Brain functional connectivity and its aberrations in mouse models of autism

Liska, Adam (2017) Brain functional connectivity and its aberrations in mouse models of autism. PhD thesis, University of Trento.

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Functional Magnetic Resonance Imaging (fMRI) has consistently highlighted aberrant functional connectivity across brain regions of autism spectrum disorder (ASD) patients. However, the manifestation and neural substrates of these alterations are highly heterogeneous and often conflicting. Moreover, their neurobiological under- pinnings and etiopathological significance remain largely unknown. A deeper understanding of the complex pathophysiological cascade leading to impaired connectivity in ASD can greatly benefit from the use of model organisms where individual pathophysiological or phenotypic components of ASD can be recreated and investigated via approaches that are either off limits or confounded by clinical heterogeneity. In this work, we first describe the intrinsic organization of the mouse brain at the macroscale as seen through resting-state fMRI (rsfMRI). The analysis of a large rsfMRI dataset revealed the presence of six distinct functional modules related to known brainwide functional partitions, including a homologue of the human default-mode network (DMN). Consistent with human studies, interconnected functional hubs were identified in several sub-regions of the DMN, in the thalamus, and in small foci within integrative cortical structures such as the insular and temporal association cortices. We then study the effects of mutations in contactin associated protein-like 2 (Cntnap2), a neurexin-related cell-adhesion protein, on functional connectivity. Homozygous mutations in this gene are strongly linked to autism and epilepsy in humans, and using rsfMRI, we showed that homozygous mice lacking Cntnap2 exhibit aberrant functional connectivity in prefrontal and midline functional hubs, an effect that was associated with reduced social investigation, a core “autism trait” in mice. Notably, viral tracing revealed reduced frequency of prefrontal-projecting neural clusters in the cingulate cortex of Cntnap2−/− mutants, suggesting a possible contribution of defective mesoscale axonal wiring to the observed functional impairments. Macroscale cortico-cortical white-matter organization appeared to be otherwise preserved in these animals. These findings revealed a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of connectivity in integrative prefrontal areas. Finally, we discuss the role mouse models could play in generating and testing mechanistic hypotheses about the elusive origin and significance of connectional aberrations observed in autism and recent progress towards this goal.

Item Type:Doctoral Thesis (PhD)
Doctoral School:Cognitive and Brain Sciences
PhD Cycle:30
Subjects:Area 06 - Scienze mediche > MED/26 NEUROLOGIA
Additional Information:Istituto Italiano di Tecnologia
Funders:Istituto Italiano di Tecnologia
Repository Staff approval on:14 Dec 2017 17:07

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