A New Atlas Reveals Dynamic Diversity of Brain Astrocytes Across Development and Species

A new atlas comprehensively maps the remarkable diversity of astrocytes, a crucial non-neuronal cell type, across the brains of mice and marmosets. While neurons often receive the most attention in discussions of brain function, healthy brain activity fundamentally relies on the intricate cooperation of various cell types. Astrocytes, the most abundant non-neuronal cells, are star-shaped and bear a multitude of responsibilities, including shaping neural circuits, participating in information processing, and providing vital nutrient and metabolic support to neurons. These individual cells exhibit dynamic roles throughout their lifespan, with astrocytes in one brain region often differing in appearance and behavior from those elsewhere.

Researchers at MIT have now provided neuroscientists with an exhaustive atlas detailing this dynamic diversity of astrocytes. The maps within this atlas illustrate the regional specialization of astrocytes across the brains of both mice and marmosets—two critical models in neuroscience research—and chart how their populations evolve during brain development, maturation, and aging.

This open-access study, published in the November 20 issue of Neuron, was led by Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences at MIT. Support for this pioneering work came from the Hock E. Tan and K. Lisa Yang Center for Autism Research, part of the Yang Tan Collective at MIT, and the National Institutes of Health’s BRAIN Initiative.

"It's crucial for us to acknowledge the role of non-neuronal cells in both health and disease," states Professor Feng, who also serves as the associate director of the McGovern Institute for Brain Research and director of the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT. Once considered mere supporting players, these cells have recently garnered increasing recognition. Astrocytes are known to be integral to brain development and function, with their dysfunction implicated in numerous psychiatric and neurodegenerative disorders. Feng notes, "Compared to neurons, our understanding, especially regarding their development, is significantly less."

Probing the Unknown

Professor Feng and Margaret Schroeder, a former graduate student in his lab, identified the critical need to understand astrocyte diversity across three dimensions: space, time, and species. Prior research from their lab, in collaboration with Steve McCarroll’s lab at Harvard University and led by Fenna Krienen, had already established that adult animals possess distinct sets of astrocytes in different brain regions.

Schroeder posed the natural next question: "How early in development does this regional patterning of astrocytes begin?"

To investigate, Schroeder and her team collected brain cells from mice and marmosets at six distinct life stages, spanning from embryonic development through old age. For each animal, cells were sampled from four specific brain regions: the prefrontal cortex, motor cortex, striatum, and thalamus.

Subsequently, working with Fenna Krienen, now an assistant professor at Princeton University, they conducted a molecular analysis of these cells. This involved creating a genetic activity profile for each cell based on its transcriptome—the collective mRNA copies of genes present. By determining which genes a cell utilizes and their activity levels, researchers gain insight into the cell's function and identity.

Dynamic Diversity

After analyzing approximately 1.4 million brain cell transcriptomes, the research group concentrated on astrocytes, comparing their gene expression patterns. The team discovered regional specialization at every life stage, from pre-birth to senescence: astrocytes from different brain regions consistently displayed similar gene expression patterns that were distinct from those of astrocytes in other areas.

This regional specialization was further evidenced by the distinct morphological characteristics of astrocytes in various brain parts, visualized using expansion microscopy. This high-resolution imaging technique, developed by McGovern colleague Edward Boyden, enables the visualization of fine cellular features.

Remarkably, astrocytes within each region transformed as the animals matured. Schroeder observed, "At our late embryonic time point, astrocytes were already regionally patterned. However, when compared to adult profiles, they had completely shifted again. This indicates significant changes occurring during postnatal development." The most pronounced alterations were detected between birth and early adolescence, a period of rapid brain rewiring as animals engage with their environment and acquire new experiences.

Feng and Schroeder hypothesize that these observed changes might be driven by the neural circuits sculpted and refined during brain maturation. Schroeder suggests, "We believe they are adapting to their local neuronal niche. The types of genes they up-regulate and modify during development point to their interactions with neurons." Feng added that astrocytes could alter their genetic programs in response to adjacent neurons, or alternatively, they might actively direct the development or function of local circuits by adopting identities optimally suited to support specific neurons.

Both mouse and marmoset brains exhibited regional astrocyte specialization and temporal shifts in these populations. However, when researchers examined the specific genes defining various astrocyte populations, data between the two species diverged. Schroeder highlighted this as a crucial caution for scientists studying astrocytes in animal models, noting that the new atlas will assist researchers in evaluating the potential cross-species relevance of their findings.

Beyond Astrocytes

With this enhanced understanding of astrocyte diversity, Professor Feng's team intends to meticulously investigate how these cells are affected by disease-related genes and how these effects evolve during development. He also points out that the gene expression data within the atlas can facilitate predictions about astrocyte-neuron interactions. "This will profoundly guide future experiments, revealing how these cellular interactions can shift with changes in either neurons or astrocytes," he concludes.

The Feng lab is keen for other researchers to utilize the vast dataset generated during the atlas's creation. Schroeder emphasizes that the team analyzed transcriptomes of all cell types within the studied brain regions, not just astrocytes. By openly sharing their findings, researchers can leverage this data to understand the spatiotemporal expression of specific genes in the brain or to delve deeper into exploring the brain's cellular diversity.