Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences68625410.31857/S0869813925050039TOAQVNEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleBehavioral Impairments in Rats with Focal Cortical Dysplasia Following Febrile SeizuresНарушения поведения у крыс с фокальной кортикальной дисплазией, перенесших фебрильные судорогиZubarevaO. E.ЗубареваО. Е.
Russian Federation
zubarevaOE@mail.ruSinyakD. S.СинякД. С.
Russian Federation
zubarevaOE@mail.ruSubhankulovM. R.СубханкуловМ. Р.
Russian Federation
zubarevaOE@mail.ruPostnikovaT. Yu.ПостниковаТ. Ю.
Russian Federation
zubarevaOE@mail.ruZaytsevA. V.ЗайцевА. В.
Russian Federation
zubarevaOE@mail.ruSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова Российской академии наук1505202511156937072806202528062025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/686254

Disruptions in cerebral cortex development during early ontogenesis often lead to pharmacoresistant epilepsy and mental disorders. One such disruption is focal cortical dysplasia (FCD), which can be modeled in experimental animals by inducing cryogenic injury to the neocortex on the first day after birth. FCD is frequently associated with the development of epilepsy and behavioral impairments, such as deficits in learning, memory, and social interaction. These effects may be more pronounced when the brain is exposed to additional challenges, such as the combination of FCD with neonatal febrile seizures (FS). However, the specific characteristics of behavioral impairments in this combined pathology remain poorly understood. This study aimed to investigate behavioral impairments in adult male Wistar rats with FCD who had experienced FS. FCD was induced in rat pups on the first day of life (P0) by localized freezing of the somatosensory cortex. On the 10th day of life (P10), FS were triggered in the rat pups through hyperthermia (exposure to warm air) for 30 minutes. Only animals with FS lasting at least 15 minutes were included in the study. The control group consisted of sham-operated rat pups that were separated from their mother for 30 minutes at P10 without exposure to heat. At 2–2.5 months of age, the animals' behavior was evaluated using the following tests: Open Field, Elevated Plus Maze, Social Interaction Test, and Spontaneous Alternation Test in the Y-Maze. The results revealed that the combination of FCD and FS in early life led to increased social activity and alterations in exploratory behavior and anxiety levels in adult rats. These findings suggest that the combined pathology selectively affects behavioral functions, potentially due to the reorganization of neural networks in the brain. The study expands our understanding of the consequences of FCD and FS on brain function development and highlights the need for further research into the mechanisms underlying these changes. This work may contribute to the development of new therapeutic strategies for patients with similar conditions.

Нарушения развития коры головного мозга в раннем онтогенезе часто приводят к формированию фармакорезистентной эпилепсии и психических расстройств. Одним из таких нарушений является фокальная кортикальная дисплазия (ФКД), которую можно смоделировать у экспериментальных животных с помощью криогенного повреждения неокортекса в первые сутки после рождения. ФКД часто сопровождается развитием эпилепсии и поведенческих нарушений, таких как ухудшение обучения, памяти и социальной активности. Предполагается, что эти изменения могут быть более выраженными при комбинированном воздействии на мозг, например при сочетании ФКД с неонатальными фебрильными судорогами (ФС). Однако особенности поведенческих нарушений при такой сочетанной патологии остаются малоизученными. Целью настоящей работы было изучение поведенческих нарушений у взрослых крыс-самцов линии Вистар с ФКД, перенесших ФС. ФКД вызывали у крысят в первые сутки жизни (P0) путем локального замораживания соматосенсорной коры. На 10-й день жизни (P10) у крысят индуцировали ФС с помощью гипертермии (обдувания теплым воздухом) в течение 30 мин. В исследование включали только тех животных, у которых ФС длились не менее 15 мин. Контрольная группа состояла из ложнооперированных крысят, которых в возрасте P10 разлучали с матерью на 30 мин без нагревания. В возрасте 2–2.5 месяцев поведение животных оценивали с помощью тестов: “Открытое поле”, “Приподнятый крестообразный лабиринт”, “Социальный тест” и “Тест спонтанного чередования рукавов в Y-образном лабиринте”. Результаты показали, что сочетание ФКД и ФС в раннем возрасте приводит у взрослых животных к повышенной социальной активности, изменениям исследовательского поведения и уровня тревожности. Эти данные указывают на избирательное влияние сочетанной патологии на поведенческие функции, что может быть связано с реорганизацией нейронных сетей в мозге. Полученные результаты расширяют представления о последствиях комбинированного воздействия ФКД и ФС на формирование мозговых функций и подчеркивают важность дальнейшего изучения механизмов, лежащих в основе этих изменений. Это может иметь значение для разработки новых подходов к терапии пациентов с подобными нарушениями.

focal cortical dysplasiafebrile seizuressocial behaviorexploratory activityepileptogenesishyperthermialocomotor activityфокальная кортикальная дисплазияфебрильные судорогисоциальное поведениеисследовательская активностьэпилептогенезгипертермиядвигательная активностьРоссийский научный фондRussian Science Foundation24-15-00293Ho CSH, Dubeau F, Séguin R, Ducharme S (2019) Prevalence of neuropsychiatric symptoms associated with malformations of cortical development. Epilepsy and Behavior 92: 306–310. https://doi.org/10.1016/j.yebeh.2019.01.011Ma Q, Chen G, Li Y, Guo Z, Zhang X (2024) The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development. Genes Dis 11: 101021. https://doi.org/10.1016/j.gendis.2023.04.041Desikan RS, Barkovich AJ (2016) Malformations of cortical development. Ann Neurol 80: 797–810. https://doi.org/10.1002/ana.24793Crino PB (2015) Focal cortical dysplasia. Semin Neurol 35: 201–208. https://doi.org/10.1055/s-0035-1552617Zhao Y, Lin J, Qi X, Cao D, Zhu F, Chen L, Tan Z, Mo T, Zeng H (2024) To explore the potential mechanisms of cognitive impairment in children with MRI-negative pharmacoresistant epilepsy due to focal cortical dysplasia: A pilot study from gray matter structure view. Heliyon 10: e26609. https://doi.org/10.1016/j.heliyon.2024.e26609Choi SA, Kim KJ (2019) The Surgical and Cognitive Outcomes of Focal Cortical Dysplasia. J Korean Neurosurg Soc 62: 321–327. https://doi.org/10.3340/jkns.2019.0005Allone C, Bonanno L, Lo Buono V, Corallo F, Palmeri R, Micchia K, Pollicino P, Bramanti A, Marino S (2020) Neuropsychological assessment and clinical evaluation in temporal lobe epilepsy with associated cortical dysplasia. J Clin Neurosci 72: 146–150. https://doi.org/10.1016/j.jocn.2019.12.041Kimura N, Takahashi Y, Shigematsu H, Imai K, Ikeda H, Ootani H, Takayama R, Mogami Y, Kimura N, Baba K, Kondou S, Inoue Y (2019) Risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia. Brain Dev 41: 77–84. https://doi.org/10.1016/j.braindev.2018.07.014Qiao L, Yu T, Ni D, Wang X, Xu C, Liu C, Zhang G, Li Y (2017) Correlation between extreme fear and focal cortical dysplasia in anterior cingulate gyrus: Evidence from a surgical case of refractory epilepsy. Clin Neurol Neurosurg 163: 121–123. https://doi.org/10.1016/j.clineuro.2017.10.025Fujimoto A, Enoki H, Niimi K, Nozaki T, Baba S, Shibamoto I, Otsuki Y, Oanishi T (2021) Epilepsy in patients with focal cortical dysplasia may be associated with autism spectrum disorder. Epilepsy and Behavior 120: 107990. https://doi.org/10.1016/j.yebeh.2021.107990Luhmann HJ (2023) Malformations-related neocortical circuits in focal seizures. Neurobiol Dis 178: 106018. https://doi.org/10.1016/j.nbd.2023.106018Dvorák K, Feit J (1977) Migration of neuroblasts through partial necrosis of the cerebral cortex in newborn rats-contribution to the problems of morphological development and developmental period of cerebral microgyria. Histological and autoradiographical study. Acta Neuropathol 38: 203–212. https://doi.org/10.1007/BF00688066Sanon NT, Desgent S, Carmant L (2012) Atypical Febrile Seizures, Mesial Temporal Lobe Epilepsy, and Dual Pathology. Epilepsy Res Treat 2012: 1–9. https://doi.org/10.1155/2012/342928Bernard C (2016) The Diathesis–Epilepsy Model: How Past Events Impact the Development of Epilepsy and Comorbidities. Cold Spring Harb Perspect Med 6: a022418. https://doi.org/10.1101/cshperspect.a022418Jacobs KM, Gutnick MJ, Prince DA (1996) Hyperexcitability in a Model of Cortical Maldevelopment. Cerebr Cortex 6: 514–523. https://doi.org/10.1093/cercor/6.3.514Luhmann HJ, Raabe K (1996) Characterization of neuronal migration disorders in neocortical structures: I. Expression of epileptiform activity in an animal model. Epilepsy Res 26: 67–74. https://doi.org/10.1016/S0920-1211(96)00041-1Luhmann HJ, Raabe K, Qü M, Zilles K (1998) Characterization of neuronal migration disorders in neocortical structures: Еxtracellular in vitro recordings. Eur J Neurosci 10: 3085–3094. https://doi.org/10.1046/j.1460-9568.1998.00311.xMalkin SL, Amakhin DV, Soboleva EB, Postnikova TY, Zaitsev AV (2025) Synaptic Dysregulation Drives Hyperexcitability in Pyramidal Neurons Surrounding Freeze-Induced Neocortical Malformations in Rats. Int J Mol Sci 2025: 1423. https://doi.org/10.3390/ijms26041423Colciaghi F, Finardi A, Frasca A, Balosso S, Nobili P, Carriero G, Locatelli D, Vezzani A, Battaglia G (2011) Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia. Brain 134: 2828–2843. https://doi.org/10.1093/brain/awr045Ouardouz M, Lema P, Awad PN, Di Cristo G, Carmant L (2010) N-methyl-D-aspartate, hyperpolarization-activated cation current (Ih) and gamma-aminobutyric acid conductances govern the risk of epileptogenesis following febrile seizures in rat hippocampus. Eur J Neurosci 31: 1252–1260. https://doi.org/10.1111/j.1460-9568.2010.07159.xScantlebury MH, Gibbs SA, Foadjo B, Lema P, Psarropoulou C, Carmant L (2005) Febrile seizures in the predisposed brain: A new model of temporal lobe epilepsy. Ann Neurol 58: 41–49. https://doi.org/10.1002/ana.20512Postnikova TY, Griflyuk AV, Amakhin DV, Kovalenko AA, Soboleva EB, Zubareva OE, Zaitsev AV (2021) Early Life Febrile Seizures Impair Hippocampal Synaptic Plasticity in Young Rats. Int J Mol Sci 22: 8218. https://doi.org/10.3390/ijms22158218Savage S, Kehr J, Olson L, Mattsson A (2011) Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation. Neuroscience 195: 60–69. https://doi.org/10.1016/j.neuroscience.2011.08.027Singh M, Singh KP, Shukla S, Dikshit M (2015) Assessment of in-utero venlafaxine induced, ROS-mediated, apoptotic neurodegeneration in fetal neocortex and neurobehavioral sequelae in rat offspring. Int J Development Neurosci 40: 60–69. https://doi.org/10.1016/j.ijdevneu.2014.10.007Prinzi C, Kostenko A, de Leo G, Gulino R, Leanza G, Caccamo A (2023) Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins. Biology (Basel) 12: 1264. https://doi.org/10.3390/biology12091264Sapiurka M, Squire LR, Clark RE (2016) Distinct roles of hippocampus and medial prefrontal cortex in spatial and nonspatial memory. Hippocampus 26: 1515–1524. https://doi.org/10.1002/hipo.22652Rosen GD, Waters NS, Galaburda AM, Denenberg VH (1995) Behavioral consequences of neonatal injury of the neocortex. Brain Res 681: 177–189. https://doi.org/10.1016/0006-8993(95)00312-EClark MG, Rosen GD, Tallal P, Fitch RH (2000) Impaired processing of complex auditory stimuli in rats with induced cerebrocortical microgyria: An animal model of developmental language disabilities. J Cogn Neurosci 12: 828–839. https://doi.org/10.1162/089892900562435Bast T, Ramantani G, Seitz A, Rating D (2006) Focal cortical dysplasia: Prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol Scand 113: 72–81. https://doi.org/10.1111/j.1600-0404.2005.00555.xMattia D, Olivier A, Avoli M (1995) Seizure‐like discharges recorded in human dysplastic neocortex maintained in vitro. Neurology 45: 1391–1395. https://doi.org/10.1212/WNL.45.7.1391Yu YH, Lee K, Sin DS, Park K-H, Park D-K, Kim D-S (2017) Altered functional efficacy of hippocampal interneuron during epileptogenesis following febrile seizures. Brain Res Bull 131: 25–38. https://doi.org/10.1016/j.brainresbull.2017.02.009Sloviter RS (1999) Status epilepticus-induced neuronal injury and network reorganization. Epilepsia 40: s34–s39. https://doi.org/10.1111/j.1528-1157.1999.tb00876.xHoogland G, Raijmakers M, Clynen E, Brône B, Rigo J-M, Swijsen A (2022) Experimental early-life febrile seizures cause a sustained increase in excitatory neurotransmission in newborn dentate granule cells. Brain Behav 12: e2505. https://doi.org/10.1002/brb3.2505Yu YH, Kim S-W, Im H, Lee YR, Kim GW, Ryu S, Park D-K, Kim D-S (2023) Febrile Seizure Causes Deficit in Social Novelty, Gliosis, and Proinflammatory Cytokine Response in the Hippocampal CA2 Region in Rats. Cells 12: 2446. https://doi.org/10.3390/cells12202446Kloc ML, Marchand DH, Holmes GL, Pressman RD, Barry JM (2022) Cognitive impairment following experimental febrile seizures is determined by sex and seizure duration. Epilepsy & Behavior 126: 108430. https://doi.org/10.1016/j.yebeh.2021.108430Sheppard E, Lalancette E, Thébault-Dagher F, Lafontaine M-P, Knoth IS, Gravel J, Lippé S (2021) Cognitive and behavioural development in children presenting with complex febrile seizures: Аt onset and school age. Epilept Disord 23: 325–336. https://doi.org/10.1684/epd.2021.1260Martinos MM, Yoong M, Patil S, Chin RFM, Neville BG, Scott RC, de Haan M (2012) Recognition memory is impaired in children after prolonged febrile seizures. Brain 135: 3153–3164. https://doi.org/10.1093/brain/aws213Griflyuk AV, Postnikova TY, Zaitsev AV (2024) Animal Models of Febrile Seizures: Limitations and Recent Advances in the Field. Cells 13: 1895. https://doi.org/10.3390/cells13221895Remonde CG, Gonzales EL, Adil KJ, Jeon SJ, Shin CY (2023) Augmented impulsive behavior in febrile seizure-induced mice. Toxicol Res 39: 37–51. https://doi.org/10.1007/s43188-022-00145-1Yu YH, Kim S-W, Im H, Song Y, Kim SJ, Lee YR, Kim GW, Hwang C, Park D-K, Kim D-S (2022) Febrile Seizures Cause Depression and Anxiogenic Behaviors in Rats. Cells 11: 3228. https://doi.org/10.3390/cells11203228Gibbs S, Chattopadhyaya B, Desgent S, Awad PN, Clerk-Lamalice O, Levesque M, Vianna RM, Rébillard RM, Delsemme AA, Hébert D, Tremblay L, Lepage M, Descarries L, Di Cristo G, Carmant L (2011) Long-term consequences of a prolonged febrile seizure in a dual pathology model. Neurobiol Dis 43: 312–321. https://doi.org/10.1016/j.nbd.2011.02.013Desgent S, Duss S, Sanon NT, Lema P, Lévesque M, Hébert D, Rébillard R-M, Bibeau K, Brochu M, Carmant L (2012) Early-Life Stress Is Associated with Gender-Based Vulnerability to Epileptogenesis in Rat Pups. PLoS One 7: e42622. https://doi.org/10.1371/journal.pone.0042622Sotoyama H, Inaba H, Iwakura Y, Namba H, Takei N, Sasaoka T, Nawa H (2022) The dual role of dopamine in the modulation of information processing in the prefrontal cortex underlying social behavior. FASEB J 36: e22160. https://doi.org/10.1096/fj.202101637RAdinolfi A, Carbone C, Leo D, Gainetdinov RR, Laviola G, Adriani W (2018) Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns. Genes Brain Behav 17: e12463. https://doi.org/10.1111/gbb.12463Liu L, Zhang L, Wang T, Chen L (2019) Dopamine D1 receptor in the medial prefrontal cortex mediates anxiety-like behaviors induced by blocking glutamatergic activity of the ventral hippocampus in rats. Brain Res 1704: 59–67. https://doi.org/10.1016/j.brainres.2018.09.024Trottier S, Evrard B, Biraben A, Chauvel P (1994) Altered patterns of catecholaminergic fibers in focal cortical dysplasia in two patients with partial seizures. Epilepsy Res 19: 161–179. https://doi.org/10.1016/0920-1211(94)90026-4