, yet the glial mechanisms underlying these abnormalities remain unclear. Here, downregulation of the endoplasmic reticulum (ER) stress sensor PERK in PFC astrocytes is identified as a mechanistic contributor to depression\u2010related phenotypes. PERK expression is markedly reduced in PFC astrocytes from individuals with MDD and in two chronic\u2010stress mouse models. Astrocyte\u2010specific PERK deletion in stress\u2010na\u00efve mice is sufficient to induce robust depressive\u2010like behaviors and widespread PFC circuit pathology, including dendritic spine loss, pyramidal neuron hypoactivity, and weakened functional connectivity. Mechanistically, PERK\u2010deficient astrocytes display reduced Nrf2 abundance, dysregulated ER and cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics, and decreased expression of the synaptogenic protein thrombospondin\u20101 (TSP1). Restoring astrocytic TSP1 via a blood\u2010brain barrier\u2010penetrant adeno\u2010associated virus rescues PFC circuit function and reverses depressive\u2010like behaviors. These findings establish astrocytic PERK deficiency as a sufficient driver of synaptic and network dysfunction underlying depressive phenotypes and highlight astrocyte\u2010directed TSP1 augmentation as a potential therapeutic strategy for MDD.\n                  <\/jats:p>","DOI":"10.1002\/advs.202510780","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T17:17:26Z","timestamp":1764523046000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Astrocytic PERK Deficiency Drives Prefrontal Circuit Dysfunction and Depressive\u2010Like Behaviors"],"prefix":"10.1002","volume":"13","author":[{"given":"Kai","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riya","family":"Gupta","sequence":"additional","affiliation":[{"name":"Barnard College of Columbia University  New York NY 10025 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke M.","family":"Morizawa","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Neuroscience Rutgers, The State University of New Jersey  Piscataway NJ 08854 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama","family":"Al\u2010Dalahmah","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura B.","family":"Dupont","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5739-9126","authenticated-orcid":false,"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Columbia University Irving Medical Center  New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,30]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60602-8"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.65"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.05.053"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2020.20030280"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01101-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0685-9"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12725"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat8078"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.74998"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/457675a"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4043"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.09.056"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.06.008"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3162"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25752"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4113"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI160016"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24358"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo2098"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/13894501113149990156"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-023-02665-2"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0250-z"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.20.7198-7209.2003"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M314219200"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021110501"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.503664"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.74"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-016-0268-5"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0162766"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13592"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.020"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300525"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2010.06.003"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12208"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25509"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1294-2"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.11.030"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4002110"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02269-8"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5153"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2013.09.001"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/232105"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(98)01349-6"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15648-4"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.08.036"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4050"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1110444108"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11617"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4386"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.03.019"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4593"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01208-z"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.04.010"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.032219.113"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01099-w"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3486"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.04.027"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-024-10125-x"},{"key":"e_1_2_9_60_1","first-page":"07","volume":"10","author":"Haddadi S.","year":"2023","journal-title":"J. Neurol. Psychol."},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.25224"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21134777"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01261-6"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2013.03.020"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep30659"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2016.144"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox6030065"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-025-02072-4"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02246-1"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34201-z"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00800-0"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.03.014"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201900563"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4201"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-0264-8"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aai8185"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/npr2.12088"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.09.025"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23589"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82859"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics11010123"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2019.108535"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2017.41"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.044"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1314"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2793-8"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421753111"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11475"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.02.041"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202104106"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4340"},{"key":"e_1_2_9_92_1","first-page":"458","volume":"26","author":"Zhou H.","year":"2023","journal-title":"Nat. Neurosci."}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202510780","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202510780","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202510780","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:10:13Z","timestamp":1770970213000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202510780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,30]]},"references-count":92,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/advs.202510780"],"URL":"https:\/\/doi.org\/10.1002\/advs.202510780","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,30]]},"assertion":[{"value":"2025-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e10780"}}