Despite significant advances in neuroscience, we are far from knowing what each neuron in the human brain does and looks like. New research, however, brings us closer to such encyclopedic knowledge.
Using molecular methods, researchers from the Salk Institute for Biological Studies in La Jolla, CA – in collaboration with the University of California (UC), San Diego – were able to map the individual differences in neurons to an unprecedented level of detail.
The team was jointly led by Joseph Ecker, director of Salk’s Genomic Analysis Laboratory, Margarita Behrens, senior staff scientist at the Salk Institute, and Eran Mukamel, of the UC San Diego Department of Cognitive Science. Their findings were published in the journal Science.
The first authors of the study are Chongyuan Luo, a research associate at the Salk Institute, and Christopher Keown, who is a cognitive science graduate student at UC San Diego.
Luo and colleagues examined neurons in both a mouse brain and a human brain. Previous efforts of single-cell identification have centered around an mRNA analysis, but, the researchers explain, RNA can change under the influence of the environment.
DNA methylomes, on the other hand, tend to be stable throughout adulthood, so the researchers decided to use these instead for neuron identification.
DNA methylomes are the result of the DNA methylation process – that is, the addition of methyl groups to the bases of a DNA molecule, which leads to epigenetic changes.
During epigenetic changes, the expression of the gene is altered – meaning that it can be “turned on” or “turned off” – but the genetic sequence, or its code, does not change.
The researchers used a single-cell methylome sequencing protocol they developed for the study and applied it to the brain cells in the frontal cortex of a young adult mouse and a young adult human.
They applied the sequencing protocol to a total of 3,377 mouse neurons (generating methylomes and covering 4.7 percent of the mouse genome), and 2,784 human neurons (covering 5.7 percent of the human genome).
Brain cells have two types of methylation as opposed to other types of cell that only have one, and the researchers mapped both types.
In total, the scientists cataloged epigenetic changes in more than 6,000 brain cells – the equivalent of a trillion DNA bases.
Based on the methylation patterns, the researchers were able to group the mouse neurons into 16 subtypes, and the human ones into 21 subtypes. The scientists also defined new subtypes of human neurons.
Significantly, the researchers found that the methylation patterns of the inhibitory neurons were more similar between mice and humans than those of the excitatory brain cells. This suggests that inhibitory neurons are particularly important, and that there may have been an evolutionary reason for preserving roughly the same patterns for these neurons.
The authors spoke to Medical News Today about the significance of their findings, saying, “Our study, for the first time, examined neuron diversity of human[s] and [mice] using a uniform technical platform.”
“We are excited by the observation that [the] human brain shows greater neuron type diversity than [the] mouse brain, which is consistent with more elaborate cortical functions in humans,” they added.
The researchers also spoke to MNT about the clinical implications of their findings.
“For many psychiatric diseases such as autism or schizophrenia, the exact cell types responsible for the disease remain elusive. Most previous studies were not able to separate cell types […] The method that we have developed extends the resolution to the single cell level, potentially allowing [us] to pinpoint cell types playing a causal role in neurological diseases.”
“Our study allows the identification of neuron subtype specific gene regulatory regions, and thus will help in interpreting genetic variants associated with neurological disorders,” the team added.
The main strength of the new research is, according to the authors, “the unique advantage of revealing how genes are being regulated in each neuron type,” which is made possible by characterizing the epigenomes of individual neurons.
The researchers also shared with us their plans for future research, saying, “Although we only analyzed one brain area in the current study (frontal cortex) we are excited to now begin applying this method to the entire mouse brain, and eventually to [the] whole human brain, both normal and diseased.”