The effect of low- and moderate-intensity interval training on cognitive behaviors of male and female rats with VPA-induced autism.

Introduction: This study was performed to evaluate the effects of low and moderate treadmill exercise for one month on social interaction, anxiety-like behaviors, and spatial learning and memory in male and female autistic rats. Methods: Pregnant rats received valproic acid (VPA) (600 mg/kg/i.p) once on gestational day 12.5 to induce autism-like symptoms in the offspring. After delivery, the offspring were divided into six main groups, each with male and female subgroups: Control (CTL, prenatal normal saline), autism (prenatal VPA), low-intensity training (LIT,normal saline + low treadmill exercise), moderate -intensity training (MIT, normal saline + moderate treadmill exercise), VPA + LIT, and VPA + MIT. On the 60th day, the offspring were tested by the elevated plus maze (EPM), open field test (OFT), social interaction test (SIT), and Morris water maze (MWM). Results: The results showed that both LIT and MIT could partly alleviate anxiety-like behaviors induced by prenatal VPA exposure in two sexes. Social impairment was observed in the autistic rats and was improved by LIT in both sexes and MIT in females. No significant change was seen in the spatial learning and memory of autistic rats by exercise. Conclusion: The findings suggest that treadmill exercise can be helpful for improving some autism-like behaviors. Further studies are needed to investigate the involved mechanisms.

Early postnatal handling alters social behavior, learning, and memory of pre- and postnatal VPA-induced rat models of autism in a context-based manner.

Early life events are known to greatly affect brain development, cortical neurogenesis, and Hypothalamic-pituitary-adrenal activity. Mainly characterized by impairment in social communication, language, and cognitive development, autism spectrum disorder (ASD) refers to a class of neuropsychiatric disorders with numerous genetic and environmental risk factors. In the early handling (EH) method, daily separation of infants from their mother, physical touching, and exposure to a new environment occur. Here, we studied the effect of EH on Social interaction, learning, and memory in rats exposed pre-or post-natally to valproic acid (VPA). Gestational VPA exposure (600 mg/kg) led to some severe autistic-like traits, more notable in the social behavior of the male sex, along with unchanged to partially altered spatial learning and memory function and reduced avoidance memory. In comparison, while causing a sex-dependent increase in spatial memory, subcutaneous injection of VPA (400 mg/kg) in infancy resulted in limited adverse autistic features, including a decrease in males' social preference, as well as reduced avoidance memory. The results indicated that neonatal handling significantly improved multiple social behavior and memory deficits in prenatally injected rats. In contrast, EH in rats receiving postnatal VPA elicited a restricted advantage on social novelty tendency; while negatively affecting some other social behavior criteria and spatial learning of males and encouraging sex-dependent repetitive behaviors in the social setting. The controversial influence of postnatal handling on juvenile rats of postnatal VPA treatment vs. prenatal VPA treatment opens up the potential for future research on the context-based consequence of early-life handling stress using different behavioral tasks and to benefit therapeutic procedures through understanding the sex- and age-specific neurobiology of short-term environmental manipulation in animal models of autism.

The effect of early handling on anxiety-like behaviors of rats exposed to valproic acid pre-and post-natally.

INTRODUCTION: Autism spectrum disorder (ASD) is a complex, behaviorally defined disorder of the immature brain as a result of genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). This syndrome is known for its high prevalence. On the other hand, postnatal manipulations have been shown to affect brain development, cortical neuroscience, and pituitary-adrenal activity. In early handling (EH) procedure, pups are removed from their mother on a daily basis from birth to lactation, are physically touched, and exposed to the (a) new environment. In the present study, the effect of EH on anxiety-like behaviors in rats exposed pre- and post-natally to valproic acid was investigated. METHODS: Pregnant Wistar rats were randomly separated into six groups which are prenatal saline, Prenatal VPA, Prenatal VPA + EH and postnatal saline, Postnatal VPA, Postnatal VPA + EH. VPA administration was performed either on ED12.5 (600 mg/kg, i.p.) or PD 2-4 (400 mg/kg, s.c.). In the groups receiving EH, pups underwent physical handling from PD 1 to 21. On postnatal day 21 all offspring were weaned and the behavioral tests were performed on 30 and 31 days of age. Elevated plus maze and open field tests were used to investigate anxiety-like behaviors. RESULTS: The results revealed that intraperitoneal injection of valrpoic acid (600 mg.kg) during pregnancy significantly reduced OAT% in males (p < 0.01) and females in a non-significant manner (p > 0.05). In comparison, rearing counts of prenatal VPA groups significantly increased in female sex (p < 0.05) in the EPM test. Following postnatal VPA administration (400 mg/kg), decrease in the time spent in central zone occurred in female rats in the open filed (p < 0.05), as well as a significant increase in the number of grooming of the male sex (p < 0.05). Applying Early Handling to male and female Wistar rats receiving prenatal VPA significantly reversed the OAT% fall (p < 0.05). EH in postnatally VPA exposed animals significantly decreased the OAT% and OAE% criteria, while increasing the locomotor activity of the female sex (p < 0.05). Compared with the postnatal VPA group, no significant change was reported in the EPM performance of postnatal VPA + EH group in neither of sexes (p > 0.05). CONCLUSION: The findings of this study suggest that injections of valproic acid during pregnancy lead to anxiety-like behaviors in male offspring, which EH can improve (attenuate) to some extent. VPA injections on the second to the fourth day of infancy did not have a profound effect on anxiety level. Further behavioral studies need to be performed using other devices to investigate anxiety-like behaviors and to determine the mechanisms involved in these behaviors.

Sex dependent alterations of resveratrol on social behaviors and nociceptive reactivity in VPA-induced autistic-like model in rats.

INTRODUCTION: The present study was designed to clarify the effects of resveratrol (RSV) on social behavioral alterations and nociceptive reactivity in valproic acid (VPA)-induced autistic-like model in female and male rats. METHODS: Pregnant Wistar rats were randomly divided in five groups. Animals received saline, DMSO, VPA, RSV and RSV + VPA. VPA was administered (600 mg/kg, i. p.) on embryonic day 12.5 (E12.5) and pretreatment by resveratrol (3.6 mg/kg, s. c.) was applied on E6.5 until E18.5. All offspring were weaned on postnatal day 21 and the experiments were done in male and female rats on day 60. Social interaction, hot plate and tail flick tests were set out to assess social deficits and pain threshold, respectively. Sociability index (SI), Social novelty index (SNI) and latency time were calculated as the standard indices of social behaviors and pain threshold, respectively. RESULTS: The results indicated that systemic intraperitoneal administration of VPA (600 mg/kg) significantly decreased SI and SNI in social interaction test (SIT) especially in male rats, indicating the social impairments caused by VPA. RSV (3.6 mg/kg, s. c.) reversed VPA-induced social deficits in male rats, but not in female group. VPA administration resulted in significant increase in latency time in the hot plate and tail flick tests in male rats, whereas it had no such dramatic effect in females. RSV administration in combination with VPA had no significant effect on latency time compared to the valproic acid group in male rats. It is important to note that RSV by itself had no significant effect on SI, SNI and latency time in female and male rats. CONCLUSION: It can be concluded that valproic acid produces autistic-like behaviors and increases pain threshold in male rats which may be ameliorated at least in part by resveratrol administration. Further studies are needed to elucidate the molecular mechanisms involved in valproic acid and resveratrol-induced effects.