{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:06:50Z","timestamp":1791860810047,"version":"4.3.4"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","award":["M970"],"award-info":[{"award-number":["M970"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/J002739\/1"],"award-info":[{"award-number":["MR\/J002739\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N029488\/1"],"award-info":[{"award-number":["MR\/N029488\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/J002739\/1"],"award-info":[{"award-number":["MR\/J002739\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N029488\/1"],"award-info":[{"award-number":["MR\/N029488\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"EC | Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["848158"],"award-info":[{"award-number":["848158"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07\/03\u2009C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (<jats:italic>n<\/jats:italic>\u2009=\u200918) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (<jats:italic>n<\/jats:italic>\u2009=\u200918). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean\u2009\u00b1\u2009SD: 229.9\u2009\u00b1\u200979.1\u2009pg\/ml, vs. 32.5\u2009\u00b1\u20099.5\u2009pg\/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.<\/jats:p>","DOI":"10.1038\/s41380-022-01741-1","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T01:02:55Z","timestamp":1664931775000},"page":"5049-5061","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4410-7865","authenticated-orcid":false,"given":"Alessandra","family":"Borsini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6061-6064","authenticated-orcid":false,"given":"Blair","family":"Merrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Edgeworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5767-4207","authenticated-orcid":false,"given":"Gargi","family":"Mandal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6512-9065","authenticated-orcid":false,"given":"Deepak P.","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7305-1069","authenticated-orcid":false,"given":"Anthony C.","family":"Vernon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Nebbia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1260-8083","authenticated-orcid":false,"given":"Sandrine","family":"Thuret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-5091","authenticated-orcid":false,"given":"Carmine M.","family":"Pariante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"1741_CR1","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","volume":"323","author":"Z Wu","year":"2020","unstructured":"Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323:1239\u201342.","journal-title":"JAMA."},{"key":"1741_CR2","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1001\/jama.2020.5394","volume":"323","author":"G Grasselli","year":"2020","unstructured":"Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323:1574\u201381.","journal-title":"JAMA."},{"key":"1741_CR3","doi-asserted-by":"crossref","first-page":"138996","DOI":"10.1016\/j.scitotenv.2020.138996","volume":"730","author":"T Acter","year":"2020","unstructured":"Acter T, Uddin N, Das J, Akhter A, Choudhury TR, Kim S. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) pandemic: A global health emergency. Sci Total Environ. 2020;730:138996.","journal-title":"Sci Total Environ"},{"key":"1741_CR4","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1007\/s00415-020-09939-5","volume":"267","author":"P Gklinos","year":"2020","unstructured":"Gklinos P. Neurological manifestations of COVID-19: a review of what we know so far. J Neurol. 2020;267:2485\u20139.","journal-title":"J Neurol"},{"key":"1741_CR5","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S2215-0366(21)00084-5","volume":"8","author":"M Taquet","year":"2021","unstructured":"Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8:416\u201327.","journal-title":"Lancet Psychiatry"},{"key":"1741_CR6","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1001\/jama.2017.12067","volume":"318","author":"ES Oh","year":"2017","unstructured":"Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in older persons: advances in diagnosis and treatment. JAMA. 2017;318:1161\u201374.","journal-title":"JAMA"},{"key":"1741_CR7","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1001\/jamaneurol.2020.1127","volume":"77","author":"L Mao","year":"2020","unstructured":"Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77:683\u201390.","journal-title":"JAMA Neurol."},{"key":"1741_CR8","doi-asserted-by":"crossref","first-page":"e2029540","DOI":"10.1001\/jamanetworkopen.2020.29540","volume":"3","author":"M Kennedy","year":"2020","unstructured":"Kennedy M, Helfand BKI, Gou RY, Gartaganis SL, Webb M, Moccia JM, et al. Delirium in older patients with COVID-19 presenting to the emergency department. JAMA Netw Open. 2020;3:e2029540.","journal-title":"JAMA Netw Open"},{"key":"1741_CR9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S2213-2600(20)30552-X","volume":"9","author":"BT Pun","year":"2021","unstructured":"Pun BT, Badenes R, Heras La Calle G, Orun OM, Chen W, Raman R, et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study. Lancet Respir Med. 2021;9:239\u201350.","journal-title":"Lancet Respir Med"},{"key":"1741_CR10","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/ageing\/afaa094","volume":"49","author":"S O\u2019Hanlon","year":"2020","unstructured":"O\u2019Hanlon S, Inouye SK. Delirium: a missing piece in the COVID-19 pandemic puzzle. Age Ageing. 2020;49:497\u20138.","journal-title":"Age Ageing"},{"key":"1741_CR11","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","volume":"395","author":"P Mehta","year":"2020","unstructured":"Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033\u20134.","journal-title":"Lancet"},{"key":"1741_CR12","doi-asserted-by":"crossref","first-page":"e139834","DOI":"10.1172\/jci.insight.139834","volume":"5","author":"Y Zhao","year":"2020","unstructured":"Zhao Y, Qin L, Zhang P, Li K, Liang L, Sun J, et al. Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. JCI Insight. 2020;5:e139834.","journal-title":"JCI Insight"},{"key":"1741_CR13","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","volume":"395","author":"C Huang","year":"2020","unstructured":"Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497\u2013506.","journal-title":"Lancet"},{"key":"1741_CR14","first-page":"18","volume":"6","author":"A Yarlagadda","year":"2009","unstructured":"Yarlagadda A, Alfson E, Clayton AH. The blood brain barrier and the role of cytokines in neuropsychiatry. Psychiatry (Edgmont). 2009;6:18\u201322.","journal-title":"Psychiatry (Edgmont)"},{"key":"1741_CR15","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/s41380-020-0651-6","volume":"26","author":"IA Gampierakis","year":"2021","unstructured":"Gampierakis IA, Koutmani Y, Semitekolou M, Morianos I, Polissidis A, Katsouda A, et al. Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD). Mol Psychiatry. 2021;26:1248\u201363.","journal-title":"Mol Psychiatry"},{"key":"1741_CR16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/s41380-020-00925-x","volume":"26","author":"W Marx","year":"2021","unstructured":"Marx W, Lane M, Hockey M, Aslam H, Berk M, Walder K, et al. Diet and depression: exploring the biological mechanisms of action. Mol Psychiatry. 2021;26:134\u201350.","journal-title":"Mol Psychiatry"},{"key":"1741_CR17","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1755-5949.2010.00173.x","volume":"17","author":"MJ Simone","year":"2011","unstructured":"Simone MJ, Tan ZS. The role of inflammation in the pathogenesis of delirium and dementia in older adults: a review. CNS Neurosci Ther. 2011;17:506\u201313.","journal-title":"CNS Neurosci Ther"},{"key":"1741_CR18","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrn.2017.45","volume":"18","author":"C Anacker","year":"2017","unstructured":"Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility\u2014linking memory and mood. Nat Rev Neurosci. 2017;18:335\u201346.","journal-title":"Nat Rev Neurosci"},{"key":"1741_CR19","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ebiom.2018.10.021","volume":"37","author":"A Alam","year":"2018","unstructured":"Alam A, Hana Z, Jin Z, Suen KC, Ma D. Surgery, neuroinflammation and cognitive impairment. EBioMedicine. 2018;37:547\u201356.","journal-title":"EBioMedicine"},{"key":"1741_CR20","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.biopsych.2020.07.018","volume":"88","author":"M Boldrini","year":"2020","unstructured":"Boldrini M. The many avenues leading to adult neurogenesis adaptations. Biol Psychiatry. 2020;88:588\u201390.","journal-title":"Biol Psychiatry"},{"key":"1741_CR21","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1164\/rccm.202005-1583OC","volume":"202","author":"OJ McElvaney","year":"2020","unstructured":"McElvaney OJ, McEvoy NL, McElvaney OF, Carroll TP, Murphy MP, Dunlea DM, et al. Characterization of the inflammatory response to severe COVID-19 illness. Am J Respiratory Crit care Med. 2020;202:812\u201321.","journal-title":"Am J Respiratory Crit care Med"},{"key":"1741_CR22","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1093\/ijnp\/pyaa055","volume":"23","author":"A Borsini","year":"2020","unstructured":"Borsini A, Di Benedetto MG, Giacobbe J, Pariante CM. Pro- and anti-inflammatory properties of interleukin (IL6) in vitro: relevance for major depression and for human hippocampal neurogenesis. Int J Neuropsychopharmacol. 2020;23:738\u201350.","journal-title":"Int J Neuropsychopharmacol"},{"key":"1741_CR23","doi-asserted-by":"crossref","first-page":"6773","DOI":"10.1038\/s41380-021-01160-8","volume":"26","author":"A Borsini","year":"2021","unstructured":"Borsini A, Nicolaou A, Camacho-Munoz D, Kendall AC, Di Benedetto MG, Giacobbe J, et al. Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis. Mol Psychiatry. 2021;26:6773\u201388.","journal-title":"Mol Psychiatry"},{"key":"1741_CR24","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/ijnp\/pyx083","volume":"21","author":"A Borsini","year":"2018","unstructured":"Borsini A, Cattaneo A, Malpighi C, Thuret S, Harrison NA, Consortium MRCI, et al. Interferon-alpha reduces human hippocampal neurogenesis and increases apoptosis via activation of distinct STAT1-dependent mechanisms. Int J Neuropsychopharmacol. 2018;21:187\u2013200.","journal-title":"Int J Neuropsychopharmacol"},{"key":"1741_CR25","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.bbi.2017.05.006","volume":"65","author":"A Borsini","year":"2017","unstructured":"Borsini A, Alboni S, Horowitz MA, Tojo LM, Cannazza G, Su KP, et al. Rescue of IL-1 beta-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants. Brain Behav Immun. 2017;65:230\u20138.","journal-title":"Brain Behav Immun"},{"key":"1741_CR26","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.biopsych.2009.12.008","volume":"67","author":"R Crupi","year":"2010","unstructured":"Crupi R, Cambiaghi M, Spatz L, Hen R, Thorn M, Friedman E, et al. Reduced adult neurogenesis and altered emotional behaviors in autoimmune-prone B-cell activating factor transgenic mice. Biol Psychiatry. 2010;67:558\u201366.","journal-title":"Biol Psychiatry"},{"key":"1741_CR27","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.biopsych.2020.11.007","volume":"90","author":"JW Koo","year":"2021","unstructured":"Koo JW, Wohleb ES. How stress shapes neuroimmune function: implications for the neurobiology of psychiatric disorders. Biol Psychiatry. 2021;90:74\u201384.","journal-title":"Biol Psychiatry"},{"key":"1741_CR28","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.bbi.2019.06.018","volume":"81","author":"A Borsini","year":"2019","unstructured":"Borsini A, Pariante CM, Zunszain PA, Hepgul N, Russell A, Zajkowska Z, et al. The role of circulatory systemic environment in predicting interferon-alpha-induced depression: The neurogenic process as a potential mechanism. Brain Behav Immun. 2019;81:220\u20137.","journal-title":"Brain Behav Immun"},{"key":"1741_CR29","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.2147\/NDT.S199746","volume":"15","author":"G Perini","year":"2019","unstructured":"Perini G, Cotta Ramusino M, Sinforiani E, Bernini S, Petrachi R, Costa A. Cognitive impairment in depression: recent advances and novel treatments. Neuropsychiatr Dis Treat. 2019;15:1249\u201358.","journal-title":"Neuropsychiatr Dis Treat"},{"key":"1741_CR30","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/npp.2011.277","volume":"37","author":"PA Zunszain","year":"2012","unstructured":"Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, et al. Interleukin-1beta: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacol. 2012;37:939\u201349.","journal-title":"Neuropsychopharmacol"},{"key":"1741_CR31","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/npp.2012.253","volume":"38","author":"C Anacker","year":"2013","unstructured":"Anacker C, Cattaneo A, Luoni A, Musaelyan K, Zunszain PA, Milanesi E, et al. Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacol. 2013;38:872\u201383.","journal-title":"Neuropsychopharmacol"},{"key":"1741_CR32","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/mp.2011.26","volume":"16","author":"C Anacker","year":"2011","unstructured":"Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011;16:738\u201350.","journal-title":"Mol Psychiatry"},{"key":"1741_CR33","doi-asserted-by":"crossref","first-page":"8708","DOI":"10.1073\/pnas.1300886110","volume":"110","author":"C Anacker","year":"2013","unstructured":"Anacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni R, et al. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc Natl Acad Sci USA. 2013;110:8708\u201313.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1741_CR34","doi-asserted-by":"crossref","first-page":"pyu076","DOI":"10.1093\/ijnp\/pyu076","volume":"18","author":"MA Horowitz","year":"2014","unstructured":"Horowitz MA, Wertz J, Zhu DH, Cattaneo A, Musaelyan K, Nikkheslat N, et al. Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. Int J Neuropsychopharmacol. 2014;18:pyu076.","journal-title":"Int J Neuropsychopharmacol"},{"key":"1741_CR35","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.14336\/AD.2021.0409","volume":"12","author":"C de Lucia","year":"2021","unstructured":"de Lucia C, Murphy T, Maruszak A, Wright P, Powell TR, Hartopp N, et al. Serum from older adults increases apoptosis and molecular aging markers in human hippocampal progenitor cells. Aging Dis. 2021;12:2151\u201372.","journal-title":"Aging Dis"},{"key":"1741_CR36","doi-asserted-by":"crossref","DOI":"10.1038\/s41398-020-00908-0","volume":"10","author":"A Borsini","year":"2020","unstructured":"Borsini A, Stangl D, Jeffries AR, Pariante CM, Thuret S. The role of omega-3 fatty acids in preventing glucocorticoid-induced reduction in human hippocampal neurogenesis and increase in apoptosis. Transl Psychiatry. 2020;10:219.","journal-title":"Transl Psychiatry"},{"key":"1741_CR37","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/ijnp\/pyx083","volume":"21","author":"A Borsini","year":"2018","unstructured":"Borsini A, Cattaneo A, Malpighi C, Thuret S, Harrison NA, Zunszain PA, et al. Interferon-alpha reduces human hippocampal neurogenesis and increases apoptosis via activation of distinct STAT1-dependent mechanisms. Int J Neuropsychoph. 2018;21:187\u2013200.","journal-title":"Int J Neuropsychoph"},{"key":"1741_CR38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.neuroscience.2019.12.021","volume":"454","author":"DM Smeeth","year":"2021","unstructured":"Smeeth DM, Kourouzidou I, Duarte RRR, Powell TR, Thuret S. Prolactin, estradiol and testosterone differentially impact human hippocampal neurogenesis in an in vitro model. Neuroscience. 2021;454:15\u201339.","journal-title":"Neuroscience"},{"key":"1741_CR39","doi-asserted-by":"crossref","first-page":"806","DOI":"10.3389\/fcell.2020.00806","volume":"8","author":"V Houghton","year":"2020","unstructured":"Houghton V, Du Preez A, Lefevre-Arbogast S, de Lucia C, Low DY, Urpi-Sarda M, et al. Caffeine compromises proliferation of human hippocampal progenitor cells. Front Cell Dev Biol. 2020;8:806.","journal-title":"Front Cell Dev Biol"},{"key":"1741_CR40","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1038\/npp.2016.50","volume":"41","author":"N Hepgul","year":"2016","unstructured":"Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, et al. Transcriptomics in interferon-alpha-treated patients identifies inflammation-, neuroplasticity- and oxidative stress-related signatures as predictors and correlates of depression. Neuropsychopharmacol. 2016;41:2502\u201311.","journal-title":"Neuropsychopharmacol"},{"key":"1741_CR41","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1474-4422(21)00059-4","volume":"20","author":"The Lancet N.","year":"2021","unstructured":"The Lancet N. Long COVID: understanding the neurological effects. Lancet Neurol. 2021;20:247.","journal-title":"Lancet Neurol"},{"key":"1741_CR42","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1001\/jamapsychiatry.2021.0500","volume":"78","author":"M Boldrini","year":"2021","unstructured":"Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021;78:682\u20133.","journal-title":"JAMA Psychiatry"},{"key":"1741_CR43","first-page":"rs.3.rs-1031824","volume":"29","author":"R Klein","year":"2021","unstructured":"Klein R, Soung A, Sissoko C, Nordvig A, Canoll P, Mariani M, et al. COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis. Res Sq. 2021;29:rs.3.rs-1031824.","journal-title":"Res Sq."},{"key":"1741_CR44","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Casta\u00f1eda A, Lu P, Geraghty AC, Song E, Lee M-H, Wood J, et al. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. bioRxiv 2022: 2022.2001.2007.475453.","DOI":"10.1101\/2022.01.07.475453"},{"key":"1741_CR45","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.bbi.2020.07.037","volume":"89","author":"MG Mazza","year":"2020","unstructured":"Mazza MG, De Lorenzo R, Conte C, Poletti S, Vai B, Bollettini I, et al. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav Immun. 2020;89:594\u2013600.","journal-title":"Brain Behav Immun"},{"key":"1741_CR46","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.bbi.2021.02.021","volume":"94","author":"MG Mazza","year":"2021","unstructured":"Mazza MG, Palladini M, De Lorenzo R, Magnaghi C, Poletti S, Furlan R, et al. Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: Effect of inflammatory biomarkers at three-month follow-up. Brain Behav Immun. 2021;94:138\u201347.","journal-title":"Brain Behav Immun"},{"key":"1741_CR47","doi-asserted-by":"crossref","first-page":"e821","DOI":"10.1212\/NXI.0000000000000821","volume":"7","author":"M Bodro","year":"2020","unstructured":"Bodro M, Compta Y, Llanso L, Esteller D, Doncel-Moriano A, Mesa A, et al. Increased CSF levels of IL-1beta, IL-6, and ACE in SARS-CoV-2-associated encephalitis. Neurol Neuroimmunol Neuroinflamm. 2020;7:e821.","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"1741_CR48","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41591-020-01202-8","volume":"27","author":"P Brodin","year":"2021","unstructured":"Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021;27:28\u201333.","journal-title":"Nat Med"},{"key":"1741_CR49","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1113\/JP271502","volume":"594","author":"EA Kiernan","year":"2016","unstructured":"Kiernan EA, Smith SM, Mitchell GS, Watters JJ. Mechanisms of microglial activation in models of inflammation and hypoxia: Implications for chronic intermittent hypoxia. J Physiol. 2016;594:1563\u201377.","journal-title":"J Physiol"},{"key":"1741_CR50","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1126\/science.1088417","volume":"302","author":"ML Monje","year":"2003","unstructured":"Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760\u20135.","journal-title":"Science"},{"key":"1741_CR51","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1002\/hipo.22192","volume":"23","author":"S Zonis","year":"2013","unstructured":"Zonis S, Ljubimov VA, Mahgerefteh M, Pechnick RN, Wawrowsky K, Chesnokova V. p21Cip restrains hippocampal neurogenesis and protects neuronal progenitors from apoptosis during acute systemic inflammation. Hippocampus. 2013;23:1383\u201394.","journal-title":"Hippocampus"},{"key":"1741_CR52","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1523\/JNEUROSCI.22-02-00486.2002","volume":"22","author":"L Vallieres","year":"2002","unstructured":"Vallieres L, Campbell IL, Gage FH, Sawchenko PE. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci. 2002;22:486\u201392.","journal-title":"J Neurosci"},{"key":"1741_CR53","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0002-9440(10)63356-1","volume":"165","author":"M Hofer","year":"2004","unstructured":"Hofer M, Hausmann J, Staeheli P, Pagenstecher A. Cerebral expression of interleukin-12 induces neurological disease via differential pathways and recruits antigen-specific T cells in virus-infected mice. Am J Pathol. 2004;165:949\u201358.","journal-title":"Am J Pathol"},{"key":"1741_CR54","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jns.2010.06.004","volume":"296","author":"JT Yu","year":"2010","unstructured":"Yu JT, Lee CH, Yoo KY, Choi JH, Li H, Park OK, et al. Maintenance of anti-inflammatory cytokines and reduction of glial activation in the ischemic hippocampal CA1 region preconditioned with lipopolysaccharide. J Neurological Sci. 2010;296:69\u201378.","journal-title":"J Neurological Sci"},{"key":"1741_CR55","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1089\/vim.2004.17.411","volume":"17","author":"DD Ireland","year":"2004","unstructured":"Ireland DD, Reiss CS. Expression of IL-12 receptor by neurons. Viral Immunol. 2004;17:411\u201322.","journal-title":"Viral Immunol"},{"key":"1741_CR56","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1007\/BF03401609","volume":"1","author":"LA Turka","year":"1995","unstructured":"Turka LA, Goodman RE, Rutkowski JL, Sima AA, Merry A, Mitra RS, et al. Interleukin 12: a potential link between nerve cells and the immune response in inflammatory disorders. Mol Med. 1995;1:690\u20139.","journal-title":"Mol Med"},{"key":"1741_CR57","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/ana.26041","volume":"89","author":"OM Espindola","year":"2021","unstructured":"Espindola OM, Gomes YCP, Brandao CO, Torres RC, Siqueira M, Soares CN, et al. Inflammatory cytokine patterns associated with neurological diseases in Coronavirus Disease 2019. Ann Neurol. 2021;89:1041\u20135.","journal-title":"Ann Neurol"},{"key":"1741_CR58","doi-asserted-by":"crossref","first-page":"e1029","DOI":"10.1212\/NXI.0000000000001029","volume":"8","author":"R Bernard-Valnet","year":"2021","unstructured":"Bernard-Valnet R, Perriot S, Canales M, Pizzarotti B, Caranzano L, Castro-Jimenez M, et al. Encephalopathies associated with severe COVID-19 present neurovascular unit alterations without evidence for strong neuroinflammation. Neurol Neuroimmunol Neuroinflamm. 2021;8:e1029.","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"1741_CR59","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3390\/brainsci6020018","volume":"6","author":"S Mori","year":"2016","unstructured":"Mori S, Maher P, Conti B. Neuroimmunology of the Interleukins 13 and 4. Brain Sci. 2016;6:18.","journal-title":"Brain Sci"},{"key":"1741_CR60","doi-asserted-by":"crossref","first-page":"100254","DOI":"10.1016\/j.jadr.2021.100254","volume":"6","author":"B Vai","year":"2021","unstructured":"Vai B, Mazza MG, Cazzetta S, Calesella F, Aggio V, Lorenzi C, et al. Higher interleukin 13 differentiates patients with a positive history of suicide attempts in major depressive disorder. J Affect Disord Rep. 2021;6:100254.","journal-title":"J Affect Disord Rep."},{"key":"1741_CR61","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1001\/jama.2021.11330","volume":"326","author":"Group TWREAfC-TW.","year":"2021","unstructured":"Group TWREAfC-TW. Association between administration of il-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA. 2021;326:499\u2013518.","journal-title":"JAMA"},{"key":"1741_CR62","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s40259-020-00451-w","volume":"34","author":"A Almradi","year":"2020","unstructured":"Almradi A, Hanzel J, Sedano R, Parker CE, Feagan BG, Ma C, et al. Clinical trials of IL-12\/IL-23 inhibitors in inflammatory bowel disease. BioDrugs. 2020;34:713\u201321.","journal-title":"BioDrugs"},{"key":"1741_CR63","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2377-9-S1-S3","volume":"9","author":"WA Banks","year":"2009","unstructured":"Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9:S3.","journal-title":"BMC Neurol"},{"key":"1741_CR64","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s40425-019-0706-x","volume":"7","author":"M Bilusic","year":"2019","unstructured":"Bilusic M, Heery CR, Collins JM, Donahue RN, Palena C, Madan RA, et al. Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer. 2019;7:240.","journal-title":"J Immunother Cancer"},{"key":"1741_CR65","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1056\/NEJMoa2101643","volume":"385","author":"PO Guimaraes","year":"2021","unstructured":"Guimaraes PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, et al. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;385:406\u201315.","journal-title":"N Engl J Med"},{"key":"1741_CR66","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/S2213-2600(21)00331-3","volume":"9","author":"VC Marconi","year":"2021","unstructured":"Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9:1407\u201318.","journal-title":"Lancet Respir Med"},{"key":"1741_CR67","doi-asserted-by":"crossref","first-page":"e351","DOI":"10.1016\/S2665-9913(22)00044-3","volume":"4","author":"MK Han","year":"2022","unstructured":"Han MK, Antila M, Ficker JH, Gordeev I, Guerreros A, Bernus AL, et al. Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Rheumatol. 2022;4:e351\u2013e361.","journal-title":"Lancet Rheumatol"},{"key":"1741_CR68","volume":"10","author":"A Cattaneo","year":"2020","unstructured":"Cattaneo A, Ferrari C, Turner L, Mariani N, Enache D, Hastings C, et al. Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study. Transl Psychiatry. 2020;10:232.","journal-title":"Transl Psychiatry"},{"key":"1741_CR69","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1016\/j.cell.2021.10.027","volume":"184","author":"M Khan","year":"2021","unstructured":"Khan M, Yoo SJ, Clijsters M, Backaert W, Vanstapel A, Speleman K, et al. Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb. Cell. 2021;184:5932\u201349.e5915","journal-title":"Cell"},{"key":"1741_CR70","first-page":"2021.02.15.2125","volume":"18","author":"GE Serrano","year":"2021","unstructured":"Serrano GE, Walker JE, Arce R, Glass MJ, Vargas D, Sue LI, et al. Mapping of SARSCoV-2 brain invasion and histopathology in COVID-19 disease. medRxiv. 2021;18:2021.02.15.21251511.","journal-title":"medRxiv"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01741-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01741-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01741-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T11:21:02Z","timestamp":1680866462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01741-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,5]]},"references-count":70,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["1741"],"URL":"https:\/\/doi.org\/10.1038\/s41380-022-01741-1","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,5]]},"assertion":[{"value":"11 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"AB, CMP and ST have received research funding from Johnson & Johnson for research on depression and inflammation which included cellular work (2012\u20132018), but this work is unrelated to that funding; moreover, less than 10% of Professor Pariante\u2019s support in the last 10 years derives from commercial collaborations, including: a strategic award from the Wellcome Trust (Neuroimmunology of Mood Disorders and Alzheimer\u2019s Disease (NIMA) Consortium, grant 104025), in partnership with Janssen, GlaxoSmithKline, Lundbeck and Pfizer; and consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and V\u00e4rde Partners. ST received funding for a project on neural stem cell aging co-funded by the UK Medical Research Council and Merck Sharp & Dohme Corp. The work presented in this paper is unrelated to these awards. BM, JE, GM, DPS, ACV and GN have no conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}