Mouse brain-wide mitochondrial connectivity anchored in gene, brain and behavior.

Rosenberg A., Saggar M., Rogu P., Limoges A. W., Sandi C., Mosharov E. V., ... & Picard M. 2021. BioRxiv


The brain and behavior are under energetic constraints, which are likely driven by mitochondrial energy production capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examine the association between mitochondrial health index and stress-related behaviors in mice with diverse mitochondrial and behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain function and mitochondrial DNA (mtDNA) content were deployed on 571 samples from 17 brain regions. We find specific patterns of mito-behavior associations that vary across brain regions and behaviors. Furthermore, multi-slice network analysis applied to our brain-wide mitochondrial dataset identified three large-scale networks of brain regions. A major network composed of cortico-striatal regions exhibits highest mitochondria-behavior correlations, suggesting that this mito-based network is functionally significant. Mito-based networks can also be recapitulated using correlated gene expression and structural connectome data, thereby providing convergent multimodal evidence of mitochondrial functional organization anchored in gene, brain and behavior.