Environmental Enrichment Exerts a Selective, Stage-Dependent Modulation on the Autism-like Behavioral Phenotype Induced by Embryonic Valproic Acid in Zebrafish

Abstract

Autism Spectrum Disorder (ASD) is characterized by deficits in communication, socialization, and restricted behavioral patterns. Valproic acid (VPA) is a teratogen that, through epigenetic mechanisms, induces ASD-like phenotypes in animal models. The zebrafish (Danio rerio) represents an ideal model for evaluating these alterations due to its complex behavioral repertoire. This study analyzed the longitudinal effect of an enriched environment (EE) on VPA-induced behavioral alterations in juvenile and adult stages (n = 72; n = 18 per group: CTRL-SE, CTRL-EE, VPA-SE, and VPA-EE). Subjects were evaluated across the novel tank, mirror test, and social interaction tests. The results reveal a selective, stage-dependent modulation: in the novel tank test, VPA fish housed in EE presented a significant reduction in erratic movements (stereotypies) and increased time spent in the upper zone (reduced anxiety), whereas specific modifications in shoal approach were observed in the social interaction test. These modulating effects were evident from the juvenile stage and consolidated in adulthood across specific locomotor and exploratory metrics. It is concluded that the enriched environment may act as a neuromodulatory strategy capable of mitigating selective aspects of the autism-like behavioral phenotype in zebrafish.