Basal Ganglia Cellular Atlas Maps Cells Across Four Species, Including 21 Million Human Cells

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Scientists have assembled the first comprehensive cross-species cellular atlas of the basal ganglia, a set of interconnected brain structures involved in movement, decision-making, emotions and habit formation. The research, led by neuroscientist Hongkui Zeng of the Allen Institute in Seattle and molecular biologist Joseph Ecker of the Salk Institute, was presented in more than two dozen studies published on Thursday in Cell and related journals. The atlas covers humans, mice, macaques and marmosets, and is part of the BRAIN Initiative launched in 2014 with support from the US National Institutes of Health.

Using brain tissue from deceased human donors, the researchers examined 21 million cells in the human basal ganglia, along with millions more cells from the other three species. The atlas combines three layers of data: which genes are switched on in each cell, the epigenome—chemical compounds and proteins that regulate gene activity—and spatial maps showing where each cell type sits in the tissue. Among the findings, researchers identified a new type of brain cell associated with schizophrenia and bipolar disorder, documented cell-specific genetic changes that could play a role in autism, and discovered changes in gene activity in certain cells linked to aging.

The atlas is intended as a reference resource for researchers. “We are studying a Parkinson’s gene and can now see which cell types turn that gene on, and which DNA switches are active in those cells,” Ecker said. He added that over the longer term the atlas could help identify cell-type-specific targets for gene therapy and gene editing, and provide a baseline for comparing diseased tissue with healthy tissue. Therapies built on the new work are still years away, Ecker said. A comprehensive, cross-species aligned atlas for the entire human brain is targeted for 2028, Zeng said.

What is the basal ganglia and why does it matter?

The basal ganglia are a group of interconnected structures deep within the brain, including the striatum, globus pallidus and substantia nigra. They help select and start movements, support habit formation, reward learning, motivation and emotion. Dysfunction in the basal ganglia is associated with Parkinson’s disease, Huntington’s disease, schizophrenia, Tourette’s syndrome, bipolar disorder, obsessive-compulsive disorder and addiction. Much of what was previously known about the region, and most early testing of new treatments, came from research involving mice and monkeys, because many studies cannot ethically use living human brains.

How does the atlas help trace disease mechanisms?

Most DNA variants linked to brain disorders lie outside the protein-coding parts of genes, often in DNA 'switches' that control when and where genes turn on, and those switches are often active only in particular cell types. The atlas helps trace a disease-risk DNA variant to the specific kind of nerve cell or support cell where it acts. “That is a first step toward understanding how the variant contributes to disease, and eventually toward treating it,” Ecker said. The atlas also provides a healthy-tissue baseline for comparing with diseased tissue.

What are the next steps and the timeline for a full brain atlas?

The atlas may help researchers identify cell-type-specific targets for gene therapy and gene editing, but such applications require further research and therapies remain years away, Ecker said. The work is part of a broader effort toward a comprehensive, detailed, multimodal, cross-species aligned cell atlas for the entire human brain, with a target date of 2028, Zeng said.