By Will Dunham
WASHINGTON, Nov 12 (Reuters) - Scientists have assembled a cellular atlas of a crucial brain region called the basal ganglia involved in functions such as movement, decision making, emotions
and habit formation — an accomplishment that could help guide new treatments for several devastating diseases.
The researchers mapped the cell types and cellular gene activity in the basal ganglia, an interconnected set of structures deep within the brain, in humans as well as in mice and in macaque and marmoset monkeys. Basal ganglia dysfunction is associated with conditions such as Parkinson's disease, Huntington's disease, schizophrenia, Tourette's syndrome, bipolar disorder, obsessive-compulsive disorder and addiction.
"It is important to understand the structure and function of the basal ganglia in order to develop effective treatments of these diseases," said neuroscientist Hongkui Zeng, director of brain science at the Allen Institute in Seattle and one of the leaders of the research presented in more than two dozen studies published on Thursday in Cell and related journals.
"It is a major milestone in our journey toward a comprehensive, detailed, multimodal, cross-species aligned cell atlas for the entire human brain," with a target date sometime in 2028, Zeng added.
The research was conducted as part of the BRAIN Initiative, an effort launched in 2014 to advance the understanding of the brain with the support of the US National Institutes of Health. The work presented on Thursday offers the first comprehensive cross-species cellular roadmap for any brain region.
"Until now, there was no reference describing each cell type in the human basal ganglia together with how it regulates its genes," said Joseph Ecker, a molecular biologist and geneticist at the Salk Institute in La Jolla, California, another of the research leaders.
"In the near term, the atlas is 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. Over the longer term, the atlas can help identify cell-type-specific targets for gene therapy and gene editing," Ecker said. "It also gives a baseline for comparing diseased tissue with healthy tissue."
Therapies built on the new work are still years away, Ecker said.
Among other findings, researchers identified a new type of brain cell associated with schizophrenia and bipolar disorder, documented genetic changes in specific cell types that could play a role in autism, and discovered changes in gene activity in certain cells associated with aging.
CROSS-SPECIES COMPARISONS
Using brain tissue from deceased human donors, the researchers examined the role of 21 million cells in the basal ganglia in people, as well as millions more cells in the three other species.
"Understanding the cellular composition of this brain structure across species will allow for comparative analyses of function as well as connectivity patterns and response to pharmacological interventions," said Salk Institute neuroscientist and biochemist Margarita Behrens, another of the research leaders.
Many studies for ethical reasons cannot be performed using living human brains. Much of what was previously known about the basal ganglia, and most early testing of new treatments, had come from research involving mice and monkeys.
"We rely on animal models to probe the inner workings of brain cells and circuits in generating brain function and mediating disease effects, and to test the efficacies of therapeutic interventions," Zeng said.
The structures of the basal ganglia include the striatum, globus pallidus and substantia nigra.
"Together they help select and start movements, and they support habit formation, reward learning, motivation and emotion," Ecker said.
The atlas combines several layers of data. One shows which genes are switched on in each cell. Another involves the epigenome, a collection of chemical compounds and proteins that attach to the DNA and regulate gene activity. A third layer involves spatial maps showing where each cell type sits in the tissue of the basal ganglia.
"Most of the DNA variants linked to brain disorders lie outside the protein-coding parts of genes. Many of them sit in DNA 'switches' that control when and where genes turn on, and those switches are often active only in particular cell types," Ecker said.
The protein-coding parts of genes carry genetic instructions used to build proteins, the complex molecules that perform most of the critical work inside cells.
An atlas like this one 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.
(Reporting by Will Dunham; Editing by Daniel Wallis)
