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.

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

“…Thus, although many studies exploring the use of animal models for studying autism have focused on using males (e.g. Schneider and Przewlocki, 2005;Dufour-Rainfray et al, 2010;Bambini-Junior et al, 2011;Banerjee et al, 2014), in some studies that have compared males and females, no differences between the sexes were found (e.g. Chomiak et al, 2010), whereas in others that did find a sex difference, the effects could be more pronounced in either males (e.g.…”

“…Recently, however, several lines of converging evidence strongly suggest that the interplay between environmental and genetic factors may be contributing toward the behavioral pathologies observed in autism (Hallmayer et al, 2011;Ronald and Hoekstra, 2011). For this reason, preclinical research is now focusing on the development of transgenic and environmental animal models of autism to understand the genotype-phenotype relationship better as well as the neurobiological mechanisms that underlie the disorder (Bolivar et al, 2007;Banerjee et al, 2014). Validation of these animal models of autism is contingent upon the ability to simulate the distinctive clinical features of autism, such as the deficits in aspects of social function (Wöhr and Scattoni, 2013).…”

Viral delivery of shRNA to amygdala neurons leads to neurotoxicity and deficits in Pavlovian fear conditioning

“…Fear conditioning training and testing was essentially completed as previously performed (Banerjee, Engineer, Sauls, Morales, Kilgard, and Ploski, 2014; Ploski et al, 2011). Twenty one days post-viral infusion the rats were fear conditioned.…”

Hesperetin and it nanocrystals ameliorate social behavior deficits and oxido‐inflammatory stress in rat model of autism

“…This research report that single prenatal injection of VPA results in anxiogenic‐like behavior, remarkable decrease in social interaction and increase in repetitive behavior and freezing. previous study has shown that higher levels of anxiety‐like behavior in a rodent model of autism created by exposing rat fetuses to valproic acid on the gestational day 12.5 at an age when the neural tube closes (Banerjee et al, 2014). It is likely that anxiety‐like behavior, due to neurodevelopmental anomalies induced by VPA, or might be attributed to increased glutaminergic transmission (Cuevas‐Olguin et al, 2017).…”