Scientists have comprehensively mapped the basal ganglia, a brain region critical for turning thoughts into actions, in unprecedented detail, the National Institutes of Health announced Thursday.
The atlas, a product of the NIH BRAIN Initiative and its Cell Atlas Network, catalogues the activities, identities and locations of millions of individual cells in the basal ganglia throughout development. A collection of 27 papers describing the dataset, tools to use it, and early insights appears in Cell, Cell Reports Medicine, Cell Systems, Cell Genomics and Neuron.
"Representing the brain at this level of granularity opens so many opportunities to better understand basic brain function and the cellular underpinnings of devastating neurologic, neuropsychiatric, and substance use disorders," said John Ngai, director of the NIH BRAIN Initiative. "Already, this work is paving the way toward targeted therapies for neurodegenerative disorders such as Huntington's and Parkinson's disease."
How the map was built, and what it is already showing
Researchers catalogued cell types and activities by performing single-cell sequencing on donated postmortem human brain tissue, then used advanced imaging to link those characteristics to 3-D coordinates. They built atlases of neurons and glial cells in the mature human brain and during early development, and also mapped non-human primate, marmoset and mouse brains as resources for preclinical studies. The basal ganglia, NIH said, is a cluster of structures that helps determine how people execute deliberate physical actions, learn and focus.
Using the reference atlas as a blueprint, one research group organized raw sequencing data from people who had autism and created new brain maps of the disorder. That work revealed potentially key disruptions in certain cell populations of the striatum, the basal ganglia's intake region, that standard methods likely would not have detected. Most investigations of autism mechanisms have focused on the cortex; this study, NIH said, suggests circuits deeper in the brain may be involved. Those are early findings from the paper collection, not a new clinical diagnosis tool.
Another paper follows up on prior BRAIN Initiative work that used genetic switches, or enhancers, to target brain cells with high specificity. Here, scientists used a particular enhancer to boost levels of a dopamine precursor in striatum cells in mouse models of Parkinson's disease, showing that the precise delivery alleviated symptoms while reducing the severity of common side effects, NIH said.
Tools meant to be used
The package also describes open-source tools, including a preprocessing program that prepares data to be mapped against the reference atlas and a web platform that lets users explore the basal ganglia without specialized bioinformatics hardware. To help future atlas studies, scientists established a Neuroanatomy-anchored Information Management Platform, or NIMP, for projecting postmortem human brain samples onto a standardized 3-D atlas.
"These multi-species atlases have unlocked important new findings about how the brain develops and functions at the single-cell level," said Amy Bany Adams, acting director of NIH's National Institute of Neurological Disorders and Stroke. Andrea Beckel-Mitchener, acting director of the National Institute of Mental Health, said the computational infrastructure may be "just as notable" as the findings themselves. The work was supported by the BRAIN Initiative, which is co-led by NIMH and NINDS. The datasets are being presented as publicly available resources for other researchers, not as an immediate change in how patients are treated.