Laying the groundwork for a new understanding of the human brain

The brain is an immensely complex organ. Some 80 billion neurons form the trillions of connections that ultimately give rise to our every thought, memory, and behavior. It should come as no surprise that the neuroscience field is still working towards generating a comprehensive census of the brain — over 100 years after Ramon y Cajal documented the first neuronal cell types.

Charting this cellular atlas is a major goal of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a “grand challenge” put forth by the Obama White House in 2013. As one of the Initiative’s leading investigators, Salk Professor Dr. Joseph Ecker is working with the Center on developing integrated brain cell censuses for the BRAIN Initiative. “We rely heavily on Bing’s Center to produce cutting-edge data for the BRAIN Initiative,” Ecker said of the partnership. “They’ve been a major contributor to the NIH BICCN Project [BRAIN Initiative Cell Census Network] that has been charged with a cell-by-cell analysis of the mouse brain.”

“The BRAIN Initiative is like a layered cake,” Ecker explained, likening each layer to a different level of understanding of the brain. In this metaphor, the cellular census forms the first, most fundamental layer. The connectome, or how neurons are connected to one another, makes up the second layer. Above that is the activity of whole brain regions, which can be captured by functional imaging technologies like fMRI. Finally, artificial neural networks sit at the top, trying to recapitulate everything that is happening in the lower layers. “We’re working with the Center on the basal layer,” said Ecker.

The Center’s epigenomic and multi-omic analyses, which include single-cell analyses of open chromatin, histone modifications, and transcriptomes, complement existing neuronal censuses based solely on transcriptomics. Indeed, Ecker and the Center recently demonstrated in a publication that multiomic atlases can be used to pinpoint disease-relevant cell types with much better resolution than those built from transcriptomic data alone.

Ecker and the Center are also investigating the brains of other species, like nonhuman primates, to bridge the gap between the experimentally tractable mouse brain and the hard-to-study human brain. Not only is the human brain difficult to study for ethical reasons, it is also vastly more complex than the mouse brain. “To put it into perspective, the mouse brain has a thousand times fewer cells than the human brain,” Ecker said. Ecker also noted that individual variation in humans poses another obstacle to translating epigenomic analyses from mice to humans: “There are individual differences among mice, but not at all like those in humans.”

Asked what is next for his partnership with the Center, Ecker emphasized the challenge posed by human brain mapping. “We’re taking baby steps towards understanding how to approach studying the human brain.” Ultimately, he and the Center hope that new brain cell censuses will shed light on the specific brain cell types that cause human brain disorders like Alzheimer’s disease and schizophrenia.