{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:02Z","timestamp":1787028542884,"version":"build-2736575974"},"reference-count":79,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01GM120519-01"],"award-info":[{"award-number":["1R01GM120519-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["82101346"],"award-info":[{"award-number":["82101346"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["1R01GM120519-01"],"award-info":[{"award-number":["1R01GM120519-01"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101346"],"award-info":[{"award-number":["82101346"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.<\/jats:p>","DOI":"10.3390\/ijms25126743","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T03:46:29Z","timestamp":1718855189000},"page":"6743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6004-4713","authenticated-orcid":false,"given":"Jing","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"},{"name":"Department of Anesthesiology, The First Affiliated Hospital of Xi\u2019an Jiaotong University School of Medicine, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqiong","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"},{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University School of Medicine, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reilley Paige","family":"Mathena","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sri Harsha","family":"Boppana","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia Insun","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University School of Medicine, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrus David","family":"Mintz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","unstructured":"United States Food and Drug Administration (2019, August 27). 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