Brain Development Lab

It is often assumed that phenotypic heterogeneity in autism reflects underlying pathobiological variation. However, direct evidence supporting this link is lacking. Leveraging cross-species functional neuroimaging, we show that brain dysconnectivity patterns in autism can be parsed into biologically dissociable subtypes. Specifically, we found that functional magnetic resonance imaging (fMRI) connectivity alterations in 20 distinct genetic mouse models of autism cluster into hypoconnectivity-dominant and hyperconnectivity-dominant subtypes. These subtypes are linked to distinct biological pathways, with hypoconnectivity being associated with synaptic dysfunction and hyperconnectivity reflecting transcriptional and immune-related alterations. Here we identified analogous hypoconnectivity and hyperconnectivity subtypes in a multicenter human fMRI dataset of n = 940 individuals with idiopathic autism and n = 1,036 neurotypical individuals. The human autism subtypes are highly replicable, are associated with distinct functional network architectures and behavioral profiles and recapitulate the synaptic and immune-related pathways identified in the rodent dataset. Our work provides a new empirical framework for targeted subtyping of the autism spectrum. 

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism. 

In this work, we review the stae-of-the-art and future perspectives of cross-species studies. Advances in functional MRI (fMRI) have greatly enhanced our ability to map functional connectivity in the human brain, prompting efforts to apply these approaches to rodents and non-human primates. Here, we show how fMRI can also be used in model organisms, offering the advantage of being combined with a wide range of neuroscience techniques aimed at uncovering the neuronal basis of connectivity. This review highlights connectivity systems that are conserved across evolution, identifies a principal organizational axis within the cortex, and reveals shared spatiotemporal activity patterns across mammalian species. It also explores emerging neurocomputational tools and methodologies that enable direct comparisons and translation of fMRI findings between species. Altogether, this rapidly advancing field holds great promise for deepening our understanding of large-scale brain organization of the mammalian brain.