Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder

Hojin Cho,Hye Won Oh,Dong Goo Kim,Bumhee Park,Elizabeth Quattrocki Knight,Hae-Jeong Park,Chul Hoon Kim

doi:10.1038/s41598-017-13642-3

Abstract

The neurobiological basis of social dysfunction and the high male prevalence in autism spectrum disorder (ASD) remain poorly understood. Although network alterations presumably underlie the development of autistic-like behaviors, a clear pattern of connectivity differences specific to ASD has not yet emerged. Because the heterogeneous nature of ASD hinders investigations in human subjects, we explored brain connectivity in an etiologically homogenous rat model of ASD induced by exposure to valproic acid (VPA) in utero. We performed partial correlation analysis of cross-sectional resting-state 18F-fluorodeoxyglucose positron emission tomography scans from VPA-exposed and control rats to estimate metabolic connectivity and conducted canonical correlation analysis of metabolic activity and behavior scores. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Similarly, current analyses revealed sex-specific changes in network connectivity and identified distinct alterations in the distributed metabolic activity patterns associated with autistic-like social deficits. Specifically, diminished activity in the salience network and enhanced activity in a cortico-cerebellar circuit correlated with the severity of social behavioral deficits. Such metabolic connectivity features may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in the VPA rat model of ASD.

Highlights

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder characterized by early-onset impairments in social communication and social interaction[1]
In order to help identify the neurobiological basis of autism spectrum disorder (ASD), with regard to variability in social interactions and sex-specific manifestations, we explored the correlation between behaviors and specific alterations in neuronal connectivity in the rat model of ASD induced by prenatal exposure to valproic acid (VPA)
Indicated no significant main effects of VPA treatment or sex on the time spent with the first stranger (S1) (VPA treatment, F1,73 = 1.20, P = 0.28; sex, F1,73 = 1.33, P = 0.26) or an empty wire cage presented as a novel object (O) (VPA treatment, F1,73 = 1.78, P = 0.19; sex, F1,73 = 0.03, P = 0.86)

Summary

Introduction

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder characterized by early-onset impairments in social communication and social interaction[1]. In order to help identify the neurobiological basis of ASD, with regard to variability in social interactions and sex-specific manifestations, we explored the correlation between behaviors and specific alterations in neuronal connectivity in the rat model of ASD induced by prenatal exposure to valproic acid (VPA). Previous animal studies reported that VPA induced more extensive behavioral and molecular alterations in males than in females[16,17]. We regarded ASD as a disorder of abnormal neural connectivity[19,20,21], and examined alterations in inter-regional connectivity across the entire brain in the VPA rat model of ASD. The VPA rat model mitigates the aforementioned influences of heterogeneous causality, and thereby provides an opportunity to reveal a more direct link between behavioral manifestations of ASD and changes in brain connectivity. 18F-FDG PET images do not provide time series data for the conventional evaluation of functional connectivity, introduction of cross-sectional analysis of 18F-FDG PET imaging allows researchers to evaluate between-group differences in both regional activity and connectivity[32]

Methods

Results

Conclusion