New atlas traces how key human brain cells develop before and after birth

Scientists have long known that many developing brain cells originate in one region and migrate to another as they mature. But tracing the molecular changes that occur along that journey has been difficult, in part because some of the temporary prenatal brain structures that give rise to these cells largely disappear around birth.

One important destination for these developing cells is the basal ganglia, a group of interconnected structures deep in the brain that help control movement, habits, reward and behavior. This region is also implicated in conditions including Parkinson’s disease, Huntington’s disease, addiction, obsessive-compulsive disorder and schizophrenia.

Now, in a study published in Cell, a UCLA co-led research team has mapped this developmental process in unprecedented molecular detail, tracing how cells in and around the basal ganglia change from mid-pregnancy through infancy.

The research is part of the National Institutes of Health’s BRAIN Initiative Cell Atlas Network (BICAN), a collaborative effort among neuroscientists, computational biologists and software engineers to create a comprehensive atlas, or “parts list,” of the human brain. By providing a common reference, BICAN aims to help scientists understand how the brain develops and which cells may be involved in neurological and psychiatric conditions.

Unlike many brain cell atlases that focus mainly on which genes are active, this study examined the molecular controls that help determine when and where genes are used, as well as how DNA is organized inside cells. That added layer of information can help researchers connect genetic risk for disease to particular cell types and stages of brain development. 

“Genetic studies can tell us that particular regions of the genome are associated with disease, but they often can’t tell us which cell type is affected or when during development that genetic risk becomes relevant,” said co-senior author Chongyuan Luo, an associate professor of human genetics at the David Geffen School of Medicine at UCLA and member of the UCLA Broad Stem Cell Research Center. “This atlas gives us that cellular and developmental context.” 

Following cells from where they begin

A key focus of the study was the ganglionic eminences, temporary structures in the prenatal brain that give rise to many inhibitory neurons — cells that help regulate activity in brain circuits — including some that later migrate into the basal ganglia.

“Because these structures disappear around birth, adult brain studies miss an important early part of these neurons’ development,” said co-first author Matthew Heffel, a former doctoral student in the Luo lab. “By sampling them directly, we can compare cells near where they originate with related cells after they have migrated to other parts of the brain.”

Left to right: Mohammad Baig, Felicia Codrea, Joonho Kum, Matthew Heffel, Chongyuan Luo, Yi Zhang and Jason Ernst. | Credit: Tiare Dunlap, UCLA Broad Stem Cell Research Center

Using a technology co-developed by Luo’s laboratory called single-nucleus methyl-3C sequencing, or snm3C-seq, the researchers compared how these and other cell populations changed across development, examining both DNA methylation and 3D organization of DNA inside individual cell nuclei.

The team analyzed more than 155,000 individual cell nuclei from nine developing human brains, capturing molecular information about how their DNA was regulated and organized from mid-pregnancy through seven months after birth. Combined with previously collected developmental and adult data, the analysis encompassed nearly 287,000 cells.

The expanded dataset revealed that cells arising from different parts of the ganglionic eminences matured on markedly different schedules. Some populations appeared relatively mature by mid-pregnancy, while others continued producing immature neurons into infancy.     

One population stood out: spiny projection neurons, a major type of neuron in the basal ganglia. Compared with other developing neurons, these cells matured in an unusually coordinated way. Some also showed signs of neuronal activity as early as mid-pregnancy, suggesting they may begin contributing to the formation of basal ganglia circuits relatively early in development.

Watching the genome reorganize

The atlas also revealed unexpected changes after birth in oligodendrocytes, support cells that produce myelin, the insulating material that helps nerve fibers transmit signals efficiently.

As immature oligodendrocyte progenitor cells transitioned toward mature oligodendrocytes, their DNA temporarily shifted into a different 3D configuration. That state was associated with greater gene activity, suggesting that genome organization may be closely tied to the molecular changes required for these cells to mature. Further studies will be needed to determine whether the change in DNA organization helps drive that process.   

Finally, the researchers combined their atlas with results from large genetic studies of psychiatric disorders to investigate which developing cell populations were most closely associated with inherited disease risk.

Spiny projection neurons showed particularly strong enrichment for genetic variants associated with schizophrenia, with some subtypes also showing associations with bipolar disorder.     

The study examined typically developing brains, not tissue from people with schizophrenia, and does not show that these cells cause the disorder. Instead, the atlas gives scientists a more precise framework for investigating which cells may be most relevant and when during development disease-associated genetic differences may matter most.

Co-senior author Jason Ernst emphasized the atlas’s potential value for future disease research. 

“Researchers can compare what they see in patients or disease models with typical development to identify the cell types and molecular features that may be most relevant to disease,” said Ernst, a UCLA professor of biological chemistry, computer science and computational medicine, and also a member of the stem cell center.

The study was co-led by Dr. Mercedes Paredes of UC San Francisco and Eran Mukamel of UC San Diego and was funded by the NIH, with additional support from the Chan Zuckerberg Initiative.