Dingding Yang1,2 · Qian Liu1,2 · Hangjun Ran1,2,3 · Teng Xue1,2,4 · Yifan Lu1,2 · Xiao Yang1,2 · Jiaming Wang1,2 · Ling Liu5  · Wenting Wang1,2 · Binbin Nie6  · Guohong Cai1,2 · Shengxi Wu1,2

1 Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China 

2 The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi’an 710032, China 

3 College of Life Sciences, Yan’an University, 716000, Yan’an, China 

4 The Key Laboratory of Neural and Vascular Biology, Ministry of Education and Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang 050017, China 

5 Military Medical Innovation Center, Fourth Military Medical University, Xi’an 710032, China 

6 Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China

Abstract

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.

Keywords

Shank3; ASD; Olfactory preference; Social deficits; fMRI; c-Fos

[SpringerLink]