Summary: Collaborative efforts have produced a detailed atlas of the mouse brain, revealing how diverse cell types are organized, connect, and are regulated. These findings lay groundwork for future studies and therapies targeting brain disorders.
Source: Salk Institute
Mapping the brain requires untangling billions of cells and their connections. A multi-institutional collaboration led in part by researchers at the Salk Institute has made significant progress toward a comprehensive mouse brain atlas—a critical step toward mapping the human brain.
This work is part of the BRAIN Initiative Cell Census Network (BICCN), supported by the U.S. National Institutes of Health (NIH) BRAIN Initiative. The new findings, published in a special issue of Nature, describe how different cell types are spatially organized, how they connect across regions, and how their regulatory genomes distinguish them.
“We used the mouse brain as a model to characterize the diversity of brain cells and their regulation,” says Salk Professor and Howard Hughes Medical Institute Investigator Joseph Ecker, co-director of the BICCN. “The tools and maps we develop in mouse will inform work in primate and human brains.”
The BRAIN Initiative funds large-scale projects to improve understanding of brain function and to accelerate treatments for neurological and psychiatric disorders. The BICCN focuses specifically on constructing multimodal atlases—combining transcriptomic, epigenomic, anatomical and circuit-level data—to define cell types across mammalian brains. Salk is one of the central institutions supported to produce BICCN datasets.
Margarita Behrens, a Salk associate research professor who co-led several BICCN papers, emphasizes the practical value of this work: “This is more than a catalog. To treat brain diseases effectively, we need to identify precisely which cell types are affected.”
The Nature special issue includes 17 BICCN articles; five involve Salk researchers and highlight methods and new descriptions of mouse brain cell subtypes. Two major themes from these papers are epigenomic profiling—especially DNA methylation mapping—and linking cell identity to projection patterns across brain regions.
- DNA Methylation Atlas at Single-Cell Resolution
Although all cells in the brain share the same DNA sequence, epigenomic modifications—chemical marks that regulate gene activity—give cells distinct identities. Cytosine methylation, a common DNA modification, helps control whether genes are turned on or off and is central to defining cell types and states.
Using a single-nucleus DNA methylation sequencing method developed in the Ecker lab, the team profiled 103,982 nuclei from 45 regions of the mouse brain, including cortex, hippocampus, striatum, pallidum and olfactory areas. Analysis revealed 161 distinct clusters of cell types, each with characteristic methylation patterns and spatial localizations.
These methylation signatures not only differentiate cell types but can also predict a cell’s spatial origin down to specific layers within regions. The dataset enabled construction of taxonomies, identification of signature genes and regulatory elements, and the development of computational models that can predict cell-type identity and spatial location from methylation profiles.
“Epigenomics extends our definition of cell type,” says Hanqing Liu, a graduate student in the Ecker lab and co-first author on the methylation atlas. “We can now define hundreds of potential cell types based on regulatory DNA patterns.”
- Linking Epigenomics to Neuron Projection Patterns
Another BICCN paper, co-authored by Edward Callaway and Joseph Ecker, combined retrograde labeling with single-nucleus methylation sequencing to connect epigenomic profiles with neuronal projection targets. The team profiled 11,827 individual neurons projecting from the cortex and found that methylation patterns correlated strongly with projection destinations.
For example, neurons projecting from motor cortex to the striatum displayed distinct epigenomic signatures compared with neurons connecting primary visual cortex to the thalamus. These distinct regulatory landscapes help explain how projection identity, laminar position and regional specialization are encoded at the molecular level.
“Neurons communicate through specific connections, so understanding how projection patterns are established and regulated is fundamental to understanding brain function,” explains Zhuzhu Zhang, a Salk postdoctoral fellow and co-first author on the projection study.
Together, these resources form a foundational “parts list” for the mouse brain that integrates multiple molecular and anatomical layers. Callaway notes, “Having this detailed parts list is revolutionary; it opens new opportunities for studying circuits, development and disease.”
The research teams stress that this atlas is an initial but essential step. Mapping regulatory genomes and connectivity in mouse brain cells will guide future research into human brain organization and provide targets for cell-type-specific interventions in neurological and psychiatric disorders.
Funding: The methylation atlas work received support from the National Institute of Mental Health, the National Human Genome Research Institute and the Howard Hughes Medical Institute. The cortical projection studies were supported by the National Institute of Mental Health, the National Eye Institute and the Howard Hughes Medical Institute.
About this brain mapping research news
Author: Salk Communications
Source: Salk Institute
Contact: Salk Communications – Salk Institute
Image: The image is credited to Michael Nunn, Salk Institute
Original Research: Open access. “DNA Methylation Atlas of the Mouse Brain at Single-Cell Resolution” by Joseph Ecker et al., Nature.
Open access. “Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain” by Edward Callaway et al., Nature.
Open access. “A multimodal cell census and atlas of the mammalian primary motor cortex” by the BRAIN Initiative Cell Census Network (BICCN), Nature.
Abstract — DNA Methylation Atlas of the Mouse Brain at Single-Cell Resolution
Mammalian brain cells exhibit extensive diversity in gene expression, structure and function, yet the regulatory DNA landscape underlying this heterogeneity is incompletely understood. Using single-nucleus DNA methylation sequencing, researchers profiled 103,982 nuclei from 45 brain regions, identifying 161 distinct epigenetic cell clusters with specific spatial locations and projection targets. Integrating methylomes with chromatin accessibility and chromatin contact data enabled prediction of enhancer–gene interactions and construction of computational models that predict cell type and spatial origin, establishing an epigenetic basis for neuronal diversity across the mouse cerebrum.
Abstract — Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain
Linking retrograde labeling with single-nucleus DNA methylation profiling, researchers examined 11,827 cortical neurons across numerous long-range projections. Distinct epigenetic signatures corresponded to laminar and regional location and projection patterns. Subclasses of layer 5 neurons and intra-telencephalic cells were separated by epigenomic features that matched anatomical tracing, demonstrating how single-cell epigenomics connects molecular identity with neuronal projection properties.
Abstract — A Multimodal Cell Census and Atlas of the Mammalian Primary Motor Cortex
The BICCN produced a multimodal cell census of the primary motor cortex by integrating single-cell transcriptomics, chromatin accessibility, DNA methylomes, spatial transcriptomics, morphology, electrophysiology and circuit mapping. The study defines a unified molecular landscape of cortical cell types, derives a cross-species taxonomy conserved from mouse to primate and human, and links molecular and regulatory features to physiological and anatomical neuronal phenotypes, providing a framework and genetic tools to connect molecular identity to circuit function.