Involvement of the habenula in the pathophysiology of autism spectrum disorder

Jürgen Germann,Gabriel A Devenyi,Stephanie Tullo,M Mallar Chakravarty,Helena Brentani,Flavia Venetucci Gouveia,Saashi A Bedford

doi:10.1038/s41598-021-00603-0

Abstract

The habenula is a small epithalamic structure with widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central structure modulating the reward value of social interactions, behavioral adaptation, sensory integration and circadian rhythm. Autism spectrum disorder (ASD) is characterized by social communication deficits, restricted interests, repetitive behaviors, and is frequently associated with altered sensory perception and mood and sleep disorders. The habenula is implicated in all these behaviors and results of preclinical studies suggest a possible involvement of the habenula in the pathophysiology of this disorder. Using anatomical magnetic resonance imaging and automated segmentation we show that the habenula is significantly enlarged in ASD subjects compared to controls across the entire age range studied (6–30 years). No differences were observed between sexes. Furthermore, support-vector machine modeling classified ASD with 85% accuracy (model using habenula volume, age and sex) and 64% accuracy in cross validation. The Social Responsiveness Scale (SRS) significantly differed between groups, however, it was not related to individual habenula volume. The present study is the first to provide evidence in human subjects of an involvement of the habenula in the pathophysiology of ASD.

Highlights

In subjects diagnosed with BD and schizophrenia[40,41]
Comparing total bilateral habenula volume we found that ASD subjects have significantly larger bilateral habenula volumes compared to typically developing controls (TDC) (ASD subjects: 27.1 m m3 ± 5.3; TDC: 25.5 m m3 ± 4.5; t = 3.28, p = 0.001; Fig. 2B)
Investigating habenula volume in a large cohort of ASD and TDC subjects spanning in age from childhood to young adulthood we found that habenula volume is larger in subjects diagnosed with ASD across all ages

Summary

Introduction

In subjects diagnosed with BD and schizophrenia[40,41]. Previous studies have reported altered amygdala volume in subjects with ASD compared to age matched controls[25,42]. Similar to the amygdala findings, altered habenula volume across development might be found in subjects with ASD compared to age matched controls like it has been described in BD41. Reduction in oxytocin innervation in the lateral habenula, a neuropeptide closely involved in social bonding, is thought to be the underlying mechanism of social impairment in the Mecp2-null mouse model of Rett syndrome[55] In line with these findings, a study using excitatory designer receptor exclusively activated by designer drugs (DREADD) showed that frontal cortex activation suppressed social behaviour via activation of lateral habenula neurons; inhibition of these neurons prevented the social behavioural deficits observed after frontal cortex activation[5]. Possible effects of sex and individual SRS score on habenula volume were investigated

Methods

Results

Conclusion