Scientists create a cellular atlas for the basal ganglia

Scientists have assembled a cellular atlas of a crucial brain region called the basal ganglia involved in functions such as movement, decisionmaking, 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, mice, and 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 Zeng Hongkui (曾?葵), director of brain science at the Allen Institute in Seattle and one of the leaders of the research.

Their work 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 added.

Researchers also 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.

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.

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.