{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:10:04Z","timestamp":1785499804676,"version":"3.56.0"},"reference-count":154,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T00:00:00Z","timestamp":1697328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NINDS","award":["R01 NS113921"],"award-info":[{"award-number":["R01 NS113921"]}]},{"name":"NIH NINDS","award":["R01 NS107417"],"award-info":[{"award-number":["R01 NS107417"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2\u20137 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3\/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal\/total neuron ratio and increased ischemic-necrotic\/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive\/normal, Rbfox3-positive\/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted\/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.<\/jats:p>","DOI":"10.3390\/cells12202454","type":"journal-article","created":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T10:47:32Z","timestamp":1697366852000},"page":"2454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3\/NeuN in Neonatal Hypoxic-Ischemic Male Piglets"],"prefix":"10.3390","volume":"12","author":[{"given":"Christopher T.","family":"Primiani","sequence":"first","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin E.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May W.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department Pediatrics, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5482-6620","authenticated-orcid":false,"given":"Jamie","family":"Perin","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Epidemiology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kulikowicz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polan","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Lester","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Rivera-Diaz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Olberding","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark V.","family":"Niedzwiecki","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva K.","family":"Ritzl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa W.","family":"Habela","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9540-4865","authenticated-orcid":false,"given":"Xiuyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng-Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond C.","family":"Koehler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"},{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"},{"name":"The Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1016\/S0140-6736(12)60560-1","article-title":"Global, regional, and national causes of child mortality: An updated systematic analysis for 2010 with time trends since 2000","volume":"379","author":"Liu","year":"2012","journal-title":"Lancet"},{"key":"ref_2","first-page":"409","article-title":"No cry at birth: Global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths","volume":"83","author":"Lawn","year":"2005","journal-title":"Bull. 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