{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:09:52Z","timestamp":1792786192179,"version":"4.5.0"},"posted":{"date-parts":[[2025,10,25]]},"group-title":"Neuroscience","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 NS133365-01"],"award-info":[{"award-number":["R01 NS133365-01"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["R37 NS110699"],"award-info":[{"award-number":["R37 NS110699"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["R01 NS120481."],"award-info":[{"award-number":["R01 NS120481."]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Therapeutic hypothermia is cerebroprotective in experimental stroke but has shown limited clinical efficacy due to metabolically costly counter regulatory responses. Naturally occurring states such as torpor achieve hypothermia through coordinated regulation of temperature and metabolism and are associated with cerebroprotection. Here, we tested whether selective activation of a genetically defined thermoregulatory neuronal population is sufficient to induce hypothermia after ischemic injury and whether temperature-dependent cerebroprotection is accompanied by metabolic remodeling. Using chemogenetic tools, kappa opioid receptor expressing neurons in the preoptic area were activated in mice subjected to transient middle cerebral artery occlusion. Core body temperature, metabolism, infarct volume, and motor recovery were assessed under conditions permitting hypothermia or maintaining normothermia. Untargeted metabolomic profiling was performed on whole brain tissue collected 30 minutes after activation in the absence of ischemia. Activation of kappa opioid receptor expressing preoptic neurons induced a hypothermic state with coordinated metabolic changes, reduced infarct volume and improved acute motor outcomes. These effects were attenuated when body temperature was maintained at normothermia. Metabolomic profiling revealed coordinated alterations in nucleotide, phospholipid, and sphingolipid pathways. These findings link temperature dependent cerebroprotection to coordinated metabolic remodeling, with translational relevance for stroke.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.24.684192","type":"posted-content","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T09:45:17Z","timestamp":1761385517000},"source":"Crossref","is-referenced-by-count":2,"title":["Targeted preoptic neuronal activation induces a hypothermic state with metabolic reprogramming and acute cerebroprotection"],"prefix":"10.64898","author":[{"given":"Aizad","family":"Kamal","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto R.","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khairunisa","family":"Mohamad Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Biostatistics and Data Science, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Abou-Antoun","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah E.","family":"Skelton","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Kelly Cuenca","sequence":"additional","affiliation":[{"name":"Mallinckrodt Institute of Radiology, Biophotonics Research Center, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6362-4767","authenticated-orcid":false,"given":"Carla","family":"Yuede","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary J.","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Washington University, St. Louis, USA"},{"name":"Center for Mass Spectrometry and Metabolic Tracing, Washington University, St. Louis, USA"},{"name":"Department of Genetics and Medicine, Washington University, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah P.","family":"Shriver","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Washington University, St. Louis, USA"},{"name":"Center for Mass Spectrometry and Metabolic Tracing, Washington University, St. Louis, USA"},{"name":"Division of Nutritional Science and Obesity Medicine, Washington University, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Moo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, USA"},{"name":"Department of Radiology, Washington University School of Medicine, St. Louis, USA"},{"name":"Department of Biomedical Engineering, Washington University, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J.","family":"Norris","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Landsness","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101621300544000_2025.10.24.684192v2.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012689"},{"key":"2026101621300544000_2025.10.24.684192v2.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa003289"},{"key":"2026101621300544000_2025.10.24.684192v2.3","doi-asserted-by":"crossref","unstructured":"Edwards, A. D. et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 340, c363 (2010).","DOI":"10.1136\/bmj.c363"},{"key":"2026101621300544000_2025.10.24.684192v2.4","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1097\/00004647-200012000-00009","article-title":"Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model","volume":"20","year":"2000","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab"},{"key":"2026101621300544000_2025.10.24.684192v2.5","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000019603.29818.9C"},{"key":"2026101621300544000_2025.10.24.684192v2.6","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm083"},{"key":"2026101621300544000_2025.10.24.684192v2.7","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.110.595371"},{"key":"2026101621300544000_2025.10.24.684192v2.8","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.110.592295"},{"key":"2026101621300544000_2025.10.24.684192v2.9","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.014200"},{"key":"2026101621300544000_2025.10.24.684192v2.10","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.112.672923"},{"key":"2026101621300544000_2025.10.24.684192v2.11","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/B978-0-444-64074-1.00051-3","article-title":"Hypothermia in acute ischemic stroke therapy","volume":"157","year":"2018","journal-title":"Handb. Clin. Neurol"},{"key":"2026101621300544000_2025.10.24.684192v2.12","doi-asserted-by":"crossref","first-page":"S186","DOI":"10.1097\/CCM.0b013e3181aa5241","article-title":"Mechanisms of action, physiological effects, and complications of hypothermia: Crit","volume":"37","year":"2009","journal-title":"Care Med"},{"key":"2026101621300544000_2025.10.24.684192v2.13","doi-asserted-by":"crossref","unstructured":"You, J. S. , Kim, J. Y. & Yenari, M. A. Therapeutic hypothermia for stroke: Unique challenges at the bedside. Front. Neurol. 13, 951586 (2022).","DOI":"10.3389\/fneur.2022.951586"},{"key":"2026101621300544000_2025.10.24.684192v2.14","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00008.2003"},{"key":"2026101621300544000_2025.10.24.684192v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpb.2012.01.008"},{"key":"2026101621300544000_2025.10.24.684192v2.16","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.pneurobio.2016.03.002","article-title":"Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction","volume":"157","year":"2017","journal-title":"Prog. Neurobiol"},{"key":"2026101621300544000_2025.10.24.684192v2.17","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.8b00816"},{"key":"2026101621300544000_2025.10.24.684192v2.18","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.29.534718"},{"key":"2026101621300544000_2025.10.24.684192v2.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.028"},{"key":"2026101621300544000_2025.10.24.684192v2.20","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau5324"},{"key":"2026101621300544000_2025.10.24.684192v2.21","doi-asserted-by":"crossref","unstructured":"Dilsiz, P. et al. GABAergic ventrolateral preoptic projection to dorsomedial hypothalamus recapitulates post-ischemic neuroprotection by hypothermia. Cell Death Dis. 17, 304 (2026).","DOI":"10.1038\/s41419-026-08536-0"},{"key":"2026101621300544000_2025.10.24.684192v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34735-2"},{"key":"2026101621300544000_2025.10.24.684192v2.23","doi-asserted-by":"crossref","unstructured":"Cintron-Colon, R. et al. Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss. Curr. Biol. 2G , 4291\u20134299.e4 (2019).","DOI":"10.1016\/j.cub.2019.10.027"},{"key":"2026101621300544000_2025.10.24.684192v2.24","doi-asserted-by":"publisher","DOI":"10.64898\/2026.04.09.715318"},{"key":"2026101621300544000_2025.10.24.684192v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(98)00251-6"},{"key":"2026101621300544000_2025.10.24.684192v2.26","unstructured":"Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 48G , 391\u2013399 (2012)."},{"key":"2026101621300544000_2025.10.24.684192v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2010.12.011"},{"key":"2026101621300544000_2025.10.24.684192v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtherbio.2014.03.002"},{"key":"2026101621300544000_2025.10.24.684192v2.29","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.20.1.84"},{"key":"2026101621300544000_2025.10.24.684192v2.30","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(91)90240-K"},{"key":"2026101621300544000_2025.10.24.684192v2.31","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/j.mri.2013.03.026","article-title":"Neuroprotective effect of agmatine in rats with transient cerebral ischemia using MR imaging and histopathologic evaluation","volume":"31","year":"2013","journal-title":"Magn. Reson. Imaging"},{"key":"2026101621300544000_2025.10.24.684192v2.32","doi-asserted-by":"crossref","unstructured":"Sindelar, M. et al. Longitudinal metabolomics of human plasma reveals prognostic markers of COVID-19 disease severity. Cell Rep. Med. 2, 100369 (2021).","DOI":"10.1016\/j.xcrm.2021.100369"},{"key":"2026101621300544000_2025.10.24.684192v2.33","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.cmet.2021.04.014","article-title":"Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver","volume":"33","year":"2021","journal-title":"Cell Metab"},{"key":"2026101621300544000_2025.10.24.684192v2.34","doi-asserted-by":"crossref","unstructured":"Adams, K. J. et al. Skyline for Small Molecules: A Unifying Software Package for Quantitative Metabolomics. J. Proteome Res. 1G , 1447\u20131458 (2020).","DOI":"10.1021\/acs.jproteome.9b00640"},{"key":"2026101621300544000_2025.10.24.684192v2.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2015.11.009"},{"key":"2026101621300544000_2025.10.24.684192v2.36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae253"},{"key":"2026101621300544000_2025.10.24.684192v2.37","doi-asserted-by":"crossref","unstructured":"Gaud, C. et al. BioPAN: a web-based tool to explore mammalian lipidome metabolic pathways on LIPID MAPS. F1000Research 10, 4 (2021).","DOI":"10.12688\/f1000research.28022.1"},{"key":"2026101621300544000_2025.10.24.684192v2.38","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231710108"},{"key":"2026101621300544000_2025.10.24.684192v2.39","doi-asserted-by":"crossref","unstructured":"Tani, T. , Okamoto, K. , Fujiwara, M. et al. Metabolomics analysis elucidates unique influences on purine \/ pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury. Mol. Med. 25, (2019).","DOI":"10.1186\/s10020-019-0109-y"},{"key":"2026101621300544000_2025.10.24.684192v2.40","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000155747.15679.04"},{"key":"2026101621300544000_2025.10.24.684192v2.41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07692.x"},{"key":"2026101621300544000_2025.10.24.684192v2.42","doi-asserted-by":"crossref","unstructured":"Datta, A. et al. Inosine attenuates post-stroke neuroinflammation by modulating inflammasome mediated microglial activation and polarization. Biochim. Biophys. Acta Mol. Basis Dis. 186G , 166771 (2023).","DOI":"10.1016\/j.bbadis.2023.166771"},{"key":"2026101621300544000_2025.10.24.684192v2.43","doi-asserted-by":"crossref","first-page":"10649","DOI":"10.3390\/ijms251910649","article-title":"Exploring Lysophosphatidylcholine as a Biomarker in Ischemic Stroke: The Plasma-Brain Disjunction","volume":"25","year":"2024","journal-title":"Int. J. Mol. Sci"},{"key":"2026101621300544000_2025.10.24.684192v2.44","first-page":"100151","article-title":"An imbalanced ratio between PC(16:0\/16:0) and LPC(16:0) revealed by lipidomics supports the role of the Lands cycle in ischemic brain injury","volume":"2","year":"2021","journal-title":"J. Biol. Chem"},{"key":"2026101621300544000_2025.10.24.684192v2.45","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/5954034"},{"key":"2026101621300544000_2025.10.24.684192v2.46","doi-asserted-by":"crossref","unstructured":"Huang, M. et al. Lysophosphatidylcholines and phosphatidylcholines as biomarkers for stroke recovery. Front. Neurol. 13, (2022).","DOI":"10.3389\/fneur.2022.1047101"},{"key":"2026101621300544000_2025.10.24.684192v2.47","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jfma.2022.08.021","article-title":"Investigating sphingolipids as biomarkers for the outcomes of acute ischemic stroke patients receiving endovascular treatment","volume":"122","year":"2023","journal-title":"J. Formos. Med. Assoc"},{"key":"2026101621300544000_2025.10.24.684192v2.48","doi-asserted-by":"crossref","unstructured":"Ouro, A. et al. Involvement of Ceramide Metabolism in Cerebral Ischemia. Front. Mol. Biosci. G , (2022).","DOI":"10.3389\/fmolb.2022.864618"},{"key":"2026101621300544000_2025.10.24.684192v2.49","doi-asserted-by":"crossref","unstructured":"Mohamud Yusuf, A. , et al. Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets. Neurobiol. Dis. 201, 106682 (2024).","DOI":"10.1016\/j.nbd.2024.106682"},{"key":"2026101621300544000_2025.10.24.684192v2.50","doi-asserted-by":"crossref","unstructured":"\u00c1lvarez-Sab\u00edn, J. & Rom\u00e1n, G. C. Citicoline in Vascular Cognitive Impairment and Vascular Dementia After Stroke. Stroke 42, (2011).","DOI":"10.1161\/STROKEAHA.110.606509"},{"key":"2026101621300544000_2025.10.24.684192v2.51","doi-asserted-by":"crossref","unstructured":"Arenth, P. M. , Russell, K. C. , Ricker, J. H. , et al. CDP-Choline as a Biological Supplement During Neurorecovery: A Focused Review. PMCR 3, (2011).","DOI":"10.1016\/j.pmrj.2011.03.012"},{"key":"2026101621300544000_2025.10.24.684192v2.52","doi-asserted-by":"crossref","unstructured":"Hurtado, O. , Lizasoain, I. & Moro, M. \u00c1. Neuroprotection and Recovery: Recent Data at the Bench on Citicoline. Stroke 42, (2011).","DOI":"10.1161\/STROKEAHA.110.597435"},{"key":"2026101621300544000_2025.10.24.684192v2.53","first-page":"173","article-title":"Probably role of citicoline in stroke rehabilitation: review of the literature","volume":"54","year":"2012","journal-title":"Rev. Neurol"},{"key":"2026101621300544000_2025.10.24.684192v2.54","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-004-9681-8"},{"key":"2026101621300544000_2025.10.24.684192v2.55","doi-asserted-by":"crossref","unstructured":"Van Der Veen, J. N. et al. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta BBA - Biomembr. 185G , 1558\u20131572 (2017).","DOI":"10.1016\/j.bbamem.2017.04.006"},{"key":"2026101621300544000_2025.10.24.684192v2.56","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ircmb.2015.10.001"},{"key":"2026101621300544000_2025.10.24.684192v2.57","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.109.568899"},{"key":"2026101621300544000_2025.10.24.684192v2.58","first-page":"437","article-title":"A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan. Nat","volume":"5","year":"2025","journal-title":"Aging"},{"key":"2026101621300544000_2025.10.24.684192v2.59","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/s42255-023-00804-z","article-title":"Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound","volume":"5","year":"2023","journal-title":"Nat. Metab"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.24.684192","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:30:16Z","timestamp":1792211416000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.24.684192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,25]]},"references-count":59,"URL":"https:\/\/doi.org\/10.1101\/2025.10.24.684192","relation":{},"subject":[],"published":{"date-parts":[[2025,10,25]]},"subtype":"preprint"}}