ube3a mutant zebrafish perceive the environmental signal from the retina as a threat or safe, respectively leading to increased or low anxiety levels. When the output is high anxiety levels, as in an aversive environment, social interaction is altered; however, in case the output is low anxiety levels, as in an incentive environment, social behaviors are restored. Credit: Dougnon et al., Molecular Psychiatry, 2025

Researchers from Brain Research Institute, Niigata University, Japan, have revealed that environment influences social behaviors in autism. By using zebrafish that have a mutation in ube3a, a gene linked to Angelman syndrome (AS) and autism spectrum disorders (ASD), they demonstrate that sensory processing of environmental information is determinant in the outcome of socializing or not.

The findings, published in the journal Molecular Psychiatry, suggest that environmental adjustment could hold therapeutic potential in ASD.

ASD is characterized by difficulties in social interaction and repetitive behaviors. While genetics are known to play an important role, environmental influences are increasingly recognized as crucial modulators of behaviors. Nevertheless, the interaction between environment and genetic predispositions remains largely underexplored.

The team of researchers then used zebrafish carrying a point mutation in the ube3a gene—which shares similarities with AS and ASD—in order to investigate how deeply environment affects social behaviors.

Social behaviors were investigated in both a custom-made white Styrofoam and a Plexiglass tank environment, alongside conventional anxiety-related tests. Neural activity mapping pre- and post-social interactions, and RNA sequencing were further conducted to uncover underlying mechanisms.

The zebrafish have an aversion to white colors and the Styrofoam environment was designed in white to manipulate their sense of anxiety and stress; on the opposite, the Plexiglass was made similar to the fish breeding tanks, thus appearing more familiar and safer.

In an interview, first author Dr. Godfried Dougnon, assistant professor at the Department of Neuroscience of Disease, Brain Research Institute at Niigata University said, "ube3a mutant zebrafish displayed less time spent in contact with their conspecifics and higher anxiety levels in the stressful Styrofoam container, but these behaviors improved when the test was conducted in a preferred acrylic tank."

He went on to explain that additional behavioral tests further confirmed higher anxiety-like responses in the mutants.

"Brain activity mapping using c-Fos in situ hybridization showed altered neural activity in specific brain regions, and transcriptomic analysis revealed increased expression of genes related to vision and its comorbidities, as well as abnormalities in sensory pathways, " said senior author Dr. Hideaki Matsui, professor in the same department.

This suggests that abnormal processing of visual information leads to elevated anxiety levels and reduced social interaction in threatening environments, behaviors that are improved in a more familiar setting.

Prof. Hideaki Matsui concludes, "These findings are important because they provide new clues for approaches to autism, and moreover, they are intriguing in that they suggest that conditions often thought to be uniquely human, such as autism-like disorders, may also exist in fish."

This study demonstrates that social behavior could be affected by environment in individuals with ASD-related genetic predispositions.

These results open new therapeutic perspectives, indicating that tailoring environmental stimuli could maybe help improve some ASD-related behavioral challenges. Future work will aim to translate these findings into human, and develop environment-based intervention strategies.

More information: Godfried Dougnon et al, Environmental context modulates sociability in ube3a zebrafish mutants via alterations in sensory pathways, Molecular Psychiatry (2025). DOI: 10.1038/s41380-025-03180-0  Journal information: Molecular Psychiatry