In brain tissue from 178 adult donors, researchers found that cells capable of replenishing the brain’s myelin-making cells made up a smaller share of sampled nuclei at older ages. Across ages 30 to 80, the estimated difference in that share was about 40%. It appeared in the striatum and the prefrontal cortex.
The study, published November 12 in Cell, used nearly 3.9 million cell nuclei to ask how adult brains differ from one person to the next and which of those differences are associated with age. A companion study used a separate mapping technique to see where those molecular differences occur within the striatum.
Reading gene activity one nucleus at a time
The striatum sits deep in the brain and helps select and coordinate movements. It also participates in learning, motivation and decisions about which actions to take. Its circuits are affected in disorders such as Parkinson’s disease.
The team isolated individual nuclei from donated tissue and sequenced their RNA. A nucleus’s mix of RNA helps identify the type of cell it came from and which genes were active. The researchers sampled several structures in and around the striatum and included the prefrontal cortex for comparison.
Cell-type proportions differed substantially between people. For example, donors whose samples contained a higher share of astrocytes or microglia in one grey-matter region tended to have a higher share in other sampled grey-matter regions. Some of these patterns held after the team accounted for measures of tissue quality. The study also found that common genetic variants were associated with gene activity in ways that often differed by cell type.
What the 40% difference measures
Oligodendrocyte precursor cells can develop into oligodendrocytes, which wrap many nerve fibres in myelin. That insulation helps electrical signals travel efficiently. Across the sampled cortex and striatum, the estimated proportion of nuclei classified as precursors was about 40% lower at age 80 than at age 30. The researchers measured a relative share of sampled nuclei. The study cannot tell us how many precursor cells an individual loses over time or whether that difference changes how well their brain makes or repairs myelin.
Age was also associated with changes in gene activity within cells. The sets of genes that changed varied across cell types. The largest shifts in the sampled regions appeared in the striatum’s spiny projection neurons, which carry signals from the striatum to other parts of the brain.
Six zones within the striatum
In the companion study, researchers used a method called Slide-tags to retain information about each nucleus’s original location in the tissue. They mapped about 1.1 million cells from 19 donors and found six zones where projection neurons showed distinct patterns of gene activity. Applying those molecular signatures to a larger dataset of 131 donors, the team found that the gene-expression differences defining the zones were less pronounced at older ages. The study measured molecular signatures, so it cannot show whether physical boundaries changed.
What donated tissue can tell us
Each donor contributed tissue at one point in time. Comparisons across ages can reveal patterns, but they cannot trace how one person’s brain changed. Tissue collection and processing can also affect which nuclei are recovered, and the sampled regions represent only part of the brain.
The maps give researchers a reference for asking whether specific cell populations change differently in neurodegenerative disease than they do across typical adulthood. That comparison will require studies designed around particular diseases and clinical outcomes.
Original research · Burger and colleagues in Cell and Kraft and colleagues’ companion spatial study (both open access).
Related reading · Scientists Mapped How Human Brain Cells Change From Infancy to Age 97.