Abstract
The brain and behavior are under energetic constraints, limited 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 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 regions, defining 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 with shared mitochondrial signatures. A major network composed of cortico-striatal regions exhibited the strongest mitochondria-behavior correlations, suggesting that this mito-based network is functionally significant. Mito-based networks also overlap with regional gene expression and structural connectivity, thereby providing convergent multimodal evidence of mitochondrial respiratory chain functional organization anchored in gene, brain and behavior.
Competing Interest Statement
The authors declare no competing interest related to this work. M.P. has consulted and received funding from Epirium Bio. C.A. receives research funding from Sunovion Pharmaceuticals.
Footnotes
Manuscript and some figures have been updated.
