In a National Institutes of Health (NIH)-funded breakthrough, scientists have comprehensively mapped out a brain region critically important for turning thoughts into actions, known as the basal ganglia, in unprecedented detail. A product of the NIH Brain Research through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, the atlas catalogues the activities, identities, and locations of millions of individual cells within the basal ganglia throughout development. A new landmark collection of studies describes this dataset, tools to utilize it, and how it has yielded insights into brain function and disease.
"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, Ph.D., 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."
The BRAIN Initiative® Cell Atlas Network (BICAN) is a large-scale, multi-center effort to produce baseline representations of the brain at a single-cell resolution, which researchers could use to pinpoint exactly where, when, and which specific cells contribute to disease. Toward its goal of plotting the entire human brain, the network has completed an atlas of the basal ganglia, a cluster of brain structures that determines how we execute deliberate physical actions, learn, and focus.
The researchers catalogued cell types and activities by performing single-cell sequencing on donated postmortem human brain tissue. Then, with advanced imaging techniques, they linked these characteristics to 3D coordinates in the basal ganglia. In this way, they built atlases of neurons and glial cells in not only the mature human brain, but also during early development, producing clues as to how this key brain region emerges .
The atlases span non-human primate, marmoset, and mouse brain as well, providing resources to support more detailed studies in preclinical models.
Using the reference atlas as a blueprint to organize raw sequencing data from humans who had autism, one research group created new brain maps of the disorder . This perspective revealed potentially key disruptions in certain cell populations of the striatum, the basal ganglia's heavily trafficked intake component, which standard methods likely would not have detected. While most investigations into autism mechanisms have focused on the cortex, this study suggests circuits deeper in the brain may be involved.
"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, Ph.D., acting director of NIH's National Institute of Neurological Disorders and Stroke (NINDS). "We expect these valuable publicly available resources will continue to catalyze discoveries among the scientific community that enhance our understanding of neurological and psychiatric disorders."
Another paper in the collection follows up on prior work supported by The BRAIN Initiative that established a method of using genetic switches, or enhancers, to target brain cells with high specificity . Here, scientists used a particular enhancer to boost levels of a dopamine precursor within striatum cells in mouse models of Parkinson's disease, showing that the precision delivery alleviated symptoms while reducing the severity of common side effects.
The package describes other newly developed open-source tools, including a preprocessing program that prepares data to be mapped against the reference atlas, and a web-based platform that allows users to visually explore various dimensions of the basal ganglia without specialized bioinformatics hardware or software.
To help other researchers conduct future atlas studies, BICAN-funded scientists also established a Neuroanatomy-anchored Information Management Platform (NIMP) for projecting all studied postmortem human brain samples onto a standardized 3D brain atlas .
"The findings presented in these studies are scientifically profound in and of themselves. But what is perhaps just as notable is how much computational infrastructure these researchers have created to support and shape the future of neuroscience," said Andrea Beckel-Mitchener, Ph.D., acting director of NIH's National Institute of Mental Health (NIMH).
The collection's 27 papers appear in the journals Cell, Cell Reports Medicine, Cell Systems, Cell Genomics, and Neuron.
NIH supported this research through The BRAIN Initiative, which is co-led by NIMH and the National Institute of Neurological Disorders and Stroke (NINDS).
The Brain Research Through Advancing Innovative Neurotechnologies® Initiative and The BRAIN Initiative® are registered trademarks of the U.S. Department of Health and Human Services.
The NIH BRAIN Initiative , a multidisciplinary collaboration across 10 NIH Institutes and Centers, is uniquely positioned for cross-cutting discoveries in neuroscience to revolutionize our understanding of the human brain. By accelerating the development and application of innovative neurotechnologies, The BRAIN Initiative® is enabling researchers to understand the brain at unprecedented levels of detail in both health and disease, improving how we treat, prevent, and cure brain disorders. The BRAIN Initiative involves a multidisciplinary network of federal and non-federal partners whose missions and current research portfolios complement the goals of The BRAIN Initiative.
