Development of a Functional Connectivity Optical Imaging Protocol and Analysis Pipeline for Mouse Models of Autism Spectrum Disorder

Background: Functional connectivity mapping is a method by which brain function can be non-invasively measured on a whole-brain level using fMRI. Studies of resting-state functional connectivity in autism spectrum disorder have focused on certain developmental stages or on individuals’ level of functioning. However, genetic and environmental variation between individuals can introduce added noise to analysis of autism spectrum disorder in humans. Use of mouse models of autism can address this issue of heterogeneity by controlling for genetic and environmental differences. Optical intrinsic signal (OIS) imaging is a minimally invasive, low cost method for mouse neuroimaging, which can map resting-state functional connectivity and cortical activations in response to stimulation in mouse models of ASD and potentially offer insights into brain function in ASD.

Objectives: This study aims to develop functional connectivity optical imaging methods in mouse models of autism and to apply it to pilot groups of genetic or environmental mouse models of autism spectrum disorder (ASD).

Methods: Functional connectivity OIS imaging was performed on two cohorts of mice with autism-related behavioral phenotypes, an SSRI exposure model and a Celf6 knockout model. In each pilot group, ASD model mice were compared to age-matched wildtype controls by imaging the cerebral cortex of the anesthetized mouse at adulthood, measuring changes in reflected light intensity to calculate relative changes in hemoglobin concentrations. Resting-state functional connectivity and left forepaw stimulation data were collected across multiple runs for each mouse and averaged to produce maps of functional connectivity and variation.

Results: Contralateral homotopic connectivity varied across cortical regions at rest and cortical activation in response to forepaw stimulation varied between mice. A similarity analysis evaluated how similar (spatially) the functional connectivity patterns of the ASD mice were to a control group. No consistent pattern of dissimilarity was found in the ASD groups of mice when measured at adulthood, but a common region of high variability was identified in the individuals of both the ASD groups and controls.

Conclusions: Functional connectivity OIS imaging is a minimally invasive optical imaging method that can be used to map functional connectivity in mouse models of autism. Mapping functional connectivity with these methods in mouse models of autism can control for genetic and environmental differences which may influence imaging research results in humans.