{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:14Z","timestamp":1787199974323,"version":"build-2736575974"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The multimodal antidepressant vortioxetine combines serotonin reuptake inhibition with activity at several serotonin receptor subtypes, yet its downstream mechanisms related to neuroplasticity remain incompletely understood. This study investigated whether vortioxetine\u2019s antidepressant efficacy involves hippocampal salt-inducible kinase 2 (SIK2) and CREB-regulated transcription coactivator 1 (CRTC1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>By using chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), and chronic restraint stress (CRS) models in male C57BL\/6J mice, we assessed the effects of vortioxetine (10 and 20 mg\/kg) on depressive-like behaviors, hippocampal SIK2 and CRTC1 expression, CRTC1 subcellular localization, and CRTC1-CREB interaction in mice. Viral-mediated hippocampal CRTC1 knockdown was employed to establish causality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Vortioxetine dose-dependently reversed chronic stress-induced behavioral deficits and concurrently normalized hippocampal SIK2 upregulation and CRTC1 downregulation at both transcriptional and translational levels. Furthermore, vortioxetine restored nuclear CRTC1 translocation and enhanced CRTC1-CREB binding. Critically, hippocampal CRTC1 knockdown completely abolished the behavioral benefits of vortioxetine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that vortioxetine\u2019s antidepressant actions in male mice are associated with normalization of hippocampal SIK2\/CRTC1-related signaling and require hippocampal CRTC1, providing a novel molecular mechanism underlying its multimodal efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1837566","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:35Z","timestamp":1787199395000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The multimodal antidepressant vortioxetine exerts therapeutic effects in male mice which is associated with normalization of hippocampal SIK2\/CRTC1-related signaling and require hippocampal CRTC1"],"prefix":"10.3389","volume":"17","author":[{"given":"Hui","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Nantong Hospital to Nanjing University of Chinese Medicine","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Fan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E-hui","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Nantong Hospital to Nanjing University of Chinese Medicine","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Nantong Hospital to Nanjing University of Chinese Medicine","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-bing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Nantong Hospital to Nanjing University of Chinese Medicine","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"118020","DOI":"10.1016\/j.lfs.2020.118020","article-title":"The role of CREB and BDNF in neurobiology and treatment of alzheimer's disease","volume":"257","author":"Amidfar","year":"2020","journal-title":"Life Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3389\/fpsyt.2019.00771","article-title":"Vortioxetine for cognitive enhancement in major depression: from animal models to clinical research","volume":"10","author":"Bennabi","year":"2019","journal-title":"Front. Psychiatry"},{"key":"B3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.pnpbp.2014.12.002","article-title":"Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory","volume":"58","author":"B\u00e9try","year":"2015","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/pcn.12604","article-title":"Neural basis of major depressive disorder: beyond monoamine hypothesis","volume":"72","author":"Boku","year":"2018","journal-title":"Psychiatry Clin. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"114972","DOI":"10.1016\/j.bbr.2024.114972","article-title":"The hippocampal salt-inducible kinase 2-CREB-regulated transcription co-activator 1 system mediates the antidepressant actions of paroxetine in mice","volume":"465","author":"Cai","year":"2024","journal-title":"Behav. Brain Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.biopsych.2021.05.008","article-title":"Brain-derived neurotrophic factor signaling in depression and antidepressant action","volume":"90","author":"Castr\u00e9n","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1177\/0269881114543719","article-title":"Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus","volume":"28","author":"Dale","year":"2014","journal-title":"J. Psychopharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1042\/bcj20200502","article-title":"Nuts and bolts of the salt-inducible kinases (SIKs)","volume":"478","author":"Darling","year":"2021","journal-title":"Biochem. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.ajp.2017.01.025","article-title":"The neurobiology of depression: an integrated view","volume":"27","author":"Dean","year":"2017","journal-title":"Asian J. Psychiatr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"110203","DOI":"10.1016\/j.neuropharm.2024.110203","article-title":"Hippocampal SENP3 mediates chronic stress-induced depression-like behaviors by impairing the CREB-BDNF signaling","volume":"262","author":"Gao","year":"2025","journal-title":"Neuropharmacolo"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1017\/s1092852921000791","article-title":"Novel antidepressant drugs: beyond monoamine targets","volume":"28","author":"Gonda","year":"2023","journal-title":"CNS Spectr."},{"key":"B12","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.neuropharm.2013.05.014","article-title":"Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice","volume":"73","author":"Guilloux","year":"2013","journal-title":"Neuropharmacology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1042\/BJ20111932","article-title":"The AMPK-related kinase SIK2 is regulated by cAMP via phosphorylation at Ser358 in adipocytes","volume":"444","author":"Henriksson","year":"2012","journal-title":"Biochem. J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e2082232024","DOI":"10.1523\/jneurosci.2082-23.2024","article-title":"Chronic social defeat stress induces pathway-specific adaptations at lateral habenula neuronal outputs","volume":"44","author":"Hernandez Silva","year":"2024","journal-title":"J. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"153412","DOI":"10.1016\/j.phymed.2020.153412","article-title":"Naringenin alleviates nonalcoholic steatohepatitis in middle-aged Apoe(-\/-)mice: role of SIRT1","volume":"81","author":"Hua","year":"2021","journal-title":"Phytomedicine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"106123","DOI":"10.1016\/j.intimp.2019.106123","article-title":"Oroxylin A inhibits carcinogen-induced skin tumorigenesis through inhibition of inflammation by regulating SHCBP1 in mice","volume":"80","author":"Huang","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1093\/ijnp\/pyac054","article-title":"Effect of vortioxetine on cognitive impairment in patients with major depressive disorder: a systematic review and meta-analysis of randomized controlled trials","volume":"25","author":"Huang","year":"2022","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"109437","DOI":"10.1016\/j.neuropharm.2023.109437","article-title":"The salt-inducible kinases inhibitor HG-9-91-01 exhibits antidepressant-like actions in mice exposed to chronic unpredictable mild stress","volume":"227","author":"Huang","year":"2023","journal-title":"Neuropharmacology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.biopsych.2018.10.004","article-title":"Hippocampal salt-inducible kinase 2 plays a role in depression via the CREB-regulated transcription coactivator 1-cAMP response element binding-brain-derived neurotrophic factor pathway","volume":"85","author":"Jiang","year":"2019","journal-title":"Biol. Psychiatry"},{"key":"B20","doi-asserted-by":"publisher","first-page":"869794","DOI":"10.3389\/fphar.2022.869794","article-title":"Ferrostatin-1 ameliorates liver dysfunction via reducing iron in thioacetamide-induced acute liver injury in mice","volume":"13","author":"Jiang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.12740\/pp\/onlinefirst\/151570","article-title":"Vortioxetine - pharmacological properties and use in mood disorders. The current state of knowledge","volume":"57","author":"Krupa","year":"2023","journal-title":"Psychiatr. Pol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1177\/0269881116667710","article-title":"In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity","volume":"31","author":"Kugathasan","year":"2017","journal-title":"J. Psychopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"21108","DOI":"10.1074\/jbc.M113.540229","article-title":"Interaction between salt-inducible kinase 2 and protein phosphatase 2A regulates the activity of calcium\/calmodulin-dependent protein kinase I and protein phosphatase methylesterase-1","volume":"289","author":"Lee","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1093\/ijnp\/pyad017","article-title":"Activation of mTORC1 signaling Cascade in hippocampus and medial prefrontal cortex is required for antidepressant actions of vortioxetine in mice","volume":"26","author":"Li","year":"2023","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"624429","DOI":"10.3389\/fphar.2020.624429","article-title":"The selective SIK2 inhibitor ARN-3236 produces strong antidepressant-like efficacy in mice via the hippocampal CRTC1-CREB-BDNF pathway","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/978-3-642-45106-5_9","article-title":"BDNF and synaptic plasticity, cognitive function, and dysfunction","volume":"220","author":"Lu","year":"2014","journal-title":"Handb. Exp. Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.neuroscience.2015.05.053","article-title":"Pathogenesis of depression: insights from human and rodent studies","volume":"321","author":"M\u00e9nard","year":"2016","journal-title":"Neuroscience"},{"key":"B28","doi-asserted-by":"publisher","first-page":"390","DOI":"10.24869\/psyd.2022.390","article-title":"Neuroplasticity in depression: a narrative review with evidence-based insights","volume":"34","author":"Mudgal","year":"2022","journal-title":"Psychiatr. Danub"},{"key":"B29","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.brainresbull.2021.04.017","article-title":"Chronic unpredictable stress negatively regulates hippocampal neurogenesis and promote anxious depression-like behavior via upregulating apoptosis and inflammatory signals in adult rats","volume":"172","author":"Parul","year":"2021","journal-title":"Brain Res. Bull."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s00441-018-2978-8","article-title":"Monoaminergic system and depression","volume":"377","author":"Perez-Caballero","year":"2019","journal-title":"Cell Tissue Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s41380-019-0615-x","article-title":"Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model","volume":"25","author":"Price","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"B34","doi-asserted-by":"publisher","first-page":"20200","DOI":"10.1074\/jbc.RA118.004751","article-title":"Parathyroid hormone(1-34) and its analogs differentially modulate osteoblastic rankl expression via PKA\/SIK2\/SIK3 and PP1\/PP2A-CRTC3 signaling","volume":"293","author":"Ricarte","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.pharmthera.2014.07.001","article-title":"Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data","volume":"145","author":"Sanchez","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"B37","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.neuron.2010.12.004","article-title":"SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB","volume":"69","author":"Sasaki","year":"2011","journal-title":"Neuron"},{"key":"B38","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.biopsych.2019.01.011","article-title":"Parsing the hippocampus in depression: chronic stress, hippocampal volume, and major depressive disorder","volume":"85","author":"Sheline","year":"2019","journal-title":"Biol. Psychiatry"},{"key":"B39","doi-asserted-by":"publisher","first-page":"113463","DOI":"10.1016\/j.biopha.2022.113463","article-title":"Hypoxic ADSC-derived exosomes enhance wound healing in diabetic mice via delivery of circ-Snhg11 and induction of M2-like macrophage polarization","volume":"153","author":"Shi","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.pharep.2017.01.030","article-title":"Vortioxetine: a review of the pharmacology and clinical profile of the novel antidepressant","volume":"69","author":"Sowa-Ku\u0107ma","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.3389\/fphar.2019.01522","article-title":"Inhibitory effects of columbianadin on nociceptive behaviors in a neuropathic pain model, and on voltage-gated calcium currents in dorsal root ganglion neurons in mice","volume":"10","author":"Su","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.1038\/s41380-022-01520-y","article-title":"Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications","volume":"27","author":"Tartt","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"B43","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/PSY.0000000000000678","article-title":"Major depressive disorder in medical illness: a review of assessment, prevalence, and treatment options","volume":"81","author":"Thom","year":"2019","journal-title":"Psychosom. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s12868-017-0376-x","article-title":"Neuroplasticity pathways and protein-interaction networks are modulated by vortioxetine in rodents","volume":"18","author":"Waller","year":"","journal-title":"BMC Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.euroneuro.2016.11.014","article-title":"Chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers","volume":"27","author":"Waller","year":"","journal-title":"Eur. Neuropsychopharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"108853","DOI":"10.1016\/j.exer.2021.108853","article-title":"Chronic social defeat stress causes retinal vascular dysfunction","volume":"213","author":"Wang","year":"","journal-title":"Exp. Eye Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1037\/bne0000418","article-title":"Chronic social defeat stress mouse model: current view on its behavioral deficits and modifications","volume":"135","author":"Wang","year":"","journal-title":"Behav. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"673221","DOI":"10.3389\/fphar.2021.673221","article-title":"Hippocampal PPAR\u03b1 plays a role in the pharmacological mechanism of vortioxetine, a multimodal-acting antidepressant","volume":"12","author":"Wang","year":"","journal-title":"Front. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1124\/jpet.120.000092","article-title":"Potent therapy and transcriptional profile of combined erythropoietin-derived peptide cyclic helix B surface peptide and caspase-3 siRNA against kidney ischemia\/reperfusion injury in mice","volume":"375","author":"Wu","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B50","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/s41419-022-05122-y","article-title":"The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in drosophila","volume":"13","author":"Yin","year":"2022","journal-title":"Cell Death Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1038\/s42003-021-02735-5","article-title":"Activation of the adipocyte CREB\/CRTC pathway in obesity","volume":"4","author":"Yoon","year":"2021","journal-title":"Commun. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"113927","DOI":"10.1016\/j.bcp.2020.113927","article-title":"Modulation of SIRT1-mediated signaling cascades in the liver contributes to the amelioration of nonalcoholic steatohepatitis in high fat fed middle-aged LDL receptor knockout mice by dihydromyricetin","volume":"175","author":"Zeng","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1080\/13880209.2020.1738502","article-title":"Inhibition of tanshinone IIA on renin activity protected against osteoporosis in diabetic mice","volume":"58","author":"Zhang","year":"2020","journal-title":"Pharm. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"105977","DOI":"10.1016\/j.intimp.2019.105977","article-title":"Autophagy induction by rapamycin ameliorates experimental colitis and improves intestinal epithelial barrier function in IL-10 knockout mice","volume":"81","author":"Zhao","year":"","journal-title":"Int. Immunopharmacol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"152489","DOI":"10.1016\/j.tox.2020.152489","article-title":"Inhibition of ferroptosis attenuates busulfan-induced oligospermia in mice","volume":"440","author":"Zhao","year":"","journal-title":"Toxicology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1837566\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:36Z","timestamp":1787199396000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1837566\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":53,"alternative-id":["10.3389\/fphar.2026.1837566"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1837566","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"article-number":"1837566"}}