Research led by Harvard Junior Fellow William Allen, a joint postdoctoral fellow in Catherine Dulac’s and Xiaowei Zhuang’s Labs, has generated a “cell atlas” of RNA expression in the mouse brain as it ages. Allen and his colleagues used MERFISH, a technique developed by the Zhuang lab, and single nucleus RNA sequencing (snRNA-seq) to spatially map RNA expression of all genes in brain tissue from lab mice at three different ages–4 weeks old, 24 weeks old, and 90 weeks old. They found that many inflammation-related genes were more highly expressed in the oldest mouse brains, particularly in non-neuronal cells that support neurons or provide immune surveillance. Their results appear this week in a paper in Cell and a preprint on BioRxiv.
“We discovered that specific types of non-neuronal cells that are important for the maintenance of brain function became inflamed over time, and that these changes were particularly concentrated in the brain’s white matter (where the connections between different brain regions are) and were less pronounced within the brain’s gray matter (where the neurons are),” Allen explains.”This suggests a new avenue to look for the causes of cognitive decline and other deficits in brain function with age – for example, looking less at the neurons themselves and more at the cells that support neuronal function or their connectivity.”
The study marks an important technical accomplishment, as applying cell atlas strategies to questions about how tissues change over time requires advanced imaging and computational techniques. “The pairing of MERFISH and snRNA-seq allowed us to spatially map the expression of all genes in the mouse genome at single-cell resolution in an intact slice of mouse brain tissue,” Allen says. “Using only MERFISH would have limited us to the genes that are included in the selected gene panels, whereas using only snRNA-seq would give us genome-wide expression information but with no spatial information.”
Many of the inflammation-related genes that were highly expressed in the aged mouse brains turned up in glial and immune cells within the corpus callosum, which connects the right and left sides of the brain. Although previous studies have found correlations between inflammation and cognitive decline, this study did not delve into how transcriptomic changes affect cognition or cell function. Allen says that exploring how inflammation in the white matter, where the glial cells are concentrated, affects cognition and figuring out the mechanisms that trigger this aging-related inflammation would be good questions for future projects.
“We only measured RNAs, so there may be changes in subcellular protein localization or structure that we are missing,” he says. “We also did not connect any changes in gene expression with changes in cell function, electrophysiological activity, or cognitive behavior, which would be useful for a future study.”