Stebbings, K. A. | Search bioRxiv

bioRxiv2019

Voluntary wheel running has no impact on brain and liver mitochondrial DNA copy number or mutation measures in the PolG mouse model of aging

The mitochondrial theory of aging attributes much of the aging process to mitochondrial DNA damage. The PolGAD257A/D257A (PolG) mutant mouse was created to explore the mitochondrial theory of aging and carries a mutated proofreading region of polymerase gamma, which exclusively transcribes the mitochondrial genome. As a result, PolG mice accumulate mitochondrial DNA (mtDNA) mutations which leads to premature aging including hair loss, weight loss, kyphosis, increased rates of apoptosis, organ damage, and eventually, an early death at around 12 months. Exercise has been reported to decrease skeletal muscle mtDNA mutations and normalize protein levels in PolG mice. However, brain mtDNA changes with exercise in PolG mice have not been explored. We found no effects of exercise on mtDNA mutations or copy number in brain or liver in PolG mice, despite effects on body mass. Our results suggest that mitochondrial mutations play little role in exercise-brain interactions in the PolG model of accelerated aging. In addition to evaluating the effect of exercise on mtDNA outcomes, we also implemented novel methods for mtDNA extraction and measuring mtDNA mutations to improve efficiency and accuracy.

cell biology↗

bioRxiv2019

A novel dynamic network imaging analysis method reveals aging-related fragmentation of cortical networks in mouse

Network analysis of large-scale neuroimaging data has proven to be a particularly challenging computational problem. In this study, we adapt a novel analytical tool, known as the community dynamic inference method (CommDy), which was inspired by social network theory, for the study of brain imaging data from an aging mouse model. CommDy has been successfully used in other domains in biology; this report represents its first use in neuroscience. We used CommDy to investigate aging-related changes in network parameters in the auditory and motor cortices using flavoprotein autofluorescence imaging in brain slices and in vivo. Analysis of spontaneous activations in the auditory cortex of slices taken from young and aged animals demonstrated that cortical networks in aged brains were highly fragmented compared to networks observed in young animals. Specifically, the degree of connectivity of each activated node in the aged brains was significantly lower than those seen in the young brain, and multivariate analyses of all derived network metrics showed distinct clusters of these metrics in young vs. aged brains. CommDy network metrics were then used to build a random-forests classifier based on NMDA-receptor blockade data, which successfully recapitulated the aging findings, suggesting that the excitatory synaptic substructure of the auditory cortex may be altered during aging. A similar aging-related decline in network connectivity was also observed in spontaneous activity obtained from the awake motor cortex, suggesting that the findings in the auditory cortex are reflections of general mechanisms that occur during aging. Therefore, CommDy therefore provides a new dynamic network analytical tool to study the brain and provides links between network-level and synaptic-level dysfunction in the aging brain.

neuroscience↗