Summary: A new, freely available brain atlas reveals how brain metabolism changes throughout the life of mice.

Source: UC Davis

The first atlas of metabolites in the mouse brain has been published by a team led by UC Davis researchers. The dataset includes 1,547 different molecules across 10 brain regions in male and female laboratory mice from adolescence through adulthood and into advanced old age.

The work is published Oct. 15 in the Nature Communications. 

The complete dataset is publicly available at https://mouse.atlas.metabolomics.us/.

“This is the largest metabolome analysis available on the brain, worldwide. It covers 1,547 identified metabolites, enabling analysis of many chemical conversions for energy, neurotransmitters or complex lipids in the brain,” said Professor Oliver Fiehn, director of the West Coast Metabolomics Center at the UC Davis Genome Center and senior author on the paper.

Metabolomics is the study of the chemical fingerprints of metabolism in living cells. It uses advanced high-throughput techniques to separate and identify all the different chemicals, or metabolites, present at a given time in a cell, tissue or organ. Alongside genomics, transcriptomics and proteomics, these techniques allow scientists to better understand what is happening inside cells and tissues.

Postdoctoral scholar Jun Ding, Fiehn and colleagues sampled mice at ages 3 weeks (adolescent), 16 weeks (early adult), 59 weeks (middle age) and 92 weeks (old age). They looked at ten separate brain regions with different functions. The new atlas can be used to better understand these different functions, Fiehn said.

The results show that the brain metabolome clearly is clearly distinct between large brain regions such as the brainstem, which controls vital functions such as breathing and blood pressure, from the cerebrum, which controls movements, speech and thinking, Fiehn said. In addition, specific sections showed high concentrations of metabolites associated with particular receptors, such as adenosine, ceramides and phospholipid ethers.

They did not find any significant metabolic differences between the brains male and female mice.

Metabolome of the aging brain 

When the team compared animals of different ages, they found that overall, adult mice showed the greatest metabolic difference between brain sections. The differences between regions were less in adolescence and much less at very old ages.

“At very old age, energy functions appear to be less efficient, and the myelin sheaths that surround the axons, or wiring, of the brain change composition,” Fiehn said.

Screenshot of data from the atlas of mouse brain metabolomics shows distribution of adenosine in brain regions with age. This resource will help other scientists interpret results and develop new studies. Credit: UC Davis

Lipid molecules especially showed large differences in aging and across brain regions. These lipids deserve specific investigation to see how they relate to changes in brain function, for example in signaling.

At very old age, the response system against oxidative stress becomes very active, while proteins start breaking down into peptides at an increased rate, he said. These changes are reflected in the metabolome.

The work was conducted in collaboration with the UC Davis Mouse Biology Program, led by Professor Kent Lloyd.

“This landmark paper clearly demonstrates the power of the laboratory mouse as a model to accelerate our understanding of brain metabolism, including and especially in humans,” Lloyd said.

Additional coauthors on the paper are, at UC Davis: Zachary Rabow, Tong Shen, Jacob Folz, Christopher R. Brydges, Sili Fan, Xinchen Lu, Sajjan Mehta, Megan R. Showalter, Ying Zhang, Renee Araiza and Lynette Bower; and Jian Ji, Jiangnan University, Wuxi, China.

Funding: The work was supported by grants from the National Institutes of Health.

About this brain mapping and aging research news

Author: Andrew Fell
Source: UC Davis
Contact: Andrew Fell – UC Davis
Image: The image is credited to UC Davis

Original Research: Open access.
“A metabolome atlas of the aging mouse brain” by Jun Ding, Jian Ji, Zachary Rabow, Tong Shen, Jacob Folz, Christopher R. Brydges, Sili Fan, Xinchen Lu, Sajjan Mehta, Megan R. Showalter, Ying Zhang, Renee Araiza, Lynette R. Bower, K. C. Kent Lloyd & Oliver Fiehn. Nature Communications


Abstract

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A metabolome atlas of the aging mouse brain

The mammalian brain relies on neurochemistry to fulfill its functions. Yet, the complexity of the brain metabolome and its changes during diseases or aging remain poorly understood.

Here, we generate a metabolome atlas of the aging wildtype mouse brain from 10 anatomical regions spanning from adolescence to old age.

We combine data from three assays and structurally annotate 1,547 metabolites. Almost all metabolites significantly differ between brain regions or age groups, but not by sex.

A shift in sphingolipid patterns during aging related to myelin remodeling is accompanied by large changes in other metabolic pathways. Functionally related brain regions (brain stem, cerebrum and cerebellum) are also metabolically similar.

In cerebrum, metabolic correlations markedly weaken between adolescence and adulthood, whereas at old age, cross-region correlation patterns reflect decreased brain segregation.

We show that metabolic changes can be mapped to existing gene and protein brain atlases.

The brain metabolome atlas is publicly available (https://mouse.atlas.metabolomics.us/) and serves as a foundation dataset for future metabolomic studies.



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