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Habituation dynamics and rate (k-value) of control (C, n=18) and valproic (VPA, n=18) rats during weaning. Data are given as means ± SEM.
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Autism is a neurodevelopmental disorder with multifactorial aetiology, represented as impairment in social behaviour, communication and the occurrence of repetitive activities, which can be observed in the early life. The core features are frequently accompanied by other manifestations, including limited environmental exploration. The aim of the pr...
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Context 1
... analysis of habituation rate (k-value) has revealed a significant effect of group (F 1,28 =8.702; p<0.01), age (F 2,56 =25.503; p<0.001), and interaction age*group (F 2,56 =7.605; p<0.01). Differences in habituation rate during the weaning period were not significant between VPA and C group (Figure 2). VPA rats showed a higher rate of habituation in the open-field compared to C rats in puberty (p<0.01) ...Citations
... In summary, VPA rats did not show differences on these measures of open field test that were assessed in our study. These results are in accordance with previous findings of unchanged locomotor activity in VPA rats at weaning age (Olexova et al., 2013;Dobrovolsky et al., 2019). ...
Early motor and sensory developmental delays precede Autism Spectrum Disorder (ASD) diagnosis and may serve as early indicators of ASD. The literature on sensorimotor development in animal models is sparse, male centered, and has mixed findings. We characterized early development in a prenatal valproic acid (VPA) model of ASD and found sex-specific developmental delays in VPA rats. We created a developmental composite score combining 15 test readouts, yielding a reliable gestalt measure spanning physical, sensory, and motor development, that effectively discriminated between VPA and control groups. Considering the heterogeneity in ASD phenotype, the developmental composite offers a robust metric that can enable comparison across different animal models of ASD and can serve as an outcome measure for early intervention studies.
... We suggest that acceleration is a more sensitive parameter for detecting anxiety in VPA animals. In fact, Olexová et al. (2013), measured displacement and showed that VPAtreatment reduces habituation, but during a longer period of time (15-20 min). It is interesting that we found increased "stops" and decreased "distance/stop" in the first minute of the OFT and in the habituation stage of 3C-ST, but these parameters reached control values at the second or third minute of the test, suggesting that "stops" and "distance/stop" could be related to "acceleration." ...
Autism spectrum disorder (ASD) is a neurodevelopmental alteration characterized by social/communicative deficits, repetitive/stereotyped movements, and restricted/obsessive interests. However, there is not much information about whether movement alterations in ASD comprise modifications at the basic kinematic level, such as trajectory and velocity, which may contribute to the higher level of processing that allows the perception and interpretation of actions performed by others, and hence, impact social interaction. In order to further explore possible motor alterations in ASD, we analyzed movement parameters in the Valproate (VPA) animal model of autism. We found that VPA-treated rats displayed greater movement acceleration, reduced distance between stops, spent more time in the corner of the open-field arena, and executed a number of particular behaviors; for example, supported rearing and circling, with no major changes in distance and velocity. However, in the social interaction test, we found other alterations in the movement parameters. In addition to increased acceleration, VPA-rats displayed reduced velocity, increased stops, reduced distance/stop and lost the social/non-social area discrimination that is characteristic of control rats in acceleration and stops variables. Hence, even if prenatal VPA-treatment could have a minor effect in motor variables in a non-social context, it has a crucial effect in the capacity of the animals to adjust their kinematic variables when social/non-social context alternation is required.
... The age at which offspring were tested resulted in a number of relevant outcomes, likely specific to VPA exposure. Interestingly, older ages in the VPA groups had decreased social [66] and total [67] exploration than younger VPA-exposed rodents. Older VPA-exposed rodents had a lower discrimination index in the novel object recognition test compared to younger VPA rodents [68]. ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, few pharmacological treatments exist to alleviate these socio-behavioural impairments. Prenatal administration of valproic acid (VPA) has become an accepted animal model of ASD and has been extensively used to explore new pharmacotherapies in rodents. We conducted a systematic review of the behavioural impairments induced by the VPA model in rodents, with specific reference to 3 core socio-behavioural alterations associated with ASD: repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. We systematically reviewed studies attempting to alleviate these core behavioural alterations using pharmacological means. We include 132 studies exploring the prenatal effects of VPA in rodents. Gestational exposure to VPA in rodents has significant effects on rodent-equivalent measures of the 3 core behavioural traits characteristic of ASD in humans, inducing social impairments, repetitive behaviour, and cognitive rigidity/inflexibility after birth. This model's validity has seen it used to test potential drug treatments for ASD and is likely to continue doing so. We conclude the rodent VPA model may be suitable to examine future therapeutic interventions for ASD, providing an overview of the progress made so far.
... It is well known that prenatal exposure to valproic acid could result in neurodevelopmental disorder during adolescence (29). The offspring of pregnant Wistar rats that received an intraperitoneal injection of 600 mg/kg valproic acid demonstrated declined spontaneous movements during puberty and maturity compared with rat offspring not treated with valproic acid (30). In our work, high concentration (500 μM) of valproic acid significantly reduced the spontaneous movement of zebrafish larvae under both light and dark conditions. ...
... On the 12.5th day of pregnancy, 500 mg/kg of valproic acid (VPA, SIGMA) dissolved in saline was injected intraperitoneally to pregnant female rats in the VPA group. To the pregnant female rats in the control group only the normal saline was injected (Olexova et al., 2013). After the birth of infant rats, they were counted and their weight and the day of opening their eyes were recorded (Tamburella et al., 2012). ...
... Individuals with ASD have reduced novelty processing or enhanced familiarity preference (Maes, 2011), and VPA treated rats explore a novel environment less than controls as reported by Schneider & Przewlocki and Olexová et al (Schneider & Przewlocki, 2005;Olexová, 2013), BTBR mice also exhibit novelty aversion . ...
Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social communication and restricted behaviours, and associated with sensory alterations, gastrointestinal dysfunction and disruptions in the circadian rhythm. This study utilised two animal models of ASD, the BTBR T+tf/J and the prenatal exposure to VPA mouse models of ASD, compared to the control C57 BL/6J strain. The aim of this study was to investigate changes in circadian rhythm and peripheral sensation in the two mouse models of ASD, and identify potential pathways involved.
Methods: Home-cage testing was conducted using LABORAS platforms, to record the animals’ behaviour over 24 hours (C57 n = 8; BTBR = 9, VPA = 4). Cutaneous sensory thresholds were determined using the dynamic hot (DHP) and cold plate (DCP) tests (C57 n = 6; BTBR n = 6; VPA n = 4), and sensory function of the gastrointestinal tract was outlined using ex-vivo jejunum preparations, by recording the afferent nerve responses to mechanical and chemical stimuli. Values are mean +/- SEM analysed with two-way ANOVA using GraphPad Prism.
Results: the VPA mice exhibited altered circadian rhythm in the dark (active) phase compared to the BTBR and C57 mice (P=<0.05). In the DHP, the BTBR mice (n = 6) responded at a higher temperature (C57 - 38C; BTBR - 40C), responded significantly less to heat (P<0.0005), while VPA mice (n = 4) showed similar responses to the C57 mice. In the DCP, VPA mice start to respond at a lower temperature (C57 - 16C; VPA - 2C), responded slightly less to cold (P=0.055), while the BTBR mice showed similar responses to C57 mice.
In the afferent nerve recordings of the jejunum, the BTBR tissue exhibited significantly decreased responses to mechanical distension at a filling rate of 600 μl/min (P<0.0006; BTBR n = 9; C57 n = 10). Peak firing rate at 50 mmHg was 92.68 (+/- 12.80) imp/s-1 in recordings from C57 (n = 10) tissue and 76.49 (+/- 15.44) imp/s-1 in BTBR tissue (n = 9). BTBR afferents also showed an altered response profile to TRPV1 activation (P=<0.0001, BTBR n = 5; C57 n = 5), whereby nerve firing took significantly longer to desensitize compared to control afferents, suggesting altered function of TRPV1. Preparations from BTBR mice also exhibited significantly increased response to intraluminal application of an inflammatory soup (P<0.05), BTBR n = 5; C57 n = 5).
Conclusion: the VPA model of ASD showed marked alterations in circadian rhythm and reduced response to cold stimuli, and the BTBR mouse model of ASD exhibited significantly decreased response to heat and significantly altered afferent nerve activity from the jejunum in response to various stimuli. Future studies should investigate whether these changes correlate with CNS dysfunction or whether altered peripheral sensation could drive some of the central deficits observed in ASD.
... Clinical studies have shown that exposure to VPA in utero is associated with birth defects, cognitive deficits, and increased risk of autism (Nadebaum et al., 2011). Our data demonstrate that VPA-treated rats also exhibited autism-like behaviors and deficits in the reflex development, motor coordination, auditory and visual development, which are consistent with clinical symptoms of patients with autism and the findings of other labs' using VPA-induced rodent models of autism (Snow et al., 2008;Mehta et al., 2011;Favre et al., 2013;Olexová et al., 2013Olexová et al., , 2016Ha et al., 2017). ...
Although studies have investigated the role of gamma-aminobutyric acid (GABA)ergic signaling in rodent neural development and behaviors relevant to autism, behavioral ontogeny, as underlain by the changes in GABAergic system, is poorly characterized in different brain regions. Here, we employed a valproic acid (VPA) rat model of autism to investigate the autism-like behaviors and GABAergic glutamic acid decarboxylase 67 (GAD67) expression underlying these altered behaviors in multiple brain areas at different developmental stages from birth to adulthood. We found that VPA-treated rats exhibited behavioral abnormalities relevant to autism, including delayed nervous reflex development, altered motor coordination, delayed sensory development, autistic-like and anxiety behaviors and impaired spatial learning and memory. We also found that VPA rats had the decreased expression of GAD67 in the hippocampus (HC) and cerebellum from childhood to adulthood, while decreased GAD67 expression of the temporal cortex (TC) was only observed in adulthood. Conversely, GAD67 expression was increased in the prefrontal cortex (PFC) from adolescence to adulthood. The dysregulated GAD67 expression could alter the excitatory-inhibitory balance in the cerebral cortex, HC and cerebellum. Our findings indicate an impaired GABAergic system could be a major etiological factor occurring in the cerebral cortex, HC and cerebellum of human cases of autism, which suggests enhancement of GABA signaling would be a promising therapeutic target for its treatment.
... It is well known that prenatal exposure to valproic acid could result in neurodevelopmental disorder during adolescence (29). The offspring of pregnant Wistar rats that received an intraperitoneal injection of 600 mg/kg valproic acid demonstrated declined spontaneous movements during puberty and maturity compared with rat offspring not treated with valproic acid (30). In our work, high concentration (500 μM) of valproic acid significantly reduced the spontaneous movement of zebrafish larvae under both light and dark conditions. ...
Background:
Behavioral changes in animals reflect functional changes in their central nervous system. Neuroactive drugs that act on different neural pathways can induce specific behavioral responses; therefore, it is possible to infer the activities of neuroactive drugs by studying the behavioral changes induced by drugs of interest in animals.
Methods:
In this study, AB strain zebrafish larvae at 7 days post fertilization (dpf) were treated with different concentrations of drugs that act on different neural pathways. Changes in the swimming distances of zebrafish larvae under different illumination conditions and the differences in locomotor activities between light and dark conditions (lighting motor index) were analyzed.
Results:
Among the drugs studied, different concentrations of sulpiride had no effect on larval locomotor activity either under light or dark conditions. Progressively decreased spontaneous movements were observed in zebrafish larvae treated with increasing doses of MK-801 and valproic acid. With increasing concentrations of pentylenetetrazole and yohimbine, the spontaneous movement of larval zebrafish presented a bell-shaped response. When the illumination changed from light to dark, zebrafish larvae not treated with drugs demonstrated increased locomotor activities. However, high levels of yohimbine, pentylenetetrazole decreased the degree of change in the lighting motor index.
Conclusions:
In conclusion, drugs that affect different neural pathways exert different influences on the locomotor activities of zebrafish larvae. This study presents an initial effort to establish a framework that correlates the drug activities and the behavioral responses of zebrafish larvae under drug treatments, which may provide a potential identification of the pathways of novel drugs with neurological activities through their behavioral influences.
... The motor skills were scrutinized through the swimming performance test, and VPA was able to afford nonsignificant downregulation of the swimming scores, which was observed to be efficiently normalized by GLA. Restricted exploration is one of the core features in clinical as well as preclinical cases of autism [38]. The decrease in exploratory behavior has been accredited to reduced number of Purkinje fiber or alteration in the structure of cortex or amygdale. ...
The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.
... The cholinergic abnormalities are well studied phenomenon in mammary gland carcinogenesis. In fact, AchE inhibitor (eserine) has been reported to promote cell proliferation and tumour formation, thereby suggesting decreased AchE signalling in the mammary gland cancer cells (Olexová et al. 2013). In the same line, we perceived downregulated AchE levels in the mammary gland tissue after the MNU treatment. ...
This study was undertaken to investigate the effect of α-chymotrypsin on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized into four groups (six animals in each). Group I (sham control 0.9 % normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v.); Group III (α-chymotrypsin, 5 mg/kg, p.o.); Group IV (α-chymotrypsin, 10 mg/kg p.o.). Toxicity was induced by single i.v. injection of MNU followed by α-chymotrypsin supplementation therapy for 100 days. MNU treatment was evident with increased alveolar bud count, differentiation score, upregulated inflammatory enzymes markers (COX, LOX and NO) antioxidative stress markers (TBARs, SOD, catalase and GSH).MNU associated toxicity was also ascertained by PGP 9.5 and NF-κB expression in the mammary gland tissue followed by FAME analysis for fatty acid profiling. α-chymotrypsin afforded significant protection against the deleterious effects of MNU.
