Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging

Abstract

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviours with restricted interests. Autism-relevant phenotypes in the inbred mouse strain BTBR T+tf/J (BTBR) offer translational tools to discover biological mechanisms underlying unusual mouse behaviours analogous to symptoms of autism. Two of the most consistent findings with BTBR are lack of sociability as measured by the three-chamber social approach task and increased amount of time engaged in self-grooming in an empty cage. Here we evaluated BTBR as compared to two typical inbred strains with high sociability and low self-grooming, C57BL/6J (B6) and FVB/AntJ (FVB), on both the automated three-chambered social approach task and repetitive self-grooming assays. Brains from the behaviourally tested mice were analyzed using magnetic resonance imaging and diffusion tensor imaging to investigate potential neuroanatomical abnormalities throughout the brain; specifically, to discover neuroanatomical mechanisms which could explain the autism-relevant behavioural abnormalities. Significant differences in volume and white matter microstructure were detected in multiple anatomical regions throughout the brain of BTBR compared to B6 and FVB. Further, significant correlations were found between behavioural measures and areas of the brain known to be associated with those behaviours. For example, striatal volume was strongly correlated to time spent in self-grooming across strains. Our findings suggest that neuropathology exists in BTBR beyond the previously reported white matter abnormalities in the corpus callosum and hippocampal commissure and that these brain differences may be related to the behavioural abnormalities seen in BTBR.

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…This can be seen with the similarities between 2 independent studies of Nl3 KI [131,132], and the 2 independent BTBR studies [149,151]. However, perhaps the most significant overlap is seen in the similarities between the 16p11.2 models [28,54], in which the mice were created in 2 different laboratories, with 2 different techniques, and were inconsistent in age and sex, but still had strikingly similar findings.…”

“…MRI and DTI imaging studies summarized in Table 1, along with the earlier histological approaches mentioned [81,82,85,86,91,92], and forefront techniques such as optogenetics [157,158], are yielding highquality information about circuitry-mediated social and repetitive behaviors in mice and humans. For example, repetitive self-grooming has shown to be correlated with the striatum, globus pallidus, and thalamus, and sociability with the frontal lobe, amygdala, and nucleus accumbens [149]. Furthermore, neuroanatomical differences have been linked to learning tasks, such as the Morris water maze, which highlighted differences in the hippocampus [156].…”

“…Lerch et al [156] found that after only 5 days of training in the Morris water maze, highly significant volume differences in the mouse brain can be seen. Furthermore, in the BTBR study by Ellegood et al [149], several neuroanatomical differences were found to correlate with behavioral measures across the 3 strains of mice examined [149]. For example, repetitive behaviors, specifically grooming time, in BTBR mice significantly correlated with striatal volume.…”

“…The BTBR mouse has been examined in 3 different studies. The first compared the BTBR mouse with both C57BL/6 J and FVB/AntJ [149], investigating both volume differences and tissue microstructure differences using DTI. DTI is a technique that examines the underlying tissue microstructure based on the diffusion of water throughout the brain.…”

“…Further, several different techniques are available for the assessment of the brain using MRI. Aside from the volume differences, the underlying tissue microstructure can be assessed with DTI [131,149,151], functional information can be assessed using fMRI [151], and metabolic differences can be assessed with magnetic resonance spectroscopy [116].…”