Mapping the living mouse brain neural architecture: strain-specific patterns of brain structural and functional connectivity

Abstract

Mapping the structural and functional brain connectivity fingerprints became an essential approach in neurology and experimental neuroscience because network properties can underlie behavioral phenotypes. In mouse models, revealing strain related patterns of brain wiring have a tremendous importance, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ inbred strains are primary "genetic backgrounds" for brain disease modelling and for testing therapeutic approaches. Nevertheless, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises the question whether the observed effects are pathology specific or depend on the genetic background. Here we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice via Magnetic Resonance Imaging (MRI). We combined voxel-based morphometry (VBM), diffusion MRI and high resolution fiber mapping (hrFM) and resting state functional MRI (rs-fMRI) and depicted brain-wide dissimilarities in the morphology and "connectome" features in the two strains. Particularly C57BL/6 animals show bigger and denser frontal cortical areas, corticostriatal tracts and thalamic and midbrain pathways, and higher density of fibers in the genu and splenium of the corpus callosum. These features are fairly reflected in the functional connectograms that emphasize differences in "hubness", frontal cortical and basal forbrain connectivity. We demonstrate strongly divergent rewardaversion circuitry patterns and some variations of the default mode network features. Inter-hemispherical functional connectivity showed flexibility and adjustment regarding the structural patterns in a strain specific manner. We further provide high-resolution tractograms illustrating also inter-individual variability across inter-hemispherical callosal pathways in the BALB/cJ strain.

A systematic review of the relationship between magnetic resonance imaging based resting-state and structural networks in the rodent brain

“…In this line, the first group of studies ( n = 8) compared structural and functional networks separately between wild-type and transgenic or knockout mice. Karatas et al ( 2021 ) investigated the functional and structural network differences in two commonly used mouse inbred strains: C57BL/6 and BALB/cJ. Both strains were initially developed in the early 20th century, and are since then commercially kept and distributed as genetically homogeneous inbred strains.…”

“…In conclusion, this review confirmed prior evidence of typical features of SC-FC correlation in the healthy brain (Straathof et al, 2019 ). The correlation in the diseased brain is, however, far more complex and seems to uncouple under specific conditions, i.e., the existence of interhemispheric FC despite strongly reduced SC (Vega-Pons et al, 2016 ; Karatas et al, 2021 ). From the presently available reports on different brain diseases, general pattern and intensity of SC-FC relation changes do not emerge, suggesting that the changes are disease-specific.…”

“…It is important to note that tractography is bidirectional and not constrained by synapses, but strongly influenced by the selection of diffusion modeling and related parameters, i.e., step size, cutoff values, maximal number of streamlines (Calabrese et al, 2015 ; Karatas et al, 2021 ). Nevertheless, DTI-based fiber tracking was shown in multiple studies to be in line with the spatial organization patterns quantified with the gold standard viral tracing, for selected brain regions such as the hippocampus or sensorimotor cortex (Wu and Zhang, 2016 ; Pallast et al, 2020 ; Aswendt et al, 2021 ), and the whole brain connectome (Calabrese et al, 2015 ).…”

Monitoring Neuronal Network Disturbances of Brain Diseases: A Preclinical MRI Approach in the Rodent Brain

“…Adapted with permission from Gorges et al (2017). Karatas et al (2021) recently reported comparison of structural and functional connectivity in two healthy mouse strains (C57BL/6N and BALB/cJ) using DTI and rsfMRI. They observed inter-strain differences regarding fiber density within frontal cortices, along cortico-striatal, thalamic and midbrain pathways.…”

“…Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines. Recently, Karatas et al ( 2021 ) investigated strain specific patterns of brain structural and functional connectivity in C57BL/6N and BALB/cJ mouse strains. They demonstrated that structural dissimilarities were accompanied by specific FC patterns, emphasizing strain differences in frontal and basal forebrain functional networks as well as hubness characteristics.…”