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Juvenile mice were subjected to cardiac arrest and cardiopulmonary resuscitation, then received delayed in vivo fluoxetine or vehicle from postinjury days 10–13. Electrophysiology at day 14 showed fluoxetine restored hippocampal long-term potentiation in males but not females, aligning with increased hippocampal BDNF expression only in males. Ex vivo testing confirmed acute fluoxetine rescued LTP in male slices. Results indicate sex- and developmental-stage–dependent neuroplastic recovery.",{"@graph":69,"@context":114},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/delayed-fluoxetine-administration-restores-hippocampal-function-in-a-juvenile-global-cerebral-ischemia-mouse-model-in-a-sex-specific-manner/438090/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/delayed-fluoxetine-administration-restores-hippocampal-function-in-a-juvenile-global-cerebral-ischemia-mouse-model-in-a-sex-specific-manner/438090.png","ImageObject",300,407,{"name":92,"@type":93},"jay","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108],{"name":109,"@type":110,"acceptedAnswer":111},"What experimental timeline was used for drug administration and assessment?","Question",{"text":112,"@type":113},"Mice received fluoxetine or vehicle from postinjury days 10–13, with electrophysiological recordings performed on day 14; paired ex vivo experiments assessed acute fluoxetine effects on injured male slices.","Answer","https://schema.org",{"og:url":83,"og:type":116,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":118,"canonical":83},"index,follow",{"doc_id":120,"site_id":62},438090,1791008657,{"code":4,"msg":5,"data":123},{"doc_id":120,"user_id":124,"nickname":92,"user_avatar":125,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":126,"file_id":127,"file_url":128,"file_type":129,"file_size":130,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":131,"language":132,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":67,"update_tm":136,"read_time":41,"preview_page_count":4},3985747858866,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Wiley  \nNeural Plasticity  \nVolume 2025, Article ID 8841616, 12 pages [https://doi.org/10.1155/np/8841616](https://doi.org/10.1155/np/8841616)  \nResearch Article  \nDelayed Fluoxetine Administration Restores Hippocampal Function in a Juvenile Global Cerebral Ischemia Mouse Model in a Sex-Specific Manner  \nApril Fineberg, 1 Tanner McVey, 1 Jamie Henry, 1 Erika Tiemeyer, 1 James E. Orfila,2 and Robert M. Dietz 1  \n1Department of Pediatrics, University of Colorado, Anschutz Campus, Aurora, Colorado, USA  \n2Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA  \nCorrespondence should be addressed to Robert M. Dietz; [robert.dietz@cuanschutz.edu](robert.dietz@cuanschutz.edu)  \nReceived 12 August 2025; Revised 24 November 2025; Accepted 2 December 2025  \nAcademic Editor: Fernando Peña-Ortega  \nCopyright © 2025 April Fineberg et al. Neural Plasticity published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nGlobal cerebral ischemia (GCI) during childhood is a leading cause of long-term cognitive impairment, yet no therapies currently exist to promote recovery in survivors. We previously demonstrated that juvenile mice exhibit transient hippocampal synaptic dysfunction after GCI, associated with reduced brain-derived neurotrophic factor (BDNF) expression and partial endogenous recovery over time. In this study, we tested whether delayed treatment with fluoxetine (FLX)—a selective serotonin reuptake inhibitor (SSRI) known to enhance BDNF–TrkB signaling—could accelerate synaptic recovery. Juvenile mice underwent cardiac arrest and cardiopulmonary resuscitation, followed by in vivo FLX or vehicle administration from postinjury days 10–13. Electrophysiological recordings on day 14 revealed that FLX restored hippocampal long-term potentiation (LTP) in males but not females. This effect was paralleled by an increase in hippocampal BDNF expression in FLX-treated males, whereas no change was observed in females. Paired ex vivo experiments further confirmed that acute FLX exposure rescued LTP in GCI-injured male slices. These findings suggest that FLX promotes synaptic recovery through BDNF–TrkB signaling in males, while recovery in females may proceed via alternate, hormone-dependent mechanisms. Together, these results identify a novel therapeutic window for enhancing neuroplasticity after juvenile GCI and underscore the importance of developmental stage and biological sex in shaping responses to treatment.  \nKeywords: cardiac arrest; fluoxetine; global cerebral ischemia; juvenile; pediatric  \n1. Introduction  \nCardiac arrest remains a leading cause of global cerebral ischemia (GCI) across all age groups. Although survival rates have improved due to advances in resuscitation techniques, the long-term neurological consequences remain severe, particularly in developing brains [1–7] . In children, over 20,000 cases of cardiac arrest occur annually in the United States, often due to respiratory failure, trauma, or arrhythmia [8] . Survival rates in children vary dramatically based on setting, with in-hospital arrests associated with ~60% survival compared to only ~19% for out-of-hospital events [8] . Survivors  \nfrequently experience persistent cognitive deficits, notably in memory and learning, which can affect developmental milestones and academic achievement [1–3, 5] . Some require long-term support due to significant motor and cognitive disabilities [1, 2] . While therapeutic hypothermia is neuroprotective in neonates and adults [9, 10], randomized trials in pediatric populations have not demonstrated the same benefit [11, 12] . These discrepancies underscore the need to elucidate age-specific mechanisms of injury and recovery to inform pediatric-focused interventions.  \nBrain-derived neurotrophic factor (BDNF) plays a critica","cbCait8qoXt6JV5S","https://ap.wps.com/l/cbCait8qoXt6JV5S","pdf",2033440,12,"English","# Introduction\n## Background and clinical need\n## Role of BDNF and age-dependent mechanisms","[{\"question\":\"What experimental timeline was used for drug administration and assessment?\",\"answer\":\"Mice received fluoxetine or vehicle from postinjury days 10–13, with electrophysiological recordings performed on day 14; paired ex vivo experiments assessed acute fluoxetine effects on injured male slices.\"}]","Delayed Fluoxetine Administration Restores Hippocampal Function in a Juvenile Global Cerebral Ischemia Mouse Model in a Sex-Specific Manner | PDF",1790684151]