ALTERED CORTEX-WIDE SPONTANEOUS DYNAMICS ACCOMPANY ENHANCED SENSORY RESPONSE AMPLITUDE AND VARIABILITY IN SHANK3B MICE

Sensory processing abnormalities are a prominent feature of autism spectrum disorder (ASD), yet how sensory-evoked responses interact with ongoing brain-wide cortical activity is not fully understood. Here, we investigated whether altered spontaneous cortical dynamics shape sensory processing and behavior in the Shank3B mouse model of ASD.
Using wide-field mesoscale calcium imaging, we measured spontaneous and sensory-evoked cortical activity across the dorsal cortex under awake and lightly anesthetized conditions. Shank3B mice exhibited increased and spatially coordinated spontaneous activity, consistent with an abnormal brain-wide background state. Against this altered background, sensory-evoked responses showed increased amplitude and variability, indicating that sensory hyper-responsiveness emerges within disrupted large-scale cortical dynamics rather than as an isolated phenomenon.
To examine how background brain state relates to behavior, we combined imaging with behavioral assays assessing repetitive and social phenotypes. We further probed this relationship by modulating cortical excitatory-inhibitory balance using pharmacological (diazepam) and chemogenetic (DREADDs) interventions. Normalizing background cortical activity reduced large-scale hyperactivity and was accompanied by selective improvements in sensory responses and specific behavioral measures, indicating partial restoration of function.
Together, these findings suggest that sensory abnormalities in Shank3B mice are constrained by an altered brain-wide background state that links spontaneous activity, sensory processing, and behavior. Our results highlight large-scale cortical dynamics as an important substrate underlying ASD-relevant phenotypes and support the idea that targeting spontaneous network activity may provide a unifying framework for understanding, and partially modulating, sensory and behavioral dysfunction.