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Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero.

ABSTRACT: Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.

SUBMITTER: Banerjee A

PROVIDER: S-EPMC4228846 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero.

Banerjee Anwesha A Engineer Crystal T CT Sauls Bethany L BL Morales Anna A AA Kilgard Michael P MP Ploski Jonathan E JE

Frontiers in behavioral neuroscience 20141112

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known terat ...[more]

PMID: 25429264

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Project description:The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cell metabolism, growth, and proliferation. The overactivation of mTOR has been implicated in the pathogenesis of syndromic autism spectrum disorder (ASD), such as tuberous sclerosis complex (TSC). Treatment with the mTOR inhibitor rapamycin improved social interaction deficits in mouse models of TSC. Prenatal exposure to valproic acid (VPA) increases the incidence of ASD. Rodent pups that are exposed to VPA in utero have been used as an animal model of ASD. Activation of the mTOR signaling pathway was recently observed in rodents that were exposed to VPA in utero, and rapamycin ameliorated social interaction deficits. The present study investigated the effect of rapamycin on social interaction deficits in both adolescence and adulthood, and gene expressions in mice that were exposed to VPA in utero. We subcutaneously injected 600?mg/kg VPA in pregnant mice on gestational day 12.5 and used the pups as a model of ASD. The pups were intraperitoneally injected with rapamycin or an equal volume of vehicle once daily for 2 consecutive days. The social interaction test was conducted in the offspring after the last rapamycin administration at 5-6?weeks of ages (adolescence) or 10-11?weeks of age (adulthood). Whole brains were collected after the social interaction test in the adulthood, and microarray and Western blot analyses were performed. Mice that were exposed to VPA and treated with vehicle exhibited a decrease in social interaction compared with control mice that were treated with vehicle. Rapamycin treatment in VPA-exposed mice improved social deficits. Mice that were exposed to VPA and treated with vehicle exhibited the aberrant expression of genes in the mTOR signaling pathway, and rapamycin treatment recovered changes in the expression of some genes, including Fyb and A330094K24Rik. Rapamycin treatment suppressed S6 phosphorylation in VPA-exposed mice. Aberrant gene expression was associated with social interaction deficits in VPA-exposed mice. Rapamycin may be an effective treatment for non-syndromic ASD in adolescent and adult patients who present impairments in the mTOR signaling pathway.

Project description:BackgroundThe social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments.MethodsMale and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48-53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D1 receptor activation, levels of expression of PPARα, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions.ResultsFBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D1 receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment.LimitationsThis study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue.ConclusionsThe results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment.

Project description:BackgroundUntil now, the treatment of patients with autism spectrum disorder (ASD) remain a difficult problem. The insula is involved in empathy and sensorimotor integration, which are often impaired in individuals with ASD. Deep brain stimulation, modulating neuronal activity in specific brain circuits, has recently been considered as a promising intervention for neuropsychiatric disorders. Valproic acid (VPA) is a potential teratogenic agent, and prenatal exposure can cause autism-like symptoms including repetitive behaviors and defective sociability. Herein, we investigated the effects of continuous high-frequency deep brain stimulation in the anterior insula of rats exposed to VPA and explored cognitive functions, behavior, and molecular proteins connected to autism spectrum disorder.MethodsVPA-exposed offspring were bilaterally implanted with electrodes in the anterior insula (Day 0) with a recovery period of 1 week. (Day 0-7). High-frequency deep brain stimulation was applied from days 11 to 29. Three behavioral tests, including three-chamber social interaction test, were performed on days 7, 13, 18, 25 and 36, and several rats were used for analysis of immediate early genes and proteomic after deep brain stimulation intervention. Meanwhile, animals were subjected to a 20 day spatial learning and cognitive rigidity test using IntelliCage on day 11.ResultsDeep brain stimulation improved the sociability and social novelty preference at day 18 prior to those at day 13, and the improvement has reached the upper limit compared to day 25. As for repetitive/stereotypic-like behavior, self- grooming time were reduced at day 18 and reached the upper limit, and the numbers of burried marbles were reduced at day 13 prior to those at day 18 and day 25. The improvements of sociability and social novelty preference were persistent after the stimulation had ceased. Spatial learning ability and cognitive rigidity were unaffected. We identified 35 proteins in the anterior insula, some of which were intimately linked to autism, and their expression levels were reversed upon administration of deep brain stimulation.ConclusionsAutism-like behavior was ameliorated and autism-related proteins were reversed in the insula by deep brain stimulation intervention, these findings reveal that the insula may be a potential target for DBS in the treatment of autism, which provide a theoretical basis for its clinical application., although future studies are still warranted.

Project description:Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by restrictive patterns of behaviour and alterations in social interaction and communication. Up to 80% of children with ASD exhibit sleep-wake cycle disturbances, emphasising the pressing need for novel approaches in the treatment of ASD-associated comorbidities. While sleep disturbances have been identified in ASD individuals, little has been done to assess the contribution of the circadian system to these findings. The objective of this study is to characterise circadian behaviour and clock-gene expression in a valproic acid (VPA)-induced animal model of autism to highlight perturbations potentially contributing to these disturbances. Male and female VPA-exposed offspring underwent circadian challenges, including baseline light-dark cycles, constant dark/light and light pulse protocols. Baseline analysis showed that VPA-exposed males, but not females, had a greater distribution of wheel-running behaviour across light-dark phases and a later activity offset (p < 0.0001), while controls showed greater activity confinement to the dark phase (p = 0.0256). Constant light analysis indicated an attenuated masking response and an increase in the number of days to reach arrhythmicity (p < 0.0001). A 1-h light pulse (150 lux) at CT 15 after 6 days of constant dark showed that both sexes exposed to VPA exhibited a lesser phase-shift when compared to controls (p = 0.0043). Immunohistochemical and western-blot assays reveal no alterations in retinal organisation or function. However, immunohistochemical assay of the SCN revealed altered expression of BMAL1 expression in VPA-exposed males (p = 0.0016), and in females (p = 0.0053). These findings suggest alterations within the core clockwork of the SCN and reduced photic-entrainment capacity, independent of retinal dysfunction. The results of this study shed light on the nature of circadian dysregulation in VPA-exposed animals and highlights the urgent need for novel perspectives in the treatment of ASD-associated comorbidities.

Dataset Information

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero.

Publications

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero.

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