Parkinson’s disease, Huntington’s disease, schizophrenia, bipolar disorder, and addiction are all crippling conditions with genetic and molecular ties to the basal ganglia, an interconnected set of structures deep within the brain that are critical for movement, habit formation, decision making, and emotion.  

Today, in a massive, collaborative effort, dozens of labs and hundreds of scientists working together across nine countries and more than 50 institutions have unveiled a major advance in global neuroscience: the most detailed and comprehensive multi-species cellular atlas of the basal ganglia to date—an expansive library of brain cell types and datasets across human, macaque, marmoset, and mouse that serves as a powerful tool for understanding brain cells and what they do.

Using advanced single-cell molecular profiling technologies that measure the genetic expression of individual cells, researchers profiled 25.5 million of them from the brains of humans (21.0 million cells), rhesus and cynomolgus macaques (3.0 million cells), and marmosets (1.5 million cells). Their findings were published today in a package of 26 studies in the Cell Press family of journals. The massive body of work represents the first major working model of a standardized, cross-species brain cell reference atlas.  

“I’m very excited about the package because it’s a demonstration of the power of team science and open science, people working together and creating a common standard for the field and using that to amplify the impact that we can make,” said Hongkui Zeng, executive vice president and director of Brain Science at the Allen Institute. “Disease conditions are always cell-type-specific, so in order to understand what’s really going on in the brain, you have to have an accurate cell-type list and examine individual gene expression in each cell type.”

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“I’m very excited about the package because it’s a demonstration of the power of team science and open science, people working together and creating a common standard for the field and using that to amplify the impact that we can make,” said Hongkui Zeng, executive vice president and director of Brain Science at the Allen Institute. “Disease conditions are always cell-type-specific, so in order to understand what’s really going on in the brain, you have to have an accurate cell-type list and examine individual gene expression in each cell type.”

The atlas is also the first major output in the ongoing work of the BRAIN Initiative Cell Atlas Network (BICAN), which is working to produce a complete parts list—an atlas of all the cell types in the entire human brain—something that is within reach thanks to this first major milestone.

“It’s the sum output that really differentiates this set of studies. We have coordinated studies looking at cellular organization from the perspective of gene expression, that is, transcriptomics. We have studies looking from the perspective of epigenetic regulation, spatial analyses, analyses of morphological and physiological properties of cells,” said Ed Lein, executive vice president and director of Brain Health at the Allen Institute. “All of them largely agree with one another. This molecular classification works across different data types and labs. That really gives us confidence that this gets to the ground truth of the organization of the brain. This was designed as the template for the whole brain, and it has set the paradigm for doing the entire brain.”

key findings/

Among the 26 studies that are part of the package, several key findings stand out:

• In one study, researchers discovered a new type of brain cell, STR D2 SMYD2-HTR7, that is tied to schizophrenia and bipolar disorder. "Schizophrenia has been associated with the striatum, but it has been difficult to define which neurons are vulnerable,” said Nelson Johansen, study author and assistant investigator at the Allen Institute. “Our study revealed a rare neuron type expressing the serotonin receptor HTR7 that was not found in previous studies, which carries elevated schizophrenia risk. This atlas narrows the genetic disease signal down to a specific population that researchers can now explore.”

• In another study, scientists successfully developed a new, “smarter” version of an existing gene therapy that reduces the hallmark tremors associated with Parkinson’s disease. The new approach was both more effective in animal models and less invasive (therefore more scalable) than current treatment approaches given to humans.

• A study led by researchers at the University of California, San Francisco revealed key genetic changes in specific cell types of the basal ganglia that could play a role in autism. This new insight has the potential to lead to new treatments and a deeper understanding of this neurological condition.

• Scientists at the Broad Institute discovered widespread, cell-type-specific changes in gene expression associated with aging. Remarkably, an individual's age can be predicted from gene expression patterns across multiple cell types—a potential foundation for biological aging clocks based on brain cells.

The work is funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, the BRAIN Initiative®, as part of its mission to unravel and understand the functional and cellular complexity of the human brain in service of human health.

“The BICAN basal ganglia atlas will have enormous impact on the way we understand basic brain function and the cellular underpinnings of devastating neurologic, neuropsychiatric, and substance use disorders—a major goal of the NIH BRAIN Initiative,” said John Ngai, director of the BRAIN Initiative. “This monumental achievement is a testament to the power of team science and the determination of the hundreds of dedicated researchers comprising the BICAN consortium.”

developing a common language for neuroscience/

Notably, this was the first time a common reference system was used to classify and analyze the brain’s incredible complexity, allowing for deeper insights. “This community worked together to develop a common description of cell populations, and then everybody used it. We hope this will be a framework for the entire field,” said Lein. “Here for the first time, all the studies in the package used the same cellular framework. That’s what we’re now trying to expand to the whole brain, making a reference in the spirit of the human genome that can unify the community and accelerate progress.”

“Despite how much progress medical science has made in so many different domains of human health—cancer, cardiovascular disease—we’ve really been stumped by brain disease. It continues to be the case that a diagnosis of schizophrenia or bipolar disorder is often a devastating, lifelong affliction. And similarly, people who have neurodegenerative disease often suffer enormously and unfortunately die early due to those diseases,” said Evan Macosko, associate professor of psychiatry and neurobiology at Harvard Medical School, core member of the Broad Institute of MIT and Harvard, and study author. “This area of the brain is the ‘grand central’ for disease in both of those different domains. And we really need to have a clear understanding of how these different brain areas function if we’re going to try and fix them. Our hope is that this basic map that we’ve laid out will be that template that many neuroscientists can build on to help them understand this complex and important structure.”

“The creation of the basal ganglia atlas is a great social engineering experiment. We have dozens of labs and hundreds of scientists working together from different angles, using different techniques. But ultimately, it's critical to integrate all the data together in a meaningful way,” said Zeng. “That integration requires scientists, engineers, and technicians to develop platforms. It requires people with different expertise from different disciplines working together to make this huge effort successful.”

All data and findings will be openly shared with the global scientific community to catalyze more research and discoveries that could advance human health beyond the basal ganglia.

“We’ve created a suite of tools for people to access this data, visualize the data, mine the data, and then map their own data onto that. As soon as you map into that system, you also take advantage of all the knowledge that we’ve aggregated about these cell types,” said Lein.

It is that open philosophy rooted in a collaborative, unified scientific framework that researchers hope will lead to further insights that will advance human health and our understanding and treatment of brain disease.

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