From circuits to lifespan: translating mouse and human timelines with neuroimaging based tractography.

Abstract

Animal models are commonly used to investigate developmental processes and disease risk, but humans and model systems (e.g., mice) differ substantially in the pace of development and aging. The timeline of human developmental circuits is well known, butit is unclear how such timelines compare to those in mice. We lack age alignments across the lifespan of mice and humans. Here, we build upon our Translating Time resource, which is a tool that equates corresponding ages during development. We collected 1,125 observations from age-related changes in body, bone, dental, and brain processes to equate corresponding ages across humans, mice, and rats to boost power for comparison across humans and mice. We acquired high-resolution diffusion MR scans of mouse brains (n=16) of either sex at sequential stages of postnatal development (postnatal day 3, 4, 12, 21, 60) to track brain circuit maturation (e.g., olfactory association, transcallosal pathways). We found heterogeneity in white matter pathway growth. Corpus callosum growth largely ceases days after birth while the olfactory association pathway grows through P60. We found that a P3-4 mouse equates to a human at roughly GW24, and a P60 mouse equates to a human in teenage years. Therefore, white matter pathway maturation is extended in mice as it is in humans, but there are species-specific adaptations. For example, olfactory-related wiring is protracted in mice, which is linked to their reliance on olfaction. Our findings underscore the importance of translational tools to map common and species-specific biological processes from model systems to humans.Significance statement Mice are essential models of human brain development, but we currently lack precise age alignments across their lifespan. Here, we equate corresponding ages across mice and humans. We utilize high-resolution diffusion mouse brain scans to track the growth of brain white matter pathways, and we use our cross-species age alignments to map the timeline of these growth patterns from mouse to humans. In mice, olfactory association pathway growth continues well into the equivalent of human teenage years. The protracted development of olfactory association pathways in mice aligns with their specialized sense of smell. The generation of translational tools bridges the gap between animal models and human biology while enhancing our understanding of developmental processes generating variation across species.