Scientists Map Human Basal Ganglia at Single-Cell Resolution Across Multiple Studies

A global research collaboration working through the National Institutes of Health BRAIN Initiative Cell Atlas Network has produced a comprehensive three-dimensional atlas detailing the human basal ganglia with single-cell genetic and epigenetic resolution. Published across twenty-eight papers in Cell Press journals, the research collection characterizes the complex cellular architecture of deep brain structures responsible for critical processes including movement coordination, habit formation, reward processing, learning, and emotional control. Because dysfunction within the basal ganglia is centrally implicated in neurological and psychiatric conditions such as Parkinson’s disease, Huntington’s disease, Tourette syndrome, and substance use disorders, establishing an exhaustive census of its specialized cell types offers an essential foundation for identifying vulnerable cell populations and understanding the regulatory mechanisms underlying human neurological disease.

The basal ganglia comprise a collection of interconnected nerve cell nuclei nestled deep within the brain. While nearly every cell across an individual organism possesses an identical underlying genetic sequence, functional specialization into distinct cell types—such as specific classes of neurons and non-neuronal cells—is governed by precise epigenetic programming that regulates gene activity without changing the DNA sequence itself. Epigenetic mechanisms include chemical tags such as DNA methylation, where methyl chemical groups attach to specific locations on the DNA strand, and dynamic chromatin conformation, which alters the three-dimensional folding of chromosomes to make regulatory elements accessible or inaccessible to cellular machinery. Cumulatively, these epigenetic modifications define a cell’s distinct identity and regulate which proteins it produces.

Within the newly published package of studies, researchers from the Salk Institute led the effort to systematically map the epigenetic architecture of the human basal ganglia. In a milestone investigation published in the journal Cell, the team profiled DNA methylation patterns and three-dimensional chromatin conformation in 197,003 individual basal ganglia cells isolated from seven human donors. By integrating these measurements with existing cellular datasets, the investigators assembled a unified single-cell atlas encompassing 261,331 cells. This multimodal reference uncovered extensive cellular diversity across subregions of the basal ganglia, detailing distinct methylation signatures and demonstrating that neuronal and non-neuronal cells exhibit fundamentally different three-dimensional genome organization patterns across the structure.

In a companion study published in Cell, investigators expanded their epigenetic profiling across eight distinct human basal ganglia anatomical regions, focusing on single-cell transcriptomic profiles and histone modifications. Histone modifications represent chemical alterations to the protein spools around which genomic DNA winds, directly influencing chromatin packaging and regulating gene expression. Changes in histone tagging influence the cellular transcriptome, defined as the complete complement of RNA molecules produced within a cell that carry the instructions for protein synthesis. By capturing single-cell RNA transcriptomes and chromatin states across these eight basal ganglia structures, researchers established direct molecular connections linking cell-type-specific gene regulation with disease-associated risk loci previously discovered in human genome-wide association studies.

To build these high-dimensional cell atlases, the international research consortium established standardized technical protocols that allow hundreds of investigators across multiple institutions to systematically compare and integrate molecular measurements. Creating the atlas required developing coordinated frameworks for donor tissue collection and processing, metadata sharing, and alignment with standardized anatomical reference systems. This shared infrastructure enabled cross-species and multimodal comparisons across human, macaque, marmoset, and mouse brain specimens. Researchers noted that the rigorous standardization established for this foundational basal ganglia milestone will serve as the organizational blueprint for future projects aimed at profiling remaining brain regions as well as cataloging non-neural organ systems.

Beyond focusing exclusively on the basal ganglia, the research consortium demonstrated the broader scalability of their integrated approach by generating a multi-omic single-cell atlas spanning eighteen regions across the adult human brain. That study profiled approximately 750,000 cells by combining histone modifications, DNA methylation, chromatin accessibility, three-dimensional chromatin conformation, and single-cell RNA transcriptomes into a unified resource. By cross-referencing chromatin structures with human genetic databases, investigators mapped regulatory regions linked to complex neuropsychiatric disorders directly to specific vulnerable cell populations, providing an initial baseline for interpreting how non-coding disease-risk variants affect gene transcription in defined brain circuits.

Comparative analyses across mammalian species also played a central role in the broader research effort, including a dedicated Cell study that constructed an extensive epigenomic and transcriptomic atlas of 2.5 million cells from the adult mouse brain. In that investigation, scientists produced new measurements of histone modifications and RNA transcriptomes and integrated them with established profiles of chromatin accessibility, DNA methylation, and three-dimensional genome architecture. Because the rodent brain shares significant evolutionary, anatomical, and genetic homology with the human brain, generating matched cross-species maps allows neuroscientists to systematically evaluate how closely mouse models mirror human-specific transcriptional and epigenetic regulation in health and disease.

The published collection also includes specialized methodological and biological contributions, including a detailed transcriptomic map of individual cells across human basal ganglia tissue derived from four donors without documented neurological conditions, as well as an investigation uncovering the fine-grained diversity of astrocytes, a prominent non-neuronal glial subtype, within basal ganglia subregions. To facilitate broad scientific utility, the consortium deployed an accessible, public web-based analytical platform through which researchers worldwide can explore, cross-reference, and download the single-cell epigenomic and transcriptomic datasets. Consortium scientists emphasize that while these single-cell catalogs pinpoint specific molecular targets and provide the training data necessary for computational models to predict how disease-associated variants disrupt gene regulation, translating these findings into validated clinical interventions will require sustained experimental testing.

The landmark collection forms a major part of the broader Brain Research Through Advancing Innovative Neurotechnologies Initiative, commonly designated The BRAIN Initiative, which launched in 2014 to transform scientific understanding of the human brain. Within this national research infrastructure, the current papers stem specifically from the BRAIN Initiative Cell Atlas Network, a targeted initiative designed to systematically map neural cell types and neural circuits across species, placing primary emphasis on human biology. Salk Institute researchers served as senior and co-corresponding contributors across eight of the twenty-eight papers that compose the Cell Press release, bringing dedicated epigenetic expertise to an expansive consortium effort where other collaborating teams prioritized anatomical mapping and electrophysiological investigations.

Consortium leaders framed the release of the basal ganglia resources not as a final endpoint, but as the initial milestone in an ongoing campaign to map the entirety of the human brain cell by cell. Margarita Behrens, a research professor at Salk and senior author across multiple studies in the package, emphasized that the collaborative network aims to identify and characterize every distinct cell in the brain individually. Establishing foundational molecular datasets at this cellular scale serves as a direct prerequisite for uncovering the mechanisms of brain health, which requires cataloging genes, cellular types, anatomical positions, and neural connections from the ground up.

Scientific leaders also highlighted how high-dimensional single-cell maps will interface with computational biology and emerging machine learning frameworks. Joseph Ecker, a professor and Salk International Council Chair in Genetics who served as co-corresponding author on the collection’s central paper, noted that while an anatomical atlas identifies which cells are present, artificial intelligence models can evaluate what may happen within those cells under disease conditions. Comprehensive single-cell datasets provide the essential empirical training data that artificial intelligence systems require to interpret the brain’s regulatory logic. In future applications, researchers anticipate using these models to predict how specific disease-linked genetic variants alter gene regulation and cell function within vulnerable neuronal subsets, well before clinical symptoms emerge.

In the longer term, investigators envision creating reference atlases versatile enough to support researchers across diverse medical disciplines, spanning fields from cancer biology to neurodevelopmental conditions and Alzheimer’s disease. Biomedical researchers could query the centralized directory to identify the precise cellular subtypes implicated in a condition and explore strategies to manipulate cellular regulation to prevent or treat disease, disorder, and cognitive decline. The coordination models engineered for the basal ganglia milestone have already yielded a standardized operational framework, enabling hundreds of participating investigators to continue analyzing subsequent brain regions while offering a reusable template for parallel international projects that seek to map other major human organ systems.

To support immediate public discovery, the consortium deposited the completed basal ganglia epigenomic datasets into an accessible online repository hosted at neomorph.salk.edu/SCMDAP/BasalGanglia. The primary investigations in the collection received peer-reviewed publication on November 12, 2026, supported by funding from the National Institutes of Health alongside private philanthropic support. While the resulting maps present an unprecedented opportunity to uncover why basal ganglia disorders arise, consortium scientists caution that pinpointing causal mechanisms, designing targeted therapies, and validating them through experimental pipelines will require sustained scientific effort over time.

Subject of Research: Multimodal single-cell and epigenetic mapping of the human basal ganglia

Article Title: BRAIN Initiative scientists map human basal ganglia

Article References: BRAIN Initiative scientists map human basal ganglia. Original publication (Bibliographic details unavailable.)

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Keywords: basal ganglia, BRAIN Initiative, BICAN, epigenomics, single-cell atlas, DNA methylation, chromatin conformation, histone modifications, transcriptome, Salk Institute, Parkinson's disease, Huntington's disease, Tourette syndrome, neuroscience, astrocytes, gene regulation