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Cell Atlas Collection Reveals Detailed Mouse Brain Features

NEW YORK – Researchers have published a new mouse brain cell atlas collection that encompasses a range of genomic, single-cell, spatial genomic, and epigenomic data. The effort stems from a US National Institutes of Health-funded effort known as the "Brain research through advancing innovative neurotechnologies initiative cell census network," or BICCN.

Together, the new papers represent work by hundreds of researchers at dozens of centers around the world that aims to better understand the molecular, cellular, and spatial features found in mouse, primate, and human brains. "The ultimate aim is to improve understanding of the cellular mechanisms behind brain disorders, a leading cause of death and disability worldwide," according to an editorial accompanying the papers in Nature on Wednesday.

"The BICCN mouse-brain atlas, which is open access, is also intended to serve as a reference for scientists studying brain disorders and brain evolution across species," the editorial continued, noting that "mega brain projects, each trying to make their own reference atlas or reference model, are underway around the world."

In the first of these studies, Allen Institute for Brain Science Director Hongkui Zeng and her colleagues performed single-cell RNA sequencing on some 7 million mouse brain cells, combining data on the 4 million cells that made it through their quality control steps with spatial transcriptomic and multiplexed error-robust fluorescence in situ hybridization (MERFISH) data.

The team's data highlighted more than 5,300 diverse neuronal and non-neuronal cell type clusters falling in almost three dozen classes, 338 subclasses, and 1,201 supertypes, all visualized in an online Allen Brain Cell Atlas resource.

"The whole mouse brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development, and evolution of the mammalian brain," the authors wrote.

In another Nature paper, coauthor Zeng and other investigators at Harvard University and the Allen Institute for Brain Science further fleshed out the spatial, cellular, and molecular features found in the whole mouse brain cell atlas, digging into MERFISH data for roughly 10 million cells, together with scRNA-seq and spatial transcriptomic clues.

"[W]e generated a comprehensive atlas of molecularly defined cell types across the whole mouse brain with high molecular and spatial resolution," senior and corresponding author Xiaowei Zhuang, a chemist and chemical biologist affiliated with Harvard and the Allen Institute, and her coauthors wrote, noting that their results "provide a molecularly defined and spatially resolved cell atlas of the entire adult mouse brain, featuring complex organizations of thousands of distinct cell populations."

In yet another piece of the mouse brain cell atlas puzzle, investigators at Massachusetts General Hospital, the Broad Institute, Harvard Stem Cell and Regenerative Biology, and other centers turned to a spatial transcriptomic single-nucleus RNA sequencing approach called Slide-seq to spell out the so-called "molecular cytoarchitecture" of the mouse brain, flagging 4,998 cell clusters in the brain regions analyzed.

In the process, the team unraveled relationships between the midbrain, hindbrain, and other known neuroanatomical brain structures, the genes and cell types comprising them, and loci previously linked to neuropsychiatric traits or conditions.

"We utilized the data to uncover specific [neuropeptide] signaling interactions, leveraging the specificity of several [neuropeptides] and/or their receptors," co-corresponding authors Evan Macosko and Fei Chen, with the Broad Institute, and their colleagues reported. "We also characterized activity-related gene expression patterns across all cell types, identifying conserved genes associated with activity as well as activity-related genes that are more specific to subtypes of neurons."

Beyond that, they explained, the molecular cytoarchitecture study made it possible to start proposing mouse brain cell types that are "preferentially enriched for the expression of genes associated with human neurological and psychiatric diseases."

For their part, researchers at the Salk Institute for Biological Studies, the University of California, San Diego, and elsewhere shared findings from analyses on the adult mouse brain methylome in relation to other multiomic features.

With single-nucleus methylome sequencing and snm3C-seq chromatin conformation-methylation profiling on hundreds of thousands of cells spanning 117 adult mouse brain regions — analyzed alongside transcriptome and chromatin accessibility data — the team found millions of differentially methylated regions in the mouse brain and mapped cytosine methylation in relation to different parts of the brain, distinct cell types, and specific genes.

"Our study established a brain-wide, single-cell DNA methylome and 3D multiomic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain," senior and corresponding author Joseph Ecker, a genomic analysis researcher at the Salk Institute for Biological Studies, and his colleagues wrote.

Meanwhile, UCSD's Bing Ren and colleagues presented findings from single-cell chromatin analyses aimed at untangling candidate cis-regulatory elements (cCREs) in the adult mouse brain and their relationship to human brain cCREs.

With chromatin accessibility data for 2.3 million brain cells from 117 brain regions teased out by anatomical dissection, for example, they unearthed cCREs for nearly 1,500 brain cell subgroups, distinguishing transposable elements enriched in cCREs that appeared to be mouse-specific.

"The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome," the authors reported, noting that the cCREs found in the mouse brain "are moderately conserved in the human brain."

In the remaining studies, researchers explored epigenomic ties to neuronal projection patterns in the mouse brain, tracked transcriptome features for spinal projecting neurons, and teased out three-dimensional molecular patterns in the animal's central nervous system, while considering neocortex conservation and retinal evolution in mammals and vertebrates, respectively.

As there are also a number of other brain atlas projects underway, the Nature editorial authors emphasized that "a standardized framework for data collection and analysis, including definitions for types of cell clusters, as well as unified cell classifications and names across species, will eventually be needed," adding that an "interim step must be to begin discussion on shared data standards."