Abstract
Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.
Highlights
Across species, the neuropeptide oxytocin plays a critical role in a wide range of reproductive and complex social processes, including initiation of uterine contractions during childbirth, lactation, pair bonding, and social reward processing[1,2]
In females with autism spectrum disorder (ASD), greater nucleus accumbens (NAcc) connectivity with left prefrontal regions was associated with better functioning on the social cognition subscale of the Social Responsiveness Scale (SRS)
These gene-brain-behavior results directly mirror our previously reported findings in NT males, who showed the same pattern whereby NAcc-left prefrontal connectivity increased as a function of increased oxytocin receptor gene (OXTR) risk-alleledosage and was related to better social cognition scores on the SRS45
Summary
The neuropeptide oxytocin plays a critical role in a wide range of reproductive and complex social processes, including initiation of uterine contractions during childbirth, lactation, pair bonding, and social reward processing[1,2]. As social deficits are a core feature of ASD, the oxytocin system has attracted considerable attention as a potential target for pharmacological manipulation in individuals with autism[7,8,9]. In males with ASD, treatment with intranasal oxytocin has been shown to improve social responsivity, seemingly through effects on reward-related subcortical brain areas and frontal brain regions important for social cognition[10,11,12,13,14,15,16]. Sex-specific regulation of the oxytocin system has been reported in both
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