Mice are commonly used as models for drug research, including in neuroscience. But oftentimes the knowledge gleaned from mouse studies doesn’t translate to treatments for people. Now a research team led by the Allen Institute for Brain Science has created a “parts list” of the human brain. By comparing it with the mouse brain cells, the scientists found major differences between the two species, providing insight they believe could help guide the design of treatments for brain diseases.
The team used single-nucleus RNA sequencing to classify neuronal cells in a region of human cortex that plays a key role in many cognitive functions. The 75 distinct cell types identified are similar to cells in the mouse brain, but there are also some crucial differences, the researchers reported in a study published in Nature.
Samples of human brains were obtained either post-mortem or from epilepsy patients who had undergone brain surgery. Because isolating intact cells from brain tissue can be challenging, Ed Lein, Ph.D., an investigator at the Allen Institute and colleagues decided to profile single nuclei and grouped cells based on gene expression. Then they compared their findings with results from previous mouse analyses that used single-cell RNA sequencing.
The human cortex takes up a larger area and houses more neurons than the mouse cortex does. But Lein’s team found that, at least in terms of cell diversity, the human brain is not that much more complex. The 75 human brain cells types identified in the study—including 24 excitatory, 45 inhibitory and six non-neuronal cells—have counterparts in the mouse brain, the team found.
However, the researchers also observed “many differences in how the genes are used, what the cells look like and the proportions of different cell types in the brain,” Lein said in a statement.
One major divergence emerged from the serotonin receptors. These are proteins that allow neurons to work with the neurotransmitter serotonin, and they are known to be involved in depression, anxiety and obsessive-compulsive disorder. While the receptors are expressed in both humans and mice, their respective genes are expressed in different kinds of cells, “which 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 in a video interview.
Detailed knowledge of the brain’s cellular structure is crucial to understanding our cognitive abilities and related diseases. Scientists at the Allen Institute for Brain Science previously singled out a novel type of cell, which they called “rosehip neurons,” that’s found in humans but not mice.
Other research initiatives funded by the late Microsoft co-founder and billionaire philanthropist Paul Allen aim to elucidate different cellular processes involved in a variety of diseases. The Allen Institute for Cell Science recently made a 3D model that allows researchers to look at how key cellular structures change during cell division. That research team hopes the model will aid in cancer research.
The high-resolution view of the human brain could help researchers spot abnormalities that drive brain diseases. “Establishing this parts list will allow us to be able to understand the molecular machinery so that we can use that knowledge to design new drug treatments,” Joshua Gordon, director of the National Institute of Mental Health, said in a video interview.
For this most recent project, Lein and colleagues only examined the middle temporal gyrus of the human cortex. Next up, they plan to look at other parts of the brain. “The eventual goal will be to develop the complete parts list of the entire human brain,” Gordon said. “It’s a hugely ambitious goal, but this paper shows us that it’s a doable undertaking.”