Summary: Researchers have created the most comprehensive parts list of the human brain to date, identifying important differences between human and mouse brain cells. These findings could help explain why many drugs that work in mouse models fail in humans.
Source: Allen Institute
A new study from the Allen Institute for Brain Science presents the most detailed catalog of human brain cell types to date. This classification provides a foundation for deeper understanding of human brain organization and could transform how we study and treat brain disorders.
The study, published in the journal Nature, delivers an ultra-high-resolution comparison of human and mouse cortical cell types. The analysis shows that most human brain cell types have identifiable counterparts in the mouse brain, suggesting strong conservation across roughly 75 million years of evolution. Researchers examined which genes are active in individual cells from a specific region of the human cortex, allowing precise comparisons with mouse data.
“Just as genetic tests can reveal family relationships or long-lost relatives, we can now let genes tell the evolutionary story of our brains,” said Ed Lein, Ph.D., Investigator at the Allen Institute for Brain Science and senior author on the paper. “This high-resolution cellular map gives us a baseline for finding the specific cells that malfunction in disease.”
By aligning cell types between species, scientists can better leverage decades of rodent neuroscience while recognizing crucial human-specific differences. That alignment helps explain why many psychiatric drugs developed using mouse models fail in clinical trials: the same receptors or cell types can be used differently in the two species.
“A comprehensive parts list of the human brain is essential,” said Joshua Gordon, M.D., Ph.D., Director of the National Institute of Mental Health. “Knowing what is shared and what is unique between mice and humans will drive improved therapies for mental illness. This study demonstrates that building a complete cellular atlas of the human brain is an ambitious but achievable goal.”
The study highlighted major changes in serotonin receptors, the proteins that enable neurons to respond to the neurotransmitter serotonin and that influence appetite, mood, memory, and sleep. While both humans and mice express serotonin receptors, those receptors appear in different types of neurons across the two species. This difference could underlie why drugs that target serotonin systems sometimes behave differently in humans than in mice.
How similar — and how different — are human and mouse brains?
In some respects, the discovery that the 75 human cortical cell types identified in this study have matches in mouse echoes past findings from the Human Genome Project that humans and mice possess a comparable number of genes. “Many expect the human brain to be vastly more diverse than the mouse brain,” Lein observed. “At the level of cell-type counts, that assumption doesn’t fully hold. With an apples-to-apples comparison, however, we see significant differences in how genes are used, in cell morphology, and in the relative abundance of cell types.”
The team profiled gene expression in nearly 16,000 nuclei from the human middle temporal gyrus, a region of the temporal lobe. Samples came from donated post-mortem tissue and from surgical resections performed for epilepsy treatment. The Allen Institute is expanding this effort to profile additional brain regions and to broaden the human cell-type atlas.
Earlier Allen Institute work produced a comparable dataset of mouse cortical cells, enabling direct cross-species matching. Although many cell types align at the gene-expression level, the study also revealed pronounced species-specific differences. For example, the genes involved in neuronal connectivity show substantial divergence, suggesting that human cortical circuits may be wired differently than those in mice.
One helpful analogy is the diversity of mammalian limbs: the same basic genetic toolkit builds a human hand, a bat wing, and a whale flipper, yet each structure has a distinct form and function. Similarly, conserved cell types can be repurposed across species to support different anatomical arrangements and behaviors.
“There are important similarities and clear differences between human and mouse brains,” said Christof Koch, Ph.D., Chief Scientist and President of the Allen Institute for Brain Science and a coauthor of the study. “The conservation we observe shows evolutionary continuity; the differences underscore human uniqueness. Any effort to cure human brain diseases must take those human-specific features into account.”
The research team includes investigators from the Allen Institute for Brain Science and collaborators from multiple institutions, including the University of California, Davis; J. Craig Venter Institute; Columbia University; Leiden University Medical Center; Delft University of Technology; Swedish Neuroscience Institute; and the University of Washington, among others. The paper lists many contributing scientists and their laboratories.
Funding: This research was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number U01MH114812. The content is the responsibility of the authors and does not necessarily reflect the official views of the NIH.
Source:
Allen Institute
Media Contacts:
Rob Piercy – Allen Institute
Image Source:
Image adapted from an Allen Institute news release.
Original Research: Closed access
“Conserved cell types with divergent features in human versus mouse cortex”, Rebecca D. Hodge et al., Nature. doi: 10.1038/s41586-019-1506-7
Abstract
Conserved cell types with divergent features in human versus mouse cortex
The study used single-nucleus RNA sequencing to map cell types in the human middle temporal gyrus. Researchers identified a diverse set of excitatory and inhibitory neuron types that are often sparse, with excitatory types distributed across layers more broadly than expected. Comparison with mouse cortical single-cell datasets revealed a largely conserved cellular architecture that enabled matching homologous types and predicting human cell properties. Despite this conservation, the team found substantial species-specific differences in cell proportions, layer distributions, gene expression, and morphology, underscoring the importance of studying human brain tissue directly.