Key brain area reveals distinct zones whose boundaries blur with age

by Leah Eisenstadt, Broad Institute of MIT and Harvard

edited by Lisa Lock, reviewed by Robert Egan

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Scientists in the Center for Human Brain Variation at the Broad Institute have charted previously hidden architecture and patterns of cellular makeup in a key part of the brain called the striatum, which is involved in decision-making and movement and is affected in psychiatric disorders, addiction and neurodegeneration. The findings reveal six new zones within the striatum based on gene expression patterns. They also demonstrate how the zones' boundaries blur with age and highlight ways that advancing age and genetic variation affect gene expression in the brain.

The discoveries are from Broad-led studies that appear alongside two dozen other studies in Cell and related journals from hundreds of scientists in the BRAIN Initiative Cell Atlas Network (BICAN), a flagship project of the National Institutes of Health's BRAIN Initiative, which aims to build a detailed cellular map of the human brain.

"The findings of genomics and neuroscience over the last decade have uncovered incredible complexity in the brain that can seem overwhelming, but by identifying structures and organizing principles as we've done here, we can make sense of that complexity and its relevance to human health and disease," said Evan Macosko, study leader, core institute member and the Edward Scolnick Professor of the Broad Institute, and an associate professor of psychiatry at Massachusetts General Hospital and of neurobiology at Harvard Medical School.

Changing minds

With the goal of eventually mapping the whole human brain, BICAN researchers first set out to study the basal ganglia, a network of structures that regulate movement and behavior and influence many diseases and conditions.

In one of the new papers published in Cell, Broad scientists showed how cell-type proportions in the striatum, the largest structure in the basal ganglia, vary widely from person to person. With support from Broad Clinical Labs, they performed single-nucleus RNA sequencing on 4 million cells from the striatum and the prefrontal cortex of nearly 200 adult postmortem brains.

They found that while the balance of different cell types was consistent across an individual's brain tissues, cellular makeup varied significantly between people, especially for non-neuronal cells such as astrocytes and microglia. They also observed changes with age in all brain regions studied, with the abundance of one cell type known as oligodendrocyte progenitor cells declining by approximately 40% from age 30 to 80. In addition, patterns of gene expression changed with age in all cell types, with particularly large changes in projection neurons, which communicate with distant brain regions.

"By establishing common ranges for cell-type proportions and for gene expression, this work provides important context for studying disease," said co-first author Steven Burger, a computational scientist in the lab of Broad institute member and study leader Steve McCarroll, who is also a professor of biomedical science and genetics at Harvard Medical School.

In another study in Cell, Broad researchers employed Slide-tags, a spatial mapping method invented by Macosko and Broad core institute member Fei Chen that pinpoints the location of individual cells within tissues. Adapting Slide-tags to capture larger tissue areas, they analyzed more than 1 million cells across the striatum of 19 postmortem brains and identified six zones in which projection neurons exhibited distinct gene expression profiles within the striatum. Each zone appeared to express genes related to certain brain functions.

"We call it hidden histology because the cells in these zones all look the same under the microscope, but have very strong transcriptional differences and are strikingly consistent from person to person," said Macosko.

The team next explored the impact of aging on these six zones in more than 130 brains from the first study. They discovered that with increasing age, the zone boundaries began to blur, with less distinction in gene expression among zones.

In a third Broad-led effort, published in Cell Reports Methods, Mehrtash Babadi, Bing-Xing Huo and colleagues generated a new framework for integrating large single-cell datasets spanning multiple molecular modalities at the scale needed for a brain atlas. Their framework, multiVIB, brings together heterogeneous datasets while minimizing incorrect matches and preserving biologically meaningful variation. This provides a more reliable and scalable foundation for building comprehensive brain cell atlases that can continuously incorporate new data.

With complementary findings from other BICAN researchers using spatial, functional, epigenomic and other approaches, these studies demonstrate how cutting-edge methods such as Slide-tags that generate high-resolution data at scale can help chart and redefine what's known about a complex organ like the brain.

"This is just the start of the atlas," said Kiku Ichihara, managing director of the Center for Human Brain Variation at Broad and one of the studies' leaders. "Through BICAN, we will now use the tools and methods that we've been applying to the basal ganglia to continue on to the rest of the brain."

The researchers have shared their data and workflows openly for the studies on common variation and striatal zones, in addition to a portal for exploring the spatial datasets and common variation in gene expression, and they encourage other scientific groups to explore their results.

The multiVIB software and tutorials are freely available on GitHub and Zenodo, and the integrated datasets can be explored through Broad's Single Cell Portal.

Publication details

Steven C. Burger et al., Common variation of cell abundances and gene expression in the human striatum, Cell (2026). DOI: 10.1016/j.cell.2026.10.026

Andrew W. Kraft et al., Mesoscale molecular architecture of the striatum across cell types and adult aging, Cell (2026). DOI: 10.1016/j.cell.2026.10.029

Yang Xu et al., multiVIB: A unified probabilistic contrastive learning framework for atlas-scale integration of single-cell multi-omics data, Cell Reports Methods (2026). DOI: 10.1016/j.crmeth.2026.101664

Journal information: Cell Reports Methods , Cell

Key medical concepts

Corpus StriatumGene ExpressionAging

Clinical categories

Neurology Provided by Broad Institute of MIT and Harvard Who's behind this story?

Lisa Lock

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