Scientists create largest-ever map of brain region tied to Parkinson’s, Alzheimer’s, schizophrenia and autism

If you are reading this article, it is because your basal ganglia have allowed you to do so. These small structures, located deep in the center of the human brain, are together no larger than two grapes, yet they are essential for voluntary movement, decision-making, habit formation and emotions. This compact control hub is also implicated in a wide range of neurological and psychiatric disorders, including Parkinson’s disease, Alzheimer’s disease, autism, schizophrenia and addiction.It is the ideal place to begin mapping the human brain in unprecedented detail. And that is precisely what a large international consortium of scientists from nine countries has done in research published on Thursday: the first cell-by-cell atlas of the human basal ganglia, accompanied by comparable maps of three other mammals: macaques, marmosets and mice. The study represents the most comprehensive cross-species map ever produced of this brain region, and its authors hope it will shed light on both normal brain function and the many disorders that affect it.One of neuroscience’s greatest ambitions is to better understand mental illness by identifying which cells, in which parts of the brain, are involved in each disorder. This new atlas is the most extensive catalog of cell types in the basal ganglia to date and marks an important step toward a future comprehensive map of every cell type in the human brain, a universe containing more than 85 billion neurons and trillions of connections between them.“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,” says 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 25.5 million cells from human brains (21 million), cynomolgus macaques (three million) and marmosets (1.5 million). The findings were published on Thursday in a collection of 26 papers across journals in the Cell group.The new atlas builds on previous maps of the human cerebral cortex and an earlier draft atlas of the entire human brain. Its major innovation is that it 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 atlas is the latest achievement of the BRAIN Initiative, a major U.S. research program launched in 2014 that has so far received roughly $750 million in funding. Its ultimate goal is to produce a comprehensive catalogue of every cell type in the human brain.“To understand what is truly happening in the brain, we need an accurate list of cell types and to study gene expression in each of them,” explains Hongkui Zeng, executive vice president and director of neuroscience at the Allen Institute, one of the main organizations behind the project, in a press release. The new atlas involved hundreds of scientists from nine countries and 50 academic institutions.The researchers also 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 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. The findings could pave the way for new treatments and a deeper understanding of the disorder.Several of the papers focus on how the brain changes with age and how those changes can be used to measure the organ’s aging process. Scientists at the Broad Institute discovered widespread age-related changes in gene expression that affect different cell types in distinct ways. Their findings make it possible to predict a person’s age from gene-expression patterns across multiple types of brain cells.Another study shows that the proportions of different cell types in the striatum, the largest structure within the basal ganglia, vary considerably from one individual to another. Researchers performed single-nucleus RNA sequencing on four million cells from the striatum and prefrontal cortex of nearly 200 deceased adults. The results revealed that while the relative proportions of cell types remain fairly consistent across different brain regions within the same person, cellular composition varies markedly between individuals.These differences were especially pronounced in non-neuronal cells such as astrocytes and microglia. 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 was one of the architects of the BRAIN Initiative. He notes that while other brain atlases have previously been produced under the project, this one is “the most comprehensive, and the consortium behind it is larger than on previous occasions.” Yuste emphasizes the importance of identifying every cell type in the human brain, a goal that he describes as “the dream of Santiago Ramón y Cajal,” in reference to the Spanish scientist who was awarded the 1906 Nobel Prize in Physiology or Medicine for uncovering the structure of the brain and the rest of the nervous system, showing that they are built from distinct types of neurons. Part of his pioneering work focused on the striatum, the largest structure within the basal ganglia.“The basal ganglia are a complex part of the brain, with extraordinarily intricate neuronal circuitry that is still poorly understood,” Yuste says by email. “Despite this, they have a vital role in our behavior, possibly selecting the actions we want to take and suppressing others, and injecting dopamine into other parts of the brain to mediate behavioral changes.” Biologist Ana Belén Muñoz Manchado, from the University of Cádiz in Spain, explains that the basal ganglia are “one of those structures where neurology and psychiatry, which we usually treat as separate fields, turn out to be looking at the same circuit.” She adds that “the value of this atlas is not only in the cellular census, although that is important, but also in the infrastructure.” According to Muñoz Manchado, until now each laboratory named cell types in its own way, making comparisons between studies extremely difficult. The new atlas establishes a common language: the same cell type receives the same designation in humans, macaques, marmosets and mice. It also provides multiple layers of information about each cell type, making identification easier for other labs. “For the first time,” she concludes, ”we are at a moment when we have the technology and tools capable of answering questions about the nervous system that have been unanswered for decades.” Sign up for our weekly newsletter to get more English-language news coverage from EL PAÍS USA Edition