Sex difference in cognitive behavioral alterations and barrel cortex neuronal responses in rats exposed prenatally to valproic acid under continuous environmental enrichment

Abstract

Autism spectrum disorder is a developmental disorder that can affect social interactions and sensory-motor behaviors. The present study investigates the effect of environmental enrichment (EE) on behavioral alterations and neuron responses associated with the barrel cortex of young adult female and male rats exposed prenatally to valproic acid (VPA). Pregnant female rats were pretreated with either saline or VPA (500 mg/kg, IP) on day 12.5 of gestation. Male and female pups were exposed to either EE or standard-setting (non-enrichment) conditions for 1 month (between postnatal day [PND] 30 and 63-65) and were divided into non-EE (control), EE, VPA, and VPA + EE groups. Three-chamber sociability and social novelty, acoustic startle reflex, and texture discrimination tests were conducted on PND 62. Responses of barrel cortex neurons of male pups were evaluated using the extracellular single-unit recording technique on PND 63-65. Results showed that the performance of rats of both sexes in social interactions, texture discrimination tasks, and acoustic startle reflex significantly decreased in the VPA groups compared with the control rats (P < 0.05). In this regard, EE attenuated the altered deficit performance observed in the VPA animals compared with the VPA-EE animals (P < 0.05). The performance of females was better than males in the discrimination tasks and acoustic startle reflex. In contrast, males were better than females in the three-chamber social interaction test. Additionally, the excitatory receptive field response magnitude of the barrel cortex neurons in the VPA + EE group increased compared with the VPA group (P < 0.05). The results suggest that continuous EE can attenuate cognitive function disturbances in autistic-like rats and, at least at the behavioral level, the effects depend on sex.

Alteration in social interaction and tactile discrimination of juvenile autistic‐like rats following tactile stimulation and whisker deprivation

“…The present study showed in the three‐chamber social interaction test, prenatal treatment with valproic acid significantly reduced the percentage of preference index to Strangers 1 and 2 during sociability and novel social phases in both sexes of the Val groups compared with the CTL groups. It has been shown that prenatal injection of valproic acid reduces the sociability and novelty indices (Hara et al., 2017; Sabzalizadeh et al., 2022; Schiavi et al., 2019), which were in‐line with our study. It has been noted that the decrease in PIST2 in this test is an important criterion for induction of the ASD in rodents (Nygaard et al., 2019).…”

“…Unlike the control groups (CTL-TS vs. CTL), TS caused an increase in the body weight gain of the Val-TS groups compared to the Val groups of both sexes (significant for females), which was in-line with the findings of previous experiments (Akatsu et al, 2015;Caldji et al, 2000;Meerlo et al, 1999;Seiffe et al, 2022). The same result was obtained in the male-Val-TS-WD rats under both TS and WD conditionings com- proic acid reduces the sociability and novelty indices (Hara et al, 2017;Sabzalizadeh et al, 2022;Schiavi et al, 2019), which were in-line with our study. It has been noted that the decrease in PIST2 in this test is an important criterion for induction of the ASD in rodents (Nygaard et al, 2019).…”

“…There are indications that motor performance and/or cognition are improved, and normal brain function is radically changed by exposure to environmental stimuli at an early age (Malabou, 2009). Although the positive effect of environmental enrichment has been proved on rats’ behaviors related to tactile discrimination and also on the neural barrel cortex functions in normal rats (Huang et al., 2021) and animal models of autism (Sabzalizadeh et al., 2022), the effects of TS treatment on the tactile and social behavior of prenatal Val‐exposed rats deprived of whiskers are unknown. The present study assessed the effects of TS treatment on social and tactile discrimination behavior and morphology of barrel cortical neurons in the rat model of autism.…”

Amelioration of cognition impairments in the valproic acid-induced animal model of autism by ciproxifan, a histamine H3-receptor antagonist

“…Animal studies have also reported social interaction deficits (Sabzalizadeh et al , 2022; Taheri et al , 2022) and increased repetitive behaviors in VPA-exposed animals (Baronio et al , 2015; Eissa et al , 2018b). Our previous study showed social deficits in adult VPA-exposed rats (Taheri et al , 2022).…”

“…It appears that genetic (De Rubeis et al , 2014; Hansen et al , 2015) and environmental (Chiarotti and Venerosi, 2020) factors influence the pathogenesis of ASD. Researchers have found that the maternal use of valproic acid (VPA) during pregnancy increases the risk of autism in humans (Ornoy, 2009) and rodents (Sabzalizadeh et al 2022; Haratizadeh et al 2023).…”