Sex-specific behavioral resilience towards ADHD-like phenotypes upon early sensory overstimulation depends on environmental exposure

Abstract Although ADHD has a genetic basis, the role of environmental influences in the development of the phenotype remains unclear. Prior studies in humans and mice have found that excessive sensory stimulation (ESS) may play a role. However, the extent to which sex and environmental context shape vulnerability or resilience to ESS remains unclear. Here, we show that ESS alone can evoke context-dependent, sex-specific, and highly variable ADHD-like symptoms in an animal model. In this study, female and male CD-1 mice were exposed to chronic audiovisual overstimulation during postnatal development. Animals were subjected to excessive sensory stimulation (ESS) for six weeks, followed by behavioral testing under low- and high-anxiogenic environmental contexts defined by distinct light intensities. Low anxiogenic contexts involved light intensities ranging between 30 and 100 lx, whereas high anxiogenic conditions used illumination levels exceeding 700 lx. Behavioral domains relevant to ADHD, including locomotor activity, anxiety-related and risk-taking behavior, and memory performance, were assessed using standardized behavioral paradigms. In low anxiogenic testing contexts, ESS effects were less pronounced on average but were associated with sex-specific divergence in ADHD-like phenotypes. Male mice displayed increased risk-taking, whereas female mice showed increased anxiety-like responses. Individual animals exhibited a highly variable vulnerability in terms of anxiety-related and cognitive responses. Increased environmental stress led to robust ADHD-like phenotypes in ESS-exposed mice of both sexes, characterized by hyperactivity, increased risk-taking behavior, and memory impairments, while also reshaping behavioral variability in a sex-specific manner, consistent with differential resilience and vulnerability. Early-life exposure to a sensory overload influences behavioral outcomes in a sex- and context-dependent manner and increases heterogeneity of behavioral trajectories. Environmental context may determine whether resilience mechanisms buffer sensory over-exposure or whether vulnerability emerges as ADHD-like phenotypes, underscoring the importance of individualized, context-dependent assessment of developmental risk relevant to pediatric ADHD.