Absence of familiarity triggers hallmarks of autism in mouse model through aberrant tail-of-striatum and prelimbic cortex signaling

Autism spectrum disorder (ASD) involves genetic and environmental components. The underlying circuit mechanisms are unclear, but behaviorally, aversion toward unfamiliarity, a hallmark of autism, might be involved. Here, we show that in Shank3(Delta C/Delta C) ASD model mice, exposure to novel environments lacking familiar features produces long-lasting failure to engage and repetitive behaviors upon re-exposure. Inclusion of familiar features at first context exposure prevented enhanced dopamine transients in tail of striatum (TS) and restored context-specific control of engagement to wild-type levels in Shank3(Delta C/Delta C) mice. Engagement upon context re-exposure depended on the activity in prelimbic cortex (PreL)-to-TS projection neurons in wild-type mice and was restored in Shank3(Delta C/Delta C) mice by the chemogenetic activation of PreL -> TS projection neurons. Environmental enrichment prevented ASD-like phenotypes by obviating the dependence on PreL -> TS activity. Therefore, novel context experience has a key role in triggering ASD-like phenotypes in genetically predisposed mice, and behavioral therapies involving familiarity and enrichment might prevent the emergence of ASD phenotypes.

Automated summary

Autism spectrum disorder (ASD), influenced by genetic and environmental factors, can be triggered by exposure to unfamiliar environments. This study shows that in Shank3(Delta C/Delta C) ASD model mice, exposure to novel environments without familiar features leads to long-lasting lack of engagement and repetitive behaviors. Including familiar features during initial exposure can prevent enhanced dopamine transients and restore engagement control to normal levels. Environmental enrichment can prevent ASD-like phenotypes by reducing the reliance on specific brain activity.