A team of scientists at The Scripps Research Institute (TSRI), University of California, San Diego (UC San Diego) and Illumina, Inc., has completed the first large-scale assessment of single neuronal “transcriptomes.” Their research reveals a surprising diversity in the molecules that human brain cells use in transcribing genetic information from DNA to RNA and producing proteins. The researchers accomplished this feat by isolating and analyzing single-neuronal nuclei from the human brain, allowing classification of 16 neuronal subtypes in the brain's cerebral cortex, the “gray matter” involved in thought, cognition and many other functions. “Through a wonderful scientific collaboration, we found an enormous amount of transcriptomic diversity from cell to cell that will be relevant to understanding the normal brain and its diseases such as Alzheimer's, Parkinson's, ALS and depression,” said TSRI Professor and neuroscientist Jerold Chun, who co-led the study with bioengineers Kun Zhang and Wei Wang of UC San Diego and Jian-Bing Fan of Illumina. The study was published on June 24 in the journal Science.
All the Same
While parts of the cerebral cortex look different under a microscope—with different cell shapes and densities that form cortical layers and larger regions having functional roles called “Brodmann Areas”—most researchers treat neurons as a fairly uniform group in their studies. “From a tiny brain sample, researchers often make assumptions that obtained information is true for the entire brain,” said Chun. But the brain isn't like other organs, Chun explained. There's a growing understanding that individual brain cells are unique, and a possibility has been that the microscopic differences among cerebral cortical areas may also reflect unique transcriptomic differences—i.e., differences in the expressed genes, or messenger RNAs (mRNAs), which carry copies of the DNA code outside the nucleus and determine which proteins the cell makes. To better understand this diversity, the researchers in the new study analyzed more than 3,200 single human neurons—more than 10-fold greater than prior publications—in six Brodmann Areas of one human cerebral cortex. With the help of newly developed tools to isolate and sequence individual cell nuclei (where genetic material is housed in a cell), the researchers deciphered the minute quantities of mRNA within each nucleus, revealing that various combinations of the 16 subtypes tended to cluster in cortical layers and Brodmann Areas, helping explain why these regions look and function differently.