In a package of 21 research studies published across ScienceScience Advances, and Science Translational Medicine, researchers present an atlas of the human and nonhuman primate brain at the cell-type level, in unprecedented detail. The researchers’ collective efforts characterized more than 3,000 human brain cell types, revealing features that distinguish humans from other primates. Understanding the human brain at such resolution will not only help pin down which cell types are most affected by specific mutations and lead to neurological diseases—it will also offer new understanding of who we are as a species.

The papers detail the exceptionally complex diversity of cells in the human brain and the nonhuman primate brain. The studies identify similarities and differences in how cells are organized and how genes are regulated in the human brain and the nonhuman primate brain.

The new work is part of the National Institute of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative (The BRAIN Initiative)—an effort launched in 2014. The studies in this package are part of the National Institutes of Health’s BRAIN Initiative Cell Census Network (BICCN), a program launched in 2017. The research is the first time that techniques to identify brain cell subtypes originally developed and applied in mice have been applied to human brains.

Three papers in the collection present the first atlas of cells in the adult human brain, mapping the transcriptional and epigenomic landscape of the brain.

In another paper, a comparison of the cellular and molecular properties of the human brain and several nonhuman primate brains (chimpanzee, gorilla, macaque, and marmoset brains) revealed clear similarities in the types, proportions, and spatial organization of cells in the cerebral cortex of humans and nonhuman primates. Examination of the genetic expression of cortical cells across species suggests that relatively small changes in gene expression in the human lineage led to changes in neuronal wiring and synaptic function that likely allowed for greater brain plasticity in humans, supporting the human brain’s ability to adapt, learn, and change.

A study exploring how cells vary in different brain regions in marmosets found a link between the properties of cells in the adult brain and the properties of those cells during development. The link suggests that developmental programming is embedded in cells when they are formed and maintained into adulthood and that some observable cellular properties in an adult may have their origins very early in life.

An exploration of the anatomy and physiology of neurons in the outermost layer of the neocortex—part of the brain involved in higher-order functions such as cognition, motor commands, and language—revealed differences in the human brain and the mouse brain that suggest this region may be an evolutionary hotspot, with changes in humans reflecting the higher demands of regulating humans’ more complex brain circuits.

Other work advances research started in 2020, by a team at the Salk, that profiled 161 types of cells in the mouse brain, based on methylation patterns. In the new paper, the researchers used the same tools to determine the methylation patterns of DNA in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male organ donors. While mouse brains are largely the same from animal to animal, and contain about 80 million neurons, human brains vary much more and contain about 80 billion neurons.

“This is really the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease,” said Joseph Ecker, PhD, director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator.

Among eight papers in the package from Science Advances, research explores how fast-spiking interneurons in humans maintain fast synchronization frequencies despite larger neuron-to-neuron distances than their rat counterparts.

Another study zeroes in on inflammation early in life—a clinically established risk factor for several neurological disorders. The impact of inflammation on human brain development is poorly understood. Focusing on the cerebellum, a brain area particularly vulnerable to postnatal perturbations, the team’s analyses reveal that inflammation is associated with changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons.

“This suite of studies represents a landmark achievement in illuminating the complexity of the human brain at the cellular level,” said John Ngai, PhD, director of the NIH BRAIN Initiative. “The scientific collaborations forged through BICCN are propelling the field forward at an exponential pace; the progress—and possibilities—have been simply breathtaking.”

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