NEW YORK – Researchers affiliated with the US National Institutes of Health's BRAIN Initiative Cell Atlas Network (BICAN) program have begun publishing the results of their efforts to establish an atlas of how neurotypical brains operate and age at the cellular level.
The Seattle-based Allen Institute recently unveiled its first major data release of single-cell and single-nucleus transcriptomic and epigenomic profiles from humans, mice, and 10 other mammalian species.
"One of the goals of BICAN is to create this reference atlas," said Shoaib Mufti, data and technology lead at the Allen Institute. "The long-term vision for us is to grow this knowledgebase into a 'one-stop shop' for all brain-related data and technology."
The release marks the first major data release from the BICAN program, which launched in 2022 supported by $500 million in grants. Mufti said that the effort that went into the current release provides a template for how to streamline the data acquisition and analysis process to make future releases more regular. The initiative hopes to release more data on a quarterly basis from now on, he said.
Mufti said that many of the tools and techniques used to compile the human brain atlas came from lessons learned in creating a complete mouse brain atlas, which the institute released in full last year. "We learned a lot through this mouse brain effort," Mufti said, "[but] the human brain is much more complex than that."
Mufti noted that next year the Allen Institute also hopes to release a map of the human basal ganglia, a group of structures near the center of the brain that allow different areas of the brain to work together.
Kiku Ichihara, director of research strategy and operations in the lab of Steve McCarroll, a BICAN-affiliated investigator at the Broad Institute, said that the basal ganglia is the initial focus of several BICAN-affiliated groups, including hers. The McCarroll lab, she said, contributed spatial and transcriptomic data from 20 brains to the dataset released through the Allen Institute.
"[Our] current data release is all from adults," she said. "We do have a developmental age component to our project, but it has been a challenge to obtain brains from younger donors."
Ichihara said that the McCarroll lab is primarily focused on inter-individual variation and hopes to eventually analyze roughly 200 brains using single-nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics. The McCarroll lab primarily gets its brains from the NIH Neurobiobank, but Ichihara said that they have also acquired some from the University of Washington's Brain Bank.
Although Ichihara said that the consortium members plan to publish a series of BICAN-related studies next year, some groups have already begun to publish papers describing their methodologies and early findings.
One example is that of an international group of BICAN researchers led by Joseph Ecker, director of the genomic analysis laboratory at the Salk Institute, in La Jolla, California, who published a study on how gene regulation evolves during the course of brain development. That study, published this week in Nature, details a map of DNA modification within the hippocampus and prefrontal cortex, two brain regions important in learning, memory, and regulating emotions. These regions are often implicated in neuropsychological disorders such as autism and schizophrenia, although their precise roles in these conditions remain poorly understood.
The team used single-nucleus methyl-3C sequencing (snm3C-seq3) to construct single-nucleus of chromatin conformation and DNA methylation. This sequencing method, developed in Ecker's lab, integrates in situ Hi-C with single-cell methylome profiling to enable the simultaneous capture of chromatin organization and DNA methylation.
Understanding how chromatin is folded within the nucleus enabled the investigators to better understand how pathogenic variants found in intergenic regions are able to exert regulatory influences on distal genes and in particular how errors in this process might lead to neuropsychological disorders.
By examining over 53,000 brain cells from donors across a range of ages that included mid-gestation through adulthood, the Salk Institute team uncovered numerous gene regulation changes that occurred during several critical developmental windows.
One such critical period appeared to occur around the midpoint of pregnancy, a developmental stage that the researchers wrote often goes overlooked due to the limited availability of corresponding brain tissue. During this period, they found that neural stem cells called radial glia switch from producing neurons to generating glial cells, which support and protect neurons. Also during this window, newly formed neurons mature and form the synaptic connections they need to communicate with other cells.
Ecker's group mapped the chromatin loops and differentially methylated regions (DMRs) identified in their study to schizophrenia-associated genetic loci and found 81 loci that contained at least one putative causal SNP overlapping either a DMR or chromatin loop-connected DMR, which correlated with the heritability of schizophrenia.
By evaluating the changes in these conformational patterns over development, the team also found that the genetic risk of schizophrenia and bipolar disorder more strongly affects post-mitotic neurons than the neuroprogenitor population in developing human brains.
"Our [three dimensional] epigenomic data generated from primary developing brain tissues provides a reference for the gene regulatory landscape and can be used for the benchmarking of neural organoid culture models," Chongyuan Luo, assistant professor of human genetics at UCLA and co-first author of the study, said via email.
Luo said that the group is currently expanding its effort to more brain regions and structures.
The BICAN initiative is now in its third year of a five-year grant period. Ichihara said that much of the first year was spent organizing the project and ensuring that none of the groups were repeating each other's work.
Both Ichihara and Mufti said BICAN researchers are looking forward to the possibility of reaching several milestones next year. In addition to the planned human basal ganglia map, for example, the Allen Institute also has been bringing together multiple research groups to publish a consensus atlas of the mouse brain, the results of which Mufti said the institute plans to announce next year.
Mufti also said that the BICAN program hopes to begin integrating its data with that of BRAIN Initiative Connectivity across Scales (CONNECTS), another NIH program that has been mapping connectivity patterns in human brains. This, he explained, will provide researchers with a resource enabling deeper insights into the mechanisms underlying neurological disorders such as Alzheimer's disease.
"We'll start to bring the connectivity data into it, hopefully early next year," Mufti said.