{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:08:39Z","timestamp":1785434919366,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,21]]},"group-title":"Neuroscience","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["1T32NS115723-01"],"award-info":[{"award-number":["1T32NS115723-01"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1F32NS136186"],"award-info":[{"award-number":["1F32NS136186"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2R37NS065434"],"award-info":[{"award-number":["2R37NS065434"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MH087463"],"award-info":[{"award-number":["MH087463"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Landis Award for Outstanding Mentorship"],"award-info":[{"award-number":["Landis Award for Outstanding Mentorship"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Iowa Neuroscience Institute","award":["Post-doctoral Fund"],"award-info":[{"award-number":["Post-doctoral Fund"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Epilepsy affects one in twenty-six individuals. A major cause of epilepsy worldwide is viral encephalitis. Central nervous system infections can provoke seizures in the short term and increase the risk of spontaneous, recurrent seizures post-infection. However, the neural mechanisms underlying seizures during acute infection are unknown. These neuronal changes can be studied in C57BL6\/J mice infected with Theiler\u2019s murine encephalomyelitis virus (TMEV). TMEV-infected mice experience seizures 3-8 days post-injection (DPI), clear the virus by DPI 14, and may develop chronic, acquired temporal lobe epilepsy. TMEV may incite seizures during the acute infection period through inflammation, reactive gliosis, and cell death in hippocampal area CA1. Here, we explore the neuronal circuits underlying acute seizures in TMEV-injected mice using c-Fos driven TRAP (targeted recombination in active populations). TRAP mice (c-Fos- CreERT2 x CAG-tdTomato) were injected with PBS or TMEV and gently handled on DPI 5 to induce seizures. 4-OHT was administered to mice either 1.5 or 3 hr after seizures to tag the active cells expressing c-Fos with tdTomato. After 1 week, the mice were sacrificed and whole mouse brains were sectioned and immunostained for tdTomato expression. Percent area of fluorescence was quantified, and comparisons were made between TMEV-injected mice and PBS controls, sites ipsilateral vs contralateral to TMEV injection site, and between sexes. TdTomato expression was elevated in the TMEV-injected mice in the ipsilateral and contralateral hippocampus, thalamus, lateral septal nucleus, basal ganglia, triangular septal nucleus, fornix, and corpus callosum. Critically, the expression pattern suggests that seizures induced on DPI 5 arise from the hilus, dentate gyrus, and CA3 hippocampal subregions. Generalized seizures during acute TMEV infection may have propagated to the contralateral hemisphere via CA3 and the hippocampal commissure. TRAP has not been previously utilized in the TMEV mouse model and these experiments address crucial questions regarding seizure spread during TMEV infection.<\/jats:p>\n                <jats:sec>\n                  <jats:title>GRAPHICAL ABSTRACT<\/jats:title>\n                  <jats:fig position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"655185v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.20.655185","type":"posted-content","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T20:40:11Z","timestamp":1747860011000},"source":"Crossref","is-referenced-by-count":1,"title":["Seizure Circuit Activity in the Theiler\u2019s Murine Encephalomyelitis Virus Model of Infection-induced Epilepsy Using Transient Recombination in Active Populations"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-9854","authenticated-orcid":false,"given":"Alexandra N.","family":"Petrucci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2423-4592","authenticated-orcid":false,"given":"Ted","family":"Abel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2660-8826","authenticated-orcid":false,"given":"Karen S.","family":"Wilcox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025052307150940000_2025.05.20.655185v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2011.03928.x"},{"key":"2025052307150940000_2025.05.20.655185v1.2","doi-asserted-by":"crossref","unstructured":"Zhang P , Yang Y , Zou J , Yang X , Liu Q , Chen Y . Seizures and epilepsy secondary to viral infection in the central nervous system. Acta Epileptologica 2, 12 (2020).","DOI":"10.1186\/s42494-020-00022-0"},{"key":"2025052307150940000_2025.05.20.655185v1.3","doi-asserted-by":"publisher","DOI":"10.1684\/epd.2022.1491"},{"key":"2025052307150940000_2025.05.20.655185v1.4","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1552619"},{"key":"2025052307150940000_2025.05.20.655185v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01535.x"},{"key":"2025052307150940000_2025.05.20.655185v1.6","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181ffc420"},{"key":"2025052307150940000_2025.05.20.655185v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02405.x"},{"key":"2025052307150940000_2025.05.20.655185v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.12.015"},{"key":"2025052307150940000_2025.05.20.655185v1.9","doi-asserted-by":"crossref","unstructured":"Zhan J , et al. Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy. Frontiers in Neuroscience 12, (2018).","DOI":"10.3389\/fnins.2018.00077"},{"key":"2025052307150940000_2025.05.20.655185v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02390.x"},{"key":"2025052307150940000_2025.05.20.655185v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1481-5"},{"key":"2025052307150940000_2025.05.20.655185v1.12","doi-asserted-by":"crossref","unstructured":"DePaula-Silva AB . The Contribution of Microglia and Brain-Infiltrating Macrophages to the Pathogenesis of Neuroinflammatory and Neurodegenerative Diseases during TMEV Infection of the Central Nervous System. Viruses 16, 119 (2024).","DOI":"10.3390\/v16010119"},{"key":"2025052307150940000_2025.05.20.655185v1.13","doi-asserted-by":"publisher","DOI":"10.1177\/15357597211040939"},{"key":"2025052307150940000_2025.05.20.655185v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2015.10.032"},{"key":"2025052307150940000_2025.05.20.655185v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.03.025"},{"key":"2025052307150940000_2025.05.20.655185v1.16","doi-asserted-by":"crossref","unstructured":"Naik AA , Sun H , Williams CL , Weller DS , Julius Zhu J , Kapur J . Mechanism of seizure- induced retrograde amnesia. Progress in Neurobiology 200, 101984 (2021).","DOI":"10.1016\/j.pneurobio.2020.101984"},{"key":"2025052307150940000_2025.05.20.655185v1.17","doi-asserted-by":"crossref","unstructured":"Singh T , Batabyal T , Kapur J . Neuronal circuits sustaining neocortical-injury-induced status epilepticus. Neurobiology of Disease 165, 105633 (2022).","DOI":"10.1016\/j.nbd.2022.105633"},{"key":"2025052307150940000_2025.05.20.655185v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25601"},{"key":"2025052307150940000_2025.05.20.655185v1.19","first-page":"2336","article-title":"Parallel pathways of seizure generalization","volume":"142","year":"2019","journal-title":"Brain"},{"key":"2025052307150940000_2025.05.20.655185v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2023.09.017"},{"key":"2025052307150940000_2025.05.20.655185v1.21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.96.6.517"},{"key":"2025052307150940000_2025.05.20.655185v1.22","doi-asserted-by":"crossref","unstructured":"Batot G , Metcalf CS , Bell LA , Pauletti A , Wilcox KS , Br\u00f6er S . A Model for Epilepsy of Infectious Etiology using Theiler\u2019s Murine Encephalomyelitis Virus. J Vis Exp, (2022).","DOI":"10.3791\/63673-v"},{"key":"2025052307150940000_2025.05.20.655185v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12550"},{"key":"2025052307150940000_2025.05.20.655185v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(72)90177-0"},{"key":"2025052307150940000_2025.05.20.655185v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4886(69)90128-9"},{"key":"2025052307150940000_2025.05.20.655185v1.26","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-004-0926-7"},{"key":"2025052307150940000_2025.05.20.655185v1.27","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2605-7"},{"key":"2025052307150940000_2025.05.20.655185v1.28","unstructured":"Franklin KBJ , Paxinos G. Paxinos and Franklin\u2019s The mouse brain in stereotaxic coordinates (2013)."},{"key":"2025052307150940000_2025.05.20.655185v1.29","doi-asserted-by":"crossref","unstructured":"Bankhead P , et al. QuPath: Open source software for digital pathology image analysis. Scientific Reports 7, 16878 (2017).","DOI":"10.1038\/s41598-017-17204-5"},{"key":"2025052307150940000_2025.05.20.655185v1.30","doi-asserted-by":"publisher","DOI":"10.3758\/BRM.41.4.1149"},{"key":"2025052307150940000_2025.05.20.655185v1.31","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18239"},{"key":"2025052307150940000_2025.05.20.655185v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2021.01.038"},{"key":"2025052307150940000_2025.05.20.655185v1.33","doi-asserted-by":"crossref","unstructured":"Patel DC , et al. Hippocampal TNF\u03b1 Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy. eNeuro 4, (2017).","DOI":"10.1523\/ENEURO.0105-17.2017"},{"key":"2025052307150940000_2025.05.20.655185v1.34","doi-asserted-by":"crossref","unstructured":"Gerhauser I , Hansmann F , Ciurkiewicz M , L\u00f6scher W , Beineke A. Facets of Theiler\u2019s Murine Encephalomyelitis Virus-Induced Diseases: An Update (2019).","DOI":"10.3390\/ijms20020448"},{"key":"2025052307150940000_2025.05.20.655185v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2012.12.008"},{"key":"2025052307150940000_2025.05.20.655185v1.36","doi-asserted-by":"crossref","unstructured":"Tatum WOIV . Mesial Temporal Lobe Epilepsy. Journal of Clinical Neurophysiology 29, (2012).","DOI":"10.1097\/WNP.0b013e31826b3ab7"},{"key":"2025052307150940000_2025.05.20.655185v1.37","unstructured":"Zappone CA. Hippocampal associational and commissural pathways: Anatomical and electrophysiological studies in the rat.). The University of Arizona. (2004)."},{"key":"2025052307150940000_2025.05.20.655185v1.38","doi-asserted-by":"crossref","unstructured":"Cherubini E , Miles R . The CA3 region of the hippocampus: how is it? What is it for? How does it do it? Front Cell Neurosci 9, 19 (2015).","DOI":"10.3389\/fncel.2015.00019"},{"key":"2025052307150940000_2025.05.20.655185v1.39","doi-asserted-by":"publisher","DOI":"10.3819\/ccbr.2013.80003"},{"key":"2025052307150940000_2025.05.20.655185v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(07)63001-5"},{"key":"2025052307150940000_2025.05.20.655185v1.41","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0130-24.2024"},{"key":"2025052307150940000_2025.05.20.655185v1.42","unstructured":"Chauhan P , Jethwa K , Rathawa A , Chauhan G , Mehra S. The Anatomy of the Hippocampus. In: Cerebral Ischemia (ed Pluta R). Exon Publications"},{"key":"2025052307150940000_2025.05.20.655185v1.43","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlw008"},{"key":"2025052307150940000_2025.05.20.655185v1.44","doi-asserted-by":"crossref","unstructured":"Bell LA , Wallis GJ , Wilcox KS . Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler\u2019s murine encephalomyelitis virus. Journal of Neuroinflammation 17, 369 (2020).","DOI":"10.1186\/s12974-020-02043-5"},{"key":"2025052307150940000_2025.05.20.655185v1.45","doi-asserted-by":"crossref","unstructured":"Cruz-Mendoza F , Jauregui-Huerta F , Aguilar-Delgadillo A , Garc\u00eda-Estrada J , Luquin S . Immediate Early Gene c-fos in the Brain: Focus on Glial Cells. Brain Sci 12, (2022).","DOI":"10.3390\/brainsci12060687"},{"key":"2025052307150940000_2025.05.20.655185v1.46","doi-asserted-by":"publisher","DOI":"10.3390\/neurosci3040050"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.20.655185","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:44:47Z","timestamp":1768466687000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.20.655185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,21]]},"references-count":46,"URL":"https:\/\/doi.org\/10.1101\/2025.05.20.655185","relation":{},"subject":[],"published":{"date-parts":[[2025,5,21]]},"subtype":"preprint"}}