Adolescent swimming exercise following maternal valproic acid treatment improves cognition and reduces stress-related symptoms in offspring mice: Role of sex and brain cytokines

Physiol Behav. 2023 Oct 1:269:114264. doi: 10.1016/j.physbeh.2023.114264. Epub 2023 Jun 7.


Valproic acid (VPA) treatment during pregnancy is a risk factor for developing autism spectrum disorder, cognitive deficits, and stress-related disorders in children. No effective therapeutic strategies are currently approved to treat or manage core symptoms of autism. Active lifestyles and physical activity are closely associated with health and quality of life during childhood and adulthood. This study aimed to evaluate whether swimming exercise during adolescence can prevent the development of cognitive dysfunction and stress-related disorders in prenatally VPA-exposed mice offspring. Pregnant mice received VPA, afterwards, offspring were subjected to swimming exercise. We assessed neurobehavioral performances and inflammatory cytokines (interleukin-(IL)6, tumor-necrosis-factor-(TNF)α, interferon-(IFN)γ, and IL-17A) in the hippocampus and prefrontal cortex of offspring. Prenatal VPA treatment increased anxiety-and anhedonia-like behavior and decreased social behavior in male and female offspring. Prenatal VPA exposure also increased behavioral despair and reduced working and recognition memory in male offspring. Although prenatal VPA increased hippocampal IL-6 and IFN-γ, and prefrontal IFN-γ and IL-17 in males, it only increased hippocampal TNF-α and IFN-γ in female offspring. Adolescent exercise made VPA-treated male and female offspring resistant to anxiety-and anhedonia-like behavior in adulthood, whereas it only made VPA-exposed male offspring resistant to behavioral despair, social and cognitive deficits in adulthood. Exercise reduced hippocampal IL-6, TNF-α, IFN-γ, and IL-17, and prefrontal IFN-γ and IL-17 in VPA-treated male offspring, whereas it reduced hippocampal TNF-α and IFN-γ in VPA-treated female offspring. This study suggests that adolescent exercise may prevent the development of stress-related symptoms, cognitive deficits, and neuroinflammation in prenatally VPA-exposed offspring mice.

Keywords: Anxiety; Autism; Depression; Immune system; Memory; Physical activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anhedonia
  • Animals
  • Autism Spectrum Disorder*
  • Behavior, Animal
  • Brain
  • Cognition
  • Cytokines
  • Disease Models, Animal
  • Female
  • Humans
  • Interleukin-17 / therapeutic use
  • Interleukin-6
  • Male
  • Mice
  • Pregnancy
  • Prenatal Exposure Delayed Effects* / chemically induced
  • Prenatal Exposure Delayed Effects* / psychology
  • Quality of Life
  • Social Behavior
  • Swimming
  • Tumor Necrosis Factor-alpha
  • Valproic Acid / therapeutic use
  • Valproic Acid / toxicity


  • Valproic Acid
  • Interleukin-17
  • Cytokines
  • Tumor Necrosis Factor-alpha
  • Interleukin-6