The basal ganglia are small structures located deep in the centre of the human brain, together no larger than two grapes, yet essential for voluntary movement, decision-making, habit formation and emotions. The new atlas is the latest achievement of the BRAIN Initiative, a U.S. research program launched in 2014 that has so far received roughly $750 million in funding, and is the latest step toward a comprehensive catalogue of every cell type in the human brain, a universe containing more than 85 billion neurons and trillions of connections.
"A diagnosis of schizophrenia or bipolar disorder remains a devastating lifelong sentence; people with neurodegenerative diseases also suffer enormously and, sadly, die prematurely because of them," said Evan Macosko, associate professor of psychiatry and neurobiology at Harvard Medical School and a co-author of the new map. "This region of the brain is the main hub for brain diseases in both areas."
The researchers profiled 21 million cells from human brains, three million from cynomolgus macaques and 1.5 million from marmosets. The atlas examines not only which genes are active in each cell but also the epigenetic mechanisms that regulate them, cellular morphology, their precise spatial coordinates within the brain and their electrical activity.
The researchers identified a previously unknown brain cell type linked to schizophrenia and bipolar disorder. The study highlights the importance of a rare neuronal subtype that expresses the serotonin receptor HTR7 and is associated with an elevated risk of schizophrenia. The findings make it possible to trace the disorder's genetic signals back to specific cells, potentially improving research into the disease and, in the future, enabling more targeted treatments.
Another study in the collection describes a new version of an existing gene therapy that reduces the tremors characteristic of Parkinson's disease. In animal models, the approach proved more effective and less invasive than treatments currently used in patients. A study led by researchers at the University of California, San Francisco identified significant genetic changes in specific cell types within the basal ganglia that may play a role in autism.
Several papers focus on how the brain changes with age. Scientists at the Broad Institute discovered widespread age-related changes in gene expression that affect different cell types in distinct ways, making it possible to predict a person's age from gene-expression patterns across multiple types of brain cells.
Another study reveals that the proportions of different cell types in the striatum, the largest structure within the basal ganglia, vary considerably between individuals. Researchers performed single-nucleus RNA sequencing on four million cells from the striatum and prefrontal cortex of nearly 200 deceased adults. While relative proportions of cell types remain fairly consistent across different brain regions within the same person, cellular composition varies markedly between individuals. The researchers also identified age-related changes across all brain regions studied. For example, the abundance of oligodendrocyte progenitor cells declines by about 40% between the ages of 30 and 80.
Spanish neurobiologist Rafael Yuste of Columbia University in New York, one of the architects of the BRAIN Initiative, said this atlas is the most comprehensive produced under the project, with a larger consortium than on previous occasions. He described identifying every cell type in the human brain as the dream of Santiago Ramón y Cajal, the Spanish scientist who won the 1906 Nobel Prize for uncovering that the brain is built from distinct types of neurons, part of whose pioneering work focused on the striatum.
Biologist Ana Belén Muñoz Manchado from the University of Cádiz in Spain said the basal ganglia are one of those structures where neurology and psychiatry turn out to be looking at the same circuit. She said the value of the atlas is not only in the cellular census but also in the infrastructure: until now each laboratory named cell types in its own way, making comparisons between studies extremely difficult. The new atlas establishes a common language, with the same cell type receiving the same designation in humans, macaques, marmosets and mice. She said that for the first time, researchers now have the technology and tools to answer questions about the nervous system that have been unanswered for decades.