Abstract
The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity and quantitatively diverged in their molecular mitochondrial phenotype signatures. Therefore, this work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the mouse brain.
Competing Interest Statement
The authors declare no competing interest related to this work. C.A. receives research funding from Sunovion Pharmaceuticals.
Footnotes
- A new title - A new Figure 4 with additional analyses of gene expression, which provide the molecular characterization and novel evidence of mitochondrial molecular specialization across the mouse brain. These results are particularly exciting because they provide independent validation from a large dataset generated from a distinct cohort of animals (Allen Mouse Brain Atlas), which largely confirm our main findings related to the identity of the biochemically-defined brain network 1. - A new Extended Data Figure S13 contains supporting data related to Figure 4. - A new Extended Data Figure S11 with the correlation between cell type composition and mitochondrial activities, mtDNA, and MHI. - Textual edits to account for these additions, including new methods and results.