Olfactory Valence-Processing Deficits and Aberrant Brain Network Connectivity Underlie Social Dysfunction in...

Olfaction is crucial for rodent social behavior, and olfactory dysfunction has been observed in multiple autism spectrum disorder (ASD) models, but its phenotype in Shank3^⁻/⁻ mice (a classic ASD model) remains unclear. We systematically assessed olfactory function in Shank3^⁻/⁻ mice by using a modified olfactory three-chamber test and optimized ultrasonic vocalization (USV) detection in combination with resting-state functional magnetic resonance imaging (rs-fMRI), whole-brain c-Fos mapping, and three-dimensional (3D) behavioral analysis. Our results showed abnormal odor preference and hyperconnectivity in olfaction-associated brain networks. Upon exposure to neutral, appetitive, and social pheromone odors, Shank3^⁻/⁻ mice displayed atypical whole-brain c-Fos activation patterns, which were coupled with synchronized locomotor suppression and stereotyped behaviors. This study maps the neural-behavioral responses to odors in Shank3^-/- mice, linking olfactory deficits to autism-like behaviors, and highlights the olfactory system as a targetable pathway for sensory-based autism therapies.