A study led by researchers at Seattle’s Allen Institute for Brain Science lays out a “parts list” for the brain, including a detailed look at the differences between the parts for human brains and mouse brains.
They say the genetic results, published today in the journal Nature, suggest that relying on mice to study how the brains of men and women work could lead neuroscientists down blind alleys.
“The answer may be that you have to go to species that are more similar to humans,” Ed Lein, an investigator at the Allen Institute who’s also affiliated with the University of Washington, told GeekWire.
It’s not that the basic parts list is all that different: The researchers found that most of the 75 different cell types identified in the human brain, based on genetic makeup, are found in the mouse brain as well.
That commonality applies even to cells that the scientists had previously thought might be uniquely human, such as the “rosehip neurons” discovered last year.
But there are significant differences in the way those genes are expressed — differences that have developed over 75 million years of evolution. “The genes themselves haven’t really changed, but their regulation can change a lot,” Lein said.
Lein drew a comparison to electronic circuits, all of which are composed of basic elements such as capacitors, resistors and inductors. Although a wristwatch and a supercomputer may use the same basic elements, their wiring diagrams are vastly different. Similarly, the “wiring diagrams” for mouse brains and human brains are structured differently.
One clinically significant issue relates to serotonin receptors, which are among the prime targets for treating depression and anxiety. The researchers found marked differences between mice and humans in the mechanisms for transmitting signals using serotonin.
That finding “should put a certain amount of doubt into the use of the mouse as a model organism to study things that affect serotonin signaling,” Lein said.
The greatest divergence in gene expression wasn’t found in cortical neurons, as had been expected, but in different types of brain cells known as microglia. Such cells are thought to function as the brain’s “immune system” and their dysfunction appears to play a key role in brain disorders such as Alzheimer’s disease. (A study making that connection was published just today in Nature Communications.)
Lein said the newly published study shows that the Allen Institute’s technique for classifying brain cells on the basis of gene expression can reveal differences and similarities that go deeper than what meets the eye.
“Now we can dive right down to this very, very fine level of resolution, which is much, much more complex than anyone had realized before. … We’re doing what Ancestry.com or 23andMe is doing, but now for cells instead of people,” he explained. “Instead of measuring the DNA to see what alleles you have that give rise to particular traits like eye color or hair color or height, now we measure the expression of genes that are active in individual cells.”
Matthew Keefe and Tomasz Nowakowski, neuroscientists at the University of California at San Francisco, used a different analogy in a companion piece also published by Nature. They hailed the study as presenting “a ‘cookbook’ of molecular recipes for the neuronal cell types in the human cerebral cortex.”
Keefe and Nowakowski noted what they said were a couple of shortcomings.
First of all, the sets of data were acquired by different means: For mice, the analysis was done on whole cells. For humans, the team profiled single nuclei from brain cells that were harvested after death, or were extracted from tissue removed during surgeries. (Those surgeries were done at Seattle’s Swedish Neuroscience Institute, University of Washington Medical Center and Harborview Medical Center.)
In addition, the cells were taken from different areas of the cortex — the visual cortex for mice, as opposed to the temporal lobe for humans.
Lein said those were fair concerns. However, he noted that previous studies have shown that the genetic results from single nuclei match the results from whole cells, and that follow-up studies will focus on the diversity in cortical cells.
“We’re moving on to look at other parts of the cortex,” he said.
Could future studies identify uniquely human brain cells that are responsible for higher cognition?
“Eventually we may discover that there are some highly specialized types, but I’d expect them to be derived from pre-existing types,” Lein said. “Your cells can become much more complex, despite being based on the same architecture. That, in fact, does seem to be the case for a lot of these human cells. They’re bigger, they’re more complex, they fire in different ways.”
The basic building blocks for mouse brains and human brains may be similar, but those building blocks can take on dramatically different functions.
“Just a teaser, but we’re seeing examples of that now,” Lein said.
Lein is the senior author of the study published in Nature, “Conserved Cell Types With Divergent Features in Human Versus Mouse Cortex.” The principal authors are Rebecca Hodge and Trygve Bakken of the Allen Institute. There are another 61 co-authors of the study, representing the Allen Institute as well as the University of California at Davis, Leiden University, Delft University of Technology, the Craig Venter Institute, the University of Washington, Swedish Neuroscience Institute, Harborview Medical Center, the University of California at San Diego and Columbia University.