Status epilepticus (SE) is the most common neurologic emergency in children. Both clinical and laboratory studies have demonstrated that SE in early life can cause brain damage and permanent behavioral abnormalities, trigger epileptogenesis, and interfere with normal brain development. In experimental rodent models, the consequences of seizures are dependent upon age, the model used, and seizure duration. In studies involving neonatal and infantile animals, the model used, experimental design, conditions during the experiment, and manipulation of animals can significantly affect the course of the experiments as well as the results obtained. Standardization of laboratory approaches, harmonization of scientific methodology, and improvement in data collection can improve the comparability of data among laboratories.

Developmental Epileptology Institute of Physiology of the Czech Academy of Science Prague Czech Republic

Zobrazit více v PubMed

Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC. Incidence, cause, and short‐term outcome of convulsive status epilepticus in childhood: prospective population‐based study. Lancet. 2006;15(368):222–9. PubMed

DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective, population‐based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46:1029–35. PubMed

Aicardi J, Chevrie JJ. Convulsive status epilepticus in infants and children. A study of 239 cases. Epilepsia. 1970;11:187–97. PubMed

Pujar S, Scott RC. Long‐term outcomes after childhood convulsive status epilepticus. Curr Opin Pediatr. 2019;31:763–8. PubMed

Raspall‐Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol. 2006;5:769–79. PubMed

Auvin S, Dupuis N. Outcome of status epilepticus. What do we learn from animal data? Epileptic Disord. 2014. Spec No;1:S37–43. PubMed

Kubová H, Lukasiuk K, Pitkanen A. New insight on the mechanisms of epileptogenesis in the developing brain. Adv Tech Stand Neurosurg. 2012;39:3–44. PubMed

Mareš P. Cognitive and affective effect of seizures: immature developing animals. In: Holmes GL, Schachter SC, editors. Behavioral aspect of epilepsy principles and practice. New York: Demos, New York, NY, USA; 2008. p. 29–33.

Holmes GL, Thompson JL. Effects of kainic acid on seizure susceptibility in the developing brain. Brain Res. 1988;467(1):51–9. PubMed

Stafstrom CE. Assessing the behavioral and cognitive effects of seizures on the developing brain. Prog Brain Res. 2002;135:377–90. PubMed

Stafstrom CE, Chronopoulos A, Thurber S, Thompson JL, Holmes GL. Age‐dependent cognitive and behavioral deficits after kainic acid seizures. Epilepsia. 1993;34:420–32. PubMed

Albala BJ, Moshé SL, Okada R. Kainic‐acid‐induced seizures: a developmental study. Brain Res. 1984;315:139–48. PubMed

Mikati MA, Werner S, Shalak L, Shamseddine A, Simaan E, Liu Z, et al. Stages of status epilepticus in the developing brain. Epilepsy Res. 2003;55:9–19. PubMed

Liu Z, Holmes GL. Basic fibroblast growth factor‐induced seizures in rats. Neurosci Lett. 1997;233(2–3):85–8. PubMed

Nitecka L, Tremblay E, Charton G, Bouillot JP, Berger ML, Ben‐Ari Y. Maturation of kainic acid seizure‐brain damage syndrome in the rat. II Histopathological sequelae. Neuroscience. 1984;13:1073–94. PubMed

Stafstrom CE, Thompson JL, Holmes GL. Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures. Brain Res Dev Brain Res. 1992;65(2):227–36. PubMed

Chang D, Baram TZ. Status epilepticus results in reversible neuronal injury in infant rat hippocampus ‐ novel use of a marker. Brain Res Dev Brain Res. 1994;77(1):133–6. PubMed PMC

Folbergrová J, Jesina P, Kubová H, Druga R, Otahál J. Status epilepticus in immature rats is associated with oxidative stress and mitochondrial dysfunction. Front Cell Neurosci. 2016;10:136. PubMed PMC

Järvelä JT, Lopez‐Picon FR, Holopainen IE. Age‐dependent cyclooxygenase‐2 induction and neuronal damage after status epilepticus in the postnatal rat hippocampus. Epilepsia. 2008;49:832–41. PubMed

Haas KZ, Sperber EF, Opanashuk LA, Stanton PK, Moshe SL. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus. 2001;11:615–25. PubMed

Mlsna LM, Koh S. Maturation‐dependent behavioral deficits and cell injury in developing animals during the subacute postictal period. Epilepsy Behav. 2013;29:190–7. PubMed PMC

Sayin U, Sutula TP, Stafstrom CE. Seizures in the developing brain cause adverse long‐term effects on spatial learning and anxiety. Epilepsia. 2004;45(12):1539–48. PubMed

Lynch M, Sayin U, Bownds J, Janumpalli S, Sutula T. Long‐term consequences of early postnatal seizures on hippocampal learning and plasticity. Eur J Neurosci. 2000;12:2252–64. PubMed

de Feo MR, Mecarelli O, Palladini G, Ricci GF. Long‐term effects of early status epilepticus on the acquisition of conditioned avoidance behavior in rats. Epilepsia. 1986;27:476–82. PubMed

Priel MR, dos Santos NF, Cavalheiro EA. Developmental aspects of the pilocarpine model of epilepsy. Epilepsy Res. 1996;26:115–21. PubMed

Suchomelová L, Lopez‐Meraz ML, Niquet J, Kubová H, Wasterlain CG. Hyperthermia aggravates status epilepticus‐induced epileptogenesis and neuronal loss in immature rats. Neuroscience. 2015;305:209–24. PubMed

Kubová H, Mareš P. Are morphologic and functional consequences of status epilepticus in infant rats progressive? Neuroscience. 2013;236:232–49. PubMed

Kubová H, Mareš P, Suchomelová L, Brožek G, Druga R, Pitkanen A. Status epilepticus in immature rats leads to behavioral and cognitive impairment and epileptogenesis. Eur J Neurosci. 2004;19:3255–65. PubMed

Dube C, Boyet S, Marescaux C, Nehlig A. Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium‐pilocarpine model of epilepsy in the immature and adult rat. Exp Neurol. 2001;167:227–41. PubMed

Nehlig A, Dubé C, Koning E. Status epilepticus induced by lithium‐pilocarpine in the immature rat does not change the long‐term susceptibility to seizures. Epilepsy Res. 2002;51:189–97. PubMed

Sankar R, Shin DH, Liu H, Mazarati A, Pereira De Vasconcelos A, Wasterlain CG. Patterns of status epilepticus‐induced neuronal injury during development and long‐term consequences. J Neurosci. 1998;18(20):8382–93. PubMed PMC

Cilio MR, Sogawa Y, Cha BH, Liu XZ, Huang LT, Holmes GL. Long‐term effects of status epilepticus in the immature brain are specific for age and model. Epilepsia. 2003;44:518–28. PubMed

Fernandes MJ, Dubé C, Boyet S, Marescaux C, Nehlig A. Correlation between hypermetabolism and neuronal damage during status epilepticus induced by lithium and pilocarpine in immature and adult rats. J Cereb Blood Flow Metab. 1999;19:195–209. PubMed

Sankar R, Shin DH, Wasterlain CG. Serum neuron‐specific enolase is a marker for neuronal damage following status epilepticus in the rat. Epilepsy Res. 1997;28:129–36. PubMed

Scholl EA, Dudek FE, Ekstrand JJ. Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine‐induced status epilepticus in the immature rat. Neuroscience. 2013;252:45–59. PubMed PMC

Druga R, Mareš P, Kubová H. Time course of neuronal damage in the hippocampus following lithium‐pilocarpine status epilepticus in 12‐day‐old rats. Brain Res. 2010;1355:174–9. PubMed

Kubová H, Druga R, Lukasiuk K, Suchomelová L, Haugvicová R, Jirmanová I, et al. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J Neurosci. 2001;21:3593–9. PubMed PMC

Lopez‐Meraz ML, Wasterlain CG, Rocha LL, Allen S, Niquet J. Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. Neurobiol Dis. 2010;37:394–402. PubMed PMC

Nairismagi J, Pitkanen A, Kettunen MI, Kauppinen RA, Kubova H. Status epilepticus in 12‐day‐old rats leads to temporal lobe neurodegeneration and volume reduction: a histologic and MRI study. Epilepsia. 2006;47:479–88. PubMed

Torolira D, Suchomelova L, Wasterlain CG, Niquet J. Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups. Epilepsy Res. 2016;120:47–54. PubMed PMC

Wu CL, Huang LT, Liou CW, Wang TJ, Tung YR, Hsu HY, et al. Lithium‐pilocarpine‐induced status epilepticus in immature rats result in long‐term deficits in spatial learning and hippocampal cell loss. Neurosci Lett. 2001;312(2):113–7. PubMed

Liu Z, Gatt A, Werner SJ, Mikati MA, Holmes GL. Long‐term behavioral deficits following pilocarpine seizures in immature rats. Epilepsy Research. 1994;19:191–204. PubMed

Hung PL, Lai MC, Yang SN, Wang CL, Liou CW, Wu CL, et al. Aminophylline exacerbates status epilepticus‐induced neuronal damages in immature rats: a morphological, motor and behavioral study. Epilepsy Res. 2002;49:218–25. PubMed

dos Santos NF, Arida RM, Filho EM, Priel MR, Cavalheiro EA. Epileptogenesis in immature rats following recurrent status epilepticus. Brain Res Brain Res Rev. 2000;32:269–76. PubMed

Mikulecká A, Druga R, Stuchlík A, Mareš P, Kubová H. Comorbidities of early‐onset temporal epilepsy: cognitive, social, emotional, and morphologic dimensions. Exp Neurol. 2019;320:113005. PubMed

Pacifico AM, Batista SP, Ribeiro FT, dos Santos PB, Silveira GB, do Nascimento BPP, et al. Dataset on sociability, cognitive function, gene and protein expression of molecules involved in social behavior, reward system and synapse function following early‐life status epilepticus in Wistar rats. Data in Brief. 2020;31:105819. PubMed PMC

Castelhano AS, Cassane Gdos S, Scorza FA, Cysneiros RM. Altered anxiety‐related and abnormal social behaviors in rats exposed to early life seizures. Front Behav Neurosci. 2013;7:36. PubMed PMC

de Oliveira DL, Fischer A, Jorge RS, da Silva MC, Leite M, Goncalves CA, et al. Effects of early‐life LiCl‐pilocarpine‐induced status epilepticus on memory and anxiety in adult rats are associated with mossy fiber sprouting and elevated CSF S100B protein. Epilepsia. 2008;49:842–52. PubMed

Persinger MA, Makarec K. Complex partial epileptic signs as a continuum from normals to epileptics: normative data and clinical populations. J Clin Psychol. 1993;49:33–45. PubMed

Liu Z, Gatt A, Mikati M, Holmes GL. Effect of temperature on kainic acid‐induced seizures. Brain Res. 1993;631(1):51–8. PubMed

el Hamdi G, de Vasconcelos AP, Vert P, Nehlig A. An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. I Behavioral characterization and determination of lumped constant. Brain Res Dev Brain Res. 1992;69:233–42. PubMed

Nehlig A, Vasconcelos AP. The model of pentylenetetrazol‐induced status epilepticus in the immature rat: short‐ and long‐term effects. Epilepsy Res. 1996;26:93–103. PubMed

Huang LT, Yang SN, Liou CW, Hung PL, Lai MC, Wang CL, et al. Pentylenetetrazol‐induced recurrent seizures in rat pups: time course on spatial learning and long‐term effects. Epilepsia. 2002;43:567–73. PubMed

Thompson K. Status epilepticus and early development: neuronal injury, neurodegeneration, and their consequences. Epilepsia Open. 2022:1–7. PubMed PMC

Liu H, Kaur J, Dashtipour K, Kinyamu R, Ribak CE, Friedman LK. Suppression of hippocampal neurogenesis is associated with developmental stage, number of perinatal seizure episodes, and glucocorticosteroid level. Exp Neurol. 2003;184:196–213. PubMed

Clancy B, Finlay BL, Darlington RB, Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007;28:931–7. PubMed PMC

Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. Environ Health Persp. 2000;108:511–33. PubMed PMC

Sanchez RM, Jensen FE. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Epilepsia. 2001;42:577–85. PubMed

Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble‐Haeusslein LJ. Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;106‐107:1–16. PubMed PMC

Avishai‐Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed‐out, or in (utero)? Trends Neurosci. 2002;25:518–24. PubMed PMC

Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3:79–83. PubMed

McCutcheon JE, Marinelli M. Age matters. Eur J Neurosci. 2009;29:997–1014. PubMed PMC

Herlenius E, Lagercrantz H. Development of neurotransmitter systems during critical periods. Exp Neurol. 2004;190(Suppl 1):S8–21. PubMed

Hernan AE, Holmes GL. Antiepileptic drug treatment strategies in neonatal epilepsy. Prog Brain Res. 2016;226:179–93. PubMed

Ellingson RI, Rose GH. Ontogenesis of the electroencephalogram. In: WAe IH, editor. Developmental neurobiology. Springfield, IL, USA: Charles C. Thomas; 1970. p. 441–74.

Mareš P, Zouhar A, Brožek G. Ontogenetic development of electrocorticogram in the rat. Act Nerv Super (Praha). 1979;21:218–25. PubMed

Dreyfus‐Brisac C. The electroencephalogram of the premature infant. World Neurol. 1962;3:5–15. PubMed

Bishnoi IR, Ossenkopp KP, Kavaliers M. Sex and age differences in locomotor and anxiety‐like behaviors in rats: From adolescence to adulthood. Dev Psychobiol. 2021;63:496–511. PubMed

Piacsek BE, Statham NJ, Goodspeed MP. Sexual maturation of male rats in continuous light. Am J Physiol. 1978;234:E262–6. PubMed

Katsarou AM, Kubova H, Auvin S, Mantegazza M, Barker‐Haliski M, Galanopoulou AS, et al. A companion to the preclinical common data elements for rodent models of pediatric acquired epilepsy: a report of the TASK3‐WG1B, pediatric and genetic models working group of the ILAE/AES joint translational TASK force. Epilepsia Open. 2022;1–34. PubMed

Mazarati A, Jones NC, Galanopoulou AS, Harte‐Hargrove LC, Kalynchuk LE, Lenck‐Santini PP, et al. A companion to the preclinical common data elements on neurobehavioral comorbidities of epilepsy: a report of the TASK3 behavior working group of the ILAE/AES Joint Translational Task Force. Epilepsia Open. 2018;3:24–52. PubMed PMC

Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA. 2002;99:15089–94. PubMed PMC

Ikonomidou C, Bittigau P, Koch C, Genz K, Hoerster F, Felderhoff‐Mueser U, et al. Neurotransmitters and apoptosis in the developing brain. Biochem Pharmacol. 2001;62(4):401–5. PubMed

Jevtovic‐Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876–82. PubMed PMC

Kaushal S, Tamer Z, Opoku F, Forcelli PA. Anticonvulsant drug‐induced cell death in the developing white matter of the rodent brain. Epilepsia. 2016;57:727–34. PubMed PMC

Olney JW, Young C, Wozniak DF, Jevtovic‐Todorovic V, Ikonomidou C. Do pediatric drugs cause developing neurons to commit suicide? Trends Pharmacol Sci. 2004;25:135–9. PubMed

Stefovska VG, Uckermann O, Czuczwar M, Smitka M, Czuczwar P, Kis J, et al. Sedative and anticonvulsant drugs suppress postnatal neurogenesis. Ann Neurol. 2008;64:434–45. PubMed

Frankel S, Medvedeva N, Gutherz S, Kulick C, Kondratyev A, Forcelli PA. Comparison of the long‐term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats. Epilepsy Behav. 2016;57:34–40. PubMed PMC

Mikulecká A, Šubrt M, Stuchlík A, Kubová H. Consequences of early postnatal benzodiazepines exposure in rats. I Cognitive‐like behavior. Front Behav Neurosci. 2014;8:101. PubMed PMC

Mikulecká A, Mareš P, Kubová H. Rebound increase in seizure susceptibility but not isolation‐induced calls after single administration of clonazepam and Ro 19‐8022 in infant rats. Epilepsy Behav. 2011;20:12–9. PubMed

Tsenov G, Kubová H, Mareš P. Which component of treatment is important for changes of cortical epileptic afterdischarges after status epilepticus in immature rats? Neurosci Lett. 2017;644:1–4. PubMed

Szczurowska E, Ergang P, Kubová H, Druga R, Salaj M, Mareš P. Influence of early life status epilepticus on the developmental expression profile of the GluA2 subunit of AMPA receptors. Exp Neurol. 2016;283:97–109. PubMed

Harshaw C, Culligan JJ, Alberts JR. Sex differences in thermogenesis structure behavior and contact within huddles of infant mice. PLoS One. 2014;9:e87405. PubMed PMC

Conklin P, Heggeness FW. Maturation of temperature homeostasis in rat. Am J Physiol. 1971;220:333–6. PubMed

Moriceau S, Sullivan RM. Neurobiology of infant attachment. Dev Psychobiol. 2005;47:230–42. PubMed PMC

Pryce CR, Feldon J. Long‐term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev. 2003;27:57–71. PubMed

Jimenez JA, Zylka MJ. Controlling litter effects to enhance rigor and reproducibility with rodent models of neurodevelopmental disorders. J Neurodev Disord. 2021;13:2. PubMed PMC

Festing MF. Design and statistical methods in studies using animal models of development. Ilar J. 2006;47:5–14. PubMed

Zorrilla EP. Multiparous species present problems (and possibilities) to developmentalists. Dev Psychobiol. 1997;30:141–50. PubMed

McCarty R. Cross‐fostering: elucidating the effects of gene x environment interactions on phenotypic development. Neurosci Biobehav Rev. 2017;73:219–54. PubMed

Agnish ND, Keller KA. The rationale for culling of rodent litters. Fundam Appl Toxicol. 1997;38:2–6. PubMed

Palmer AK, Ulbrich BC. The cult of culling. Fundam Appl Toxicol. 1997;38:7–22. PubMed

Bautista A, Garcia‐Torres E, Prager G, Hudson R, Rodel HG. Development of behavior in the litter huddle in rat pups: within‐ and between‐litter differences. Developmental Psychobiology. 2010;52:35–43. PubMed

Akman O, Moshe SL, Galanopoulou AS. Early life status epilepticus and stress have distinct and sex‐specific effects on learning, subsequent seizure outcomes, including anticonvulsant response to phenobarbital. CNS Neurosci Ther. 2015;21:181–92. PubMed PMC

Akman O, Moshe SL, Galanopoulou AS. Sex‐specific consequences of early life seizures. Neurobiol Dis. 2014;72 Pt B:153–66. PubMed PMC

Damborsky JC, Winzer‐Serhan UH. Effects of sex and chronic neonatal nicotine treatment on Na2+/K+/Cl− co‐transporter 1, K+/Cl− co‐transporter 2, brain‐derived neurotrophic factor, NMDA receptor subunit 2A and NMDA receptor subunit 2B mRNA expression in the postnatal rat hippocampus. Neuroscience. 2012;225:105–17. PubMed PMC

Galanopoulou AS. Sexually dimorphic expression of KCC2 and GABA function. Epilepsy Res. 2008;80:99–113. PubMed PMC

Premachandran H, Zhao M, Arruda‐Carvalho M. Sex differences in the development of the rodent corticolimbic system. Front Neurosci. 2020;14:583477. PubMed PMC

Castelhano AS, Ramos FO, Scorza FA, Cysneiros RM. Early life seizures in female rats lead to anxiety‐related behavior and abnormal social behavior characterized by reduced motivation to novelty and deficit in social discrimination. J Neural Transm (Vienna). 2015;122:349–55. PubMed

Galanopoulou AS. Dissociated gender‐specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons: role of GABA(a) receptors. J Neurosci. 2008;28(7):1557–67. PubMed PMC

Velišková J. Behavioral characterization of seizures in rats. Models of Seizures and Epilepsy. Amsterodam: Elsevier; 2006. p. 601–11.

Alberts JR. Infancy. In: Whishaw IQ, KOLB B, editors. The behavior of the laboratoty rat: a handbook with tests. New York: Oxford University Press; 2005. p. 266–77.

Isaacson RL, Spear LP. Early Brain Damage. A new perspective for the interpretation of early brain damage. New York, NY: Academic Press, Inc.; 1984. p. 73–98.

Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45. PubMed

Lynn DA, Brown GR. The ontogeny of exploratory behavior in male and female adolescent rats (Rattus norvegicus). Dev Psychobiol. 2009;51:513–20. PubMed PMC

Altman J, Bayer S. Postnatal development of hippocampal dentate gyrus under normal and experimental conditions. In: Isaacson RL, Pribram KH, editors. The hippocampus: structure and development. New York: Plenum Press; 1975. p. 95–122.

Geisler HC, Westerga J, Gramsbergen A. Development of posture in the rat. Acta Neurobiol Exp (Wars). 1993;53:517–23. PubMed

Gramsbergen A, Van Der AM, Geisler HC. Aspects of postural development in the rat. Equine Vet J Suppl. 1997;29:66–70. PubMed

Spear LP. The adolescent brain and age‐related behavioral manifestations. Neurosci Biobehav Rev. 2000;24:417–63. PubMed

Mikulecká A, Mareš P. Effects of mGluR5 and mGluR1 antagonists on anxiety‐like behavior and learning in developing rats. Behav Brain Res. 2009;204(1):133–9. PubMed

Pellis SM, Pellis VC. Development of righting when falling from a bipedal standing posture: evidence for the dissociation of dynamic and static righting reflexes in rats. Physiol Behav. 1994;56:659–63. PubMed

Mareš P, Kozlová L, Mikulecká A, Kubová H. The GluN2B‐selective antagonist Ro 25–6981 is effective against PTZ‐induced seizures and safe for further development in infantile rats. Pharmaceutics. 2021;13:1482. PubMed PMC

Metz GA, Whishaw IQ. Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore‐ and hindlimb stepping, placing, and co‐ordination. J Neurosci Methods. 2002;115(2):169–79. PubMed

Myhrer T. Neurotransmitter systems involved in learning and memory in the rat: a meta‐analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev. 2003;41:268–87. PubMed

Debiec J, Sullivan RM. The neurobiology of safety and threat learning in infancy. Neurobiol Learn. 2017;143:49–58. PubMed PMC

Altman J, Brunner RL, Bulut FG, Sudarshan K. The development of behavior in normal and brain‐damaged infant rats, studied with homing (nest‐seeking) as motivation. In: Weiner AVN, editor. Drugs and the developing brain. New York: Plenum; 1974. p. 321–48.

Sigling HO, Wolterink‐Donselaar IG, Spruijt BM. Home seeking behavior in rat pups: attachment vs. kin selection, oxytocin vs. vasopressin. Eur J Pharmacol. 2009;612:48–53. PubMed

Spear LP, Brake SC. Periadolescence: age‐dependent behaviour and psychopharmacological responsivity in rats. Dev Psychobiol. 1983;16:83–109. PubMed

Bronstein PM, Neiman H, Wolkoff FD, Levine MS. The development of the habituation in the rat. Anim Learn Behav. 1974;2:92–6.

Campbell BA, Stehouwer DJ. Retention of habituation and sensitization in neonatal rats. BehavNeural Biol. 1980;29:190–202. PubMed

Campbell RA, Raskin LA. Ontogeny of behavioral arousal: the role of environmental stimuli. Comp Physiol Psychol. 1978;92:176–84. PubMed

Feigley DA, Parsons PJ, Hamilton LW, Spear NE. Development of habituation to novel environment in the rat. J Comp Physiol Psychol. 1972;79:443–52. PubMed

File SE. The ontogeny of exploration in the rats: Habituation and effects of handling. Dev Psychobiol. 1978;11:321–8. PubMed

Shaywitz BA, Gordon JW, Klopper JH, Zelterman DA, Irvine J. Ontogenesis of spontaneous activity and habituation of activity in the rat pup. Dev Psychobiol. 1979;12:359–67. PubMed

Williams JM, Hamilton LW, Carlton PL. Ontogenetic dissociation of two classes of habituation. J Comp Physiol Psychol. 1975;89:733–7. PubMed

Doremus‐Fitzwater TL, Varlinskaya EI, Spear LP. Effects of pretest manipulation on elevated plus‐maze behavior in adolescent and adult male and female Sprague‐Dawley rats. Pharmacol Biochem Behav. 2009;92:413–23. PubMed PMC

Ganella DE, Kim JH. Developmental rodent models of fear and anxiety: from neurobiology to pharmacology. Br J Pharmacol. 2014;171:4556–74. PubMed PMC

Mikulecká A, Kršek P, Mareš P. Nonconvulsive kainic acid‐induced seizures elicit age‐dependent impairment of memory for the elevated plus‐maze. Epilepsy Behav. 2000;6:418–26. PubMed

Itoh J, Nabeshima T, Kameyama T. Utility of an elevated plus‐maze for dissociation of amnesic and behavioral effects of drugs in mice. Eur J Pharmacol. 1991;194(1):71–6. PubMed

Mareš P, Tichá K, Mikulecká A. Anticonvulsant and behavioral effects of GABA(B) receptor positive modulator CGP7930 in immature rats. Epilepsy Behav. 2013;28:113–20. PubMed

Medina JH, Schröder N, Izquierdo I. Two different properties of short‐ and long‐term memory. Behav Brain Res. 1999;103:119–21. PubMed

Crawley JN. Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines. Pharmacol Biochem Behav. 1981;15:695. PubMed

Carman HM, Booze RM, Mactutus CF. Long‐term retention of spatial navigation by preweanling rats. Dev Psychobiol. 2002;40:68–77. PubMed

Carman HM, Booze RM, Snow DM, Mactutus CF. Proximal versus distal cue utilization in preweanling spatial localization: the influence of cue number and location. Physiol Behav. 2003;79:157–65. PubMed

Carman HM, Mactutus CF. Ontogeny of spatial navigation in rats: a role for response requirements? Behav Neurosci. 2001;115:870–9. PubMed

Panksepp JB, Lahvis GP. Rodent empathy and affective neuroscience. Neurosci Biobehav Rev. 2011;35:1864–75. PubMed PMC

Trezza V, Baarendse PJ, Vanderschuren LJ. The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol Sci. 2010;31:463–9. PubMed PMC

Vanderschuren LJ, Achterberg EJ, Trezza V. The neurobiology of social play and its rewarding value in rats. Neurosci Biobehav Rev. 2016;70:86–105. PubMed PMC

Mikulecká A, Šubrt M, Pařízková M, Mareš P, Kubová H. Consequences of early postnatal benzodiazepines exposure in rats. II Social behavior. Front Behav Neurosci. 2014;8:169. PubMed PMC

Peters SM, Pothuizen HH, Spruijt BM. Ethological concepts enhance the translational value of animal models. Eur J Pharmacol. 2015;759:42–50. PubMed

Spruijt BM, Peters SM, de Heer RC, Pothuizen HH, van der Harst JE. Reproducibility and relevance of future behavioral sciences should benefit from a cross fertilization of past recommendations and today's technology: "Back to the future". J Neurosci Methods. 2014;234:2–12. PubMed

Anderson DJ, Perona P. Toward a science of computational ethology. Neuron. 2014;84(1):18–31. PubMed

Zilkha N, Sofer Y, Beny Y, Kimchi T. From classic ethology to modern neuroethology: overcoming the three biases in social behavior research. Curr Opin Neurobiol. 2016;38:96–108. PubMed

Schaefer AT, Claridge‐Chang A. The surveillance state of behavioral automation. Curr Opin Neurobiol. 2012;22:170–6. PubMed PMC

Hirsch E, Baram TZ, Snead OC. Ontogenic study of lithium‐pilocarpine‐induced status epilepticus in rats. Brain Res. 1992;583:120–6. PubMed

Glier C, Dzietko M, Bittigau P, Jarosz B, Korobowicz E, Ikonomidou C. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol. 2004;187:403–9. PubMed

Manthey D, Asimiadou S, Stefovska V, Kaindl AM, Fassbender J, Ikonomidou C, et al. Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Exp Neurol. 2005;193:497–503. PubMed

Kim J, Kondratyev A, Gale K. Antiepileptic drug‐induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther. 2007;323:165–73. PubMed

Katz I, Kim J, Gale K, Kondratyev A. Effects of lamotrigine alone and in combination with MK‐801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther. 2007;322:494–500. PubMed

Forcelli PA, Janssen MJ, Vicini S, Gale K. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol. 2012;72:363–72. PubMed PMC

Brown L, Gutherz S, Kulick C, Soper C, Kondratyev A, Forcelli PA. Profile of retigabine‐induced neuronal apoptosis in the developing rat brain. Epilepsia. 2016;57:660–70. PubMed PMC

Forcelli PA, Gale K, Kondratyev A. Early postnatal exposure of rats to lamotrigine, but not phenytoin, reduces seizure threshold in adulthood. Epilepsia. 2011;52:e20–2. PubMed PMC

Tsenov G, Redkozubova O, Kubová H, Mares P. Effects of lamotrigine on cortically‐elicited phenomena in adult rats: differences between acute application and late consequences of early postnatal administration. Brain Res. 2009;1258:65–70. PubMed

Gutherz SB, Kulick CV, Soper C, Kondratyev A, Gale K, Forcelli PA. Brief postnatal exposure to phenobarbital impairs passive avoidance learning and sensorimotor gating in rats. Epilepsy Behav. 2014;37:265–9. PubMed PMC

Schroeder H, Toniolo AM, Desor D, Nehlig A. Early chronic exposure to diazepam, cerebral metabolism and behavior: long‐term consequences. Encephale. 1997;23:131–41. PubMed

Schroeder H, Toniolo AM, Nehlig A, Desor D. Long‐term effects of early diazepam exposure on social differentiation in adult male rats subjected to the diving‐for‐food situation. Behav Neurosci. 1998;112:1209–17. PubMed

File SE, Tucker JC. Lorazepam treatment in the neonatal rat alters submissive behavior in adulthood. Neurobehav Toxicol Teratol. 1983;5:289–94. PubMed

File SE. Effects of neonatal administration of diazepam and lorazepam on performance of adolescent rats in tests of anxiety, aggression, learning and convulsions. Neurobehav Toxicol Teratol. 1986;8:301–6. PubMed

File SE. Behavioral changes persisting into adulthood after neonatal benzodiazepine administration in the rat. Neurobehav Toxicol Teratol. 1986;8:453–61. PubMed

File SE. The effects of neonatal administration of clonazepam on passive avoidance and on social, aggressive and exploratory behavior of adolescent male rats. Neurobehav Toxicol Teratol. 1986;8:447–52. PubMed

File SE. Diazepam and caffeine administration during the first week of life: changes in neonatal and adolescent behavior. Neurotoxicol Teratol. 1987;9:9–16. PubMed

Darbra S, Pallares M. Alterations in neonatal neurosteroids affect exploration during adolescence and prepulse inhibition in adulthood. Psychoneuroendocrinology. 2010;35:525–35. PubMed

Darbra S, Pallares M. Effects of early postnatal allopregnanolone administration on elevated plus maze anxiety scores in adult male Wistar rats. Neuropsychobiology. 2012;65:20–7. PubMed

Zimmerberg B, Kajunski EW. Sexually dimorphic effects of postnatal allopregnanolone on the development of anxiety behavior after early deprivation. Pharmacol Biochem Behav. 2004;78:465–71. PubMed

Epilepsy Research in the Institute of Physiology of the Czech Academy of Sciences in Prague