The Wistar Audiogenic Rat (WAR) strain and its contributions to epileptology and related comorbidities: History and perspectives

García-Cairasco, Norberto; Umeoka, Eduardo Henrique de Lima; Oliveira, José Antônio Cortes de

doi:10.1016/j.yebeh.2017.04.001

Cited by 75 publications

(81 citation statements)

References 238 publications

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“…Our study is the first to catalog and characterize somatic mutations present in an animal model of genetic audiogenic epilepsy generated by artificial selection for seizure susceptibility over many generations, which results in high predisposition to epilepsy as occurs in the GASH/Sal model. Other animal models of audiogenic epilepsy generated by artificial selection include the GAERS [19], the WAG/Rij [20] and the WAR [23], in which an auditory stimulus triggers the onset of audiogenic seizures. In all these models, different types of studies on seizures and pharmacological treatments have been conducted in the inferior colliculus as an epileptogenic nucleus and in auditory pathways [31,[74][75][76][77][78].…”

Section: Plos Onementioning

confidence: 99%

“…Kaitsuka and colleagues [18] generated Eef1d (Eukaryotic Translation Elongation Factor 1 Delta) knockout mice that showed severe seizures in response to loud sounds, suggesting that Eef1d plays a key role in normal brain function, especially when exposed to external stimuli. Several other audiogenic models have been reported in the literature, including the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) [19], the Wistar Albino Glaxo Rijswijk rat (WAG/Rij) [20] the Krushinsky-Molodkina rat [21], the genetically epilepsy-prone rats [22] and the Wistar Audiogenic Rat (WAR) [23], but their genetic alterations have not been described yet.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate-and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arh-gef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that PLOS ONE PLOS ONE | https://doi.

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Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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“…The Wistar Audiogenic Rat (WAR), strain, genetically selected for susceptibility to seizures [13,14], displays increased anxiety [15], and hyperactive hypothalamus-pituitary-adrenal (HPA) axis [16]. Therefore, because the WAR is an animal model of seizures with endogenous anxiety [15], and OT has anxiolytic effects [5, 9], we speculate that WAR OT-ergic system could be associated to anxiety and compulsion.…”

Section: Introductionmentioning

confidence: 99%

“…We specifically aimed to characterize the activation of a circuitry related to compulsive grooming induced by OT in naïve (no seizures experience) WARs, an experimental model of seizures [13, 14], as compared to the one we already demonstrated in Wistars [23], using behavioral tools such as scores [24], flowcharts [25] and graphs [26] of syntactic and non-syntactic chains [27, 28], and cellular tools such as OT and c-Fos microscopy with the aim of building a Markov chain model [29, 30]. The interpretation of the data was done in the context of the pathophysiology of the comorbidity of epilepsy and compulsion.…”

Section: Introductionmentioning

confidence: 99%

Oxytocin, Compulsion and Epilepsy: Insights from a Complex Behavioral and Neuronal Networks Association

Marroni

Santos

Castro

et al. 2019

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18 19 Previously we have demonstrated that microinjection of oxytocin (OT) into the central nucleus of 20 amygdala (CeA) induces hypergrooming in Wistar rats, a model of compulsion. The Wistar 21 Audiogenic Rat (WAR) strain is a genetic model of generalized tonic-clonic seizures. Here we 22 quantified grooming behavior in WAR, with grooming scores, flowcharts and directed graphs of 23 syntactic and non-syntactic grooming chains, after bilateral administration of OT or saline (SAL) into 24 the CeA and investigated the association between hypergrooming and imunohistochemistry of Fos 25 activated compulsion networks and proposing a computational model of grooming behavior. The 26 activated networks, driven from a CeA OT-dependent grooming pattern, in both Wistar and WAR were 27 detected as Fos+ regions: orbitofrontal cortex, striatum, paraventricular nucleus of the hypothalamus, 28 dentate gyrus, substantia nigra compacta and reticulata. In conclusion we can drive hypergrooming in 29 WARs, defined previously as a model of ritualistic motor behavior in Wistar rats, with OT from CeA, a 30 limbic structure and one of the principal amygdala complex outputs. Furthermore, our current pioneer 31 behavioral and cellular description considers that hypergrooming (compulsion) in WARs is a 32 comorbidity because: (1) WARs have the highest grooming scores , when exposed only to novelty (2) 33 WARs have better grooming scores than Wistars after CeA-SAL, (3) WARs perform much better than 34 Wistars in OT-CeA-dependent highly stereotyped behavioral sequences, detected by flowcharts as a 35 combination of syntactic/non-syntactic grooming chains, (4) the behavioral sequences here 36 demonstrated for grooming and hypergrooming can be modeled as quite reliable Markov chains and (5) 37 with the exception of CeA-SAL injected animals, an exquisite map of brain Fos expression was 38 detected in typical cortico-striatal-thalamic-basal ganglia-cortical circuit, among new areas, driven by 39 OT-CeA. 40 41 -900 -Ribeirão Preto -SP 45 -Brazil 46 47 48 Author Summary 49 50 Grooming is a complex set of regular behavioral sequences in rodents that can be mimicked with 51 several pharmacological or molecular biology interventions. We have demonstrated previously that 52 microinjection of the brain peptide oxytocin into the amygdala, a limbic region, induces 53 hypergrooming in Wistar rats, a model of compulsion. The Wistar Audiogenic Rat strain is a genetic 54 model of generalized seizures, in fact a model of epilepsy. Here we quantified grooming behavior in 55 Wistar Audiogenic Rats, using several behavioral tools such as grooming scores, behavioral sequences 56 and graphs of grooming chains, after bilateral administration of the oxytocin or its control (saline) into 57 the amygdala. We also investigated the association between hypergrooming and activation of 58 compulsion networks, proposing a computational (virtual) model of grooming behavior. Basically we 59 were able to detect activated networks, driven from amygdala and the consequent oxytoci...

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“…Os primeiros relatos de convulsões audiogênicas foram descritas no ano de 1924, pelo pesquisador Russo Studenzov (Poletaeva et al, 2017) (Jobe et al, 1973;Schreiber e Graham, 1976;Seyfried et al, 1980;Jobe et al, 1982;Ko et al, 1982;Zhao et al, 1985;Van Luijtelaar e Coenen, 1986;Marescaux et al, 1987;Skradski et al, 1998;Skradski et al, 2001;Doretto et al, 2003;Prieto-Martin et al, 2012;Carballosa-Gonzalez et al, 2013;Garcia-Cairasco et al, 2017;Poletaeva et al, 2017;Prieto-Martin et al, 2017).…”

Section: Modelo Experimental 1: Rato Wistar Audiogênico (War)unclassified

Alterações respiratórias e neuroanatômicas em áreas do tronco encefálico em modelos experimentais de epilepsia.

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The Wistar Audiogenic Rat (WAR) strain and its contributions to epileptology and related comorbidities: History and perspectives

Cited by 75 publications

References 238 publications

Analysis of gene variants in the GASH/Sal model of epilepsy

Analysis of gene variants in the GASH/Sal model of epilepsy

Oxytocin, Compulsion and Epilepsy: Insights from a Complex Behavioral and Neuronal Networks Association

Alterações respiratórias e neuroanatômicas em áreas do tronco encefálico em modelos experimentais de epilepsia.

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