Abstract
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 Shank3ΔC/ΔC 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 Shank3ΔC/ΔC 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 Shank3ΔC/ΔC 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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with a core of behavioral abnormalities, including social deficits, verbal and intellectual disabilities, insistence on sameness, sensory abnormalities and increased stereotypic behavioral patterns (Baron-Cohen and Belmonte, 2005; Bourgeron, 2015; Chen et al, 2015; Geschwind, 2009; Jiujias et al, 2017)
Young adult (8– 9 weeks) male mice were introduced to a novel context for 10 min and tested for social or object interactions and memory recall upon reintroduction to that same context (Figures 1A and 1B)
We found that prelimbic cortex (PreL)/tail of striatum (TS) neurons collateralized to basolateral amygdala (BLA) (Figure S4)
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with a core of behavioral abnormalities, including social deficits, verbal and intellectual disabilities, insistence on sameness, sensory abnormalities and increased stereotypic behavioral patterns (Baron-Cohen and Belmonte, 2005; Bourgeron, 2015; Chen et al, 2015; Geschwind, 2009; Jiujias et al, 2017). Given the mostly complex multigenic basis of ASD predisposition, the identification of environmental factors affecting individuals from a range of predisposed genetic backgrounds would have important therapeutic implications (BaronCohen and Belmonte, 2005; Bourgeron, 2015; Chen et al, 2020; Geschwind, 2009; Jamal et al, 2021; Sahin and Sur, 2015). It is currently unclear whether different ASD-linked phenotypes arise and develop independently or whether there might be singular causes that influence a range of behavioral abnormalities in ASD (Chen et al, 2020; Geschwind, 2009; Sahin and Sur, 2015). The identification of causal relationships among core behavioral phenotypes in ASD would provide useful indications as to relevant environmental factors and underlying brain circuit mechanisms (Baron-Cohen and Belmonte, 2005; Bourgeron, 2015; Sahin and Sur, 2015)
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