Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Post-MRI blood gas levels.

<p>p_aCO₂ partial pressure of arterial CO₂ measured at the end of the fMRI scan. p_aCO₂ partial pressure of arterial CO₂ measured at the end of the fMRI scan. Arterial blood gas values are expressed in mmHg (mean ± SEM).</p

Reduced basal functional activity in the cortex of BTBR mice.

<p>Coronal view of the brain regions exhibiting increased (yellow-red) or reduced (blue) bCBV in BTBR (N = 10) versus B6 control subjects (N = 10, Z>3.1, pc = .01) [Acb: nucleus accumbens; Hyp: hypothalamus; Ins/Pir: insular/piriform cortex; mPFC: medial prefrontal cortex; Sp: septum; Ss: somatosensory cortex; Th; thalamus; Rs: retrosplenial cortex; VDb: ventral diagonal band].</p

Major FA reduction in hippocampal commissure and corpus callosum of BTBR white matter.

<p>Voxelwise significant FA differences between BTBR (N = 9) versus B6 (N = 9, Z = 1.96, pc = .01). Representative T2-weighted anatomical images from a BTBR subject (top row) are shown for comparison. [CC: corpus callosum; DHc: dorsal hippocampal commissure; Fmi: Forceps minor of the corpus callosum].</p

Major white matter reorganisation in BTBR mice.

<p>Diffusion tensor tractography of white matter in a representative B6 (left) and BTBR (right) subject. Only white matter tracts originating from regions exhibiting statistically significant FA alterations are displayed [CC: corpus callosum; DHc: dorsal hippocampal commissure; Fmi: Forceps minor of the corpus callosum].</p

Widespread gray matter volume reductions in BTBR mice.

<p>Maps of the brain regions exhibiting altered grey matter volume in BTBR (N = 9) with respect to B6 controls (N = 9, Z>3.1, pc = .01). Blue indicates reduced, red/yellow indicates increased gray matter volume in BTBR mice vs B6 controls [Amy: amygdala; Cb: cerebellum; DHyp: dorsal hypothalamus; dPFC: dorsal prefrontal cortex; Ins: insular cortex; LTh: lateral thalamus; mPFC: medial prefrontal cortex; OB: olfactory bulbs; Rs: retrosplenial cortex; Vcxt: visual cortex].</p

Antero-posterior white matter reorganisation in BTBR mice.

<p>Diffusion tensor tractography of representative dorsal inter-hemispheric tracts in control (top) and BTBR (bottom) mice. Seed regions used for tractography are displayed in green/red [CC: corpus callosum; DHc: dorsal hippocampal commissure; Fmi: Forceps minor of the corpus callosum; Probst B.: Probst bundles].</p

BTBR exhibit widespread cortical thickness reductions.

<p>Average cortical thickness in B6 (left) and BTBR mice (center) and corresponding voxel-wise statistics (right, Z>2, pc = .01; blue indicates BTBRB6).</p