Summary: Scientists have produced the most detailed molecular map to date of how the brain develops after birth and how it responds to inflammation. Using a new spatial tri-omics approach, the research team tracked gene expression, epigenetic regulation, and protein production in defined brain regions, revealing that inflammatory processes can reactivate genetic programs normally active during early development.
The study shows that neuroinflammation does not remain confined to visibly damaged tissue. Instead, immune activity can spread to distant areas of the brain and trigger developmental programs involved in myelination — the process that builds the insulating sheath around nerve fibers and is disrupted in disorders such as multiple sclerosis (MS). These findings improve our understanding of how inflammation communicates across brain regions and may point to new strategies for treating neurodegenerative and demyelinating diseases.
Key Facts
- Tri-Omics Innovation: Spatial tri-omics simultaneously maps RNA expression, chromatin accessibility/epigenetic state, and protein levels in precise brain locations.
- Inflammation Spread: Immune activation can appear in brain regions distant from the initial lesion, indicating long-range effects of local injury.
- Relevance to MS: Neuroinflammation can reactivate developmental gene programs related to myelin formation, offering clues to mechanisms of myelin loss in multiple sclerosis.
Source: Karolinska Institute
Researchers at Karolinska Institutet and Yale University have assembled a multidimensional molecular atlas that charts postnatal brain development and the spatial response to inflammation.
Published in Nature, the study used spatial tri-omics to measure, in the same tissue locations, (1) gene activity (RNA), (2) epigenetic regulation (chromatin accessibility and histone marks), and (3) resulting protein abundance. By applying these layers together, the team traced how developmental programs evolve across regions and how they are altered by inflammatory insults.
The dataset includes analyses of mouse brains from birth through early postnatal stages and comparisons with corresponding regions of the developing human brain. This spatiotemporal tri-omic atlas documents how cells diversify and organize into functional areas and how chromatin and protein signatures change over time.
“With spatial tri-omics we can follow developmental trajectories across brain regions and also observe how those trajectories are altered when inflammation occurs,” explains Gonçalo Castelo-Branco, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
Inflammation spreads through the brain
Myelination creates the insulating myelin sheath around axons, enabling rapid nerve signal conduction. The corpus callosum is a major white-matter tract that is highly myelinated and is commonly affected in demyelinating diseases such as MS, where oligodendrocytes and myelin are targeted by immune responses.
Using a mouse model that induces focal myelin disruption, the researchers observed that microglia — the brain’s resident immune cells — activate not only at the lesion core but also in distant, apparently undamaged regions. These remote responses included changes in chromatin accessibility and gene expression associated with immune programs.
“We were surprised that inflammation could elicit molecular changes far from the initial injury,” says Rong Fan, professor at Yale University, who co-led the study. “This indicates complex interregional communication in the diseased brain.”
Implications for multiple sclerosis and myelination
A key observation is that some genetic programs typical of early postnatal development—particularly those involved in oligodendrocyte maturation and myelin gene regulation—can be reawakened during neuroinflammation. Reactivation of these developmental pathways may help explain why myelin becomes vulnerable during disease and how repair or further damage could be modulated.
The authors suggest that understanding which developmental programs are reengaged by inflammation might reveal targets to preserve myelin or promote remyelination in disorders such as MS. The atlas provides a resource for identifying molecular signatures that differentiate developmental processes from inflammatory responses and resolution.
Postdoctoral fellows Di Zhang (Yale) and Leslie Kirby (Karolinska Institutet) are co-first authors of the paper.
Funding: The research was supported by the Swedish Research Council, the Swedish Brain Foundation, the Knut and Alice Wallenberg Foundation, the EU Horizon Europe programme and the U.S. National Institutes of Health. Gonçalo Castelo-Branco reports shareholdings in Nexus Epigenomics. Rong Fan is founder and advisor to several biotech companies.
Key Questions Answered
A: A spatially resolved, multidimensional molecular atlas that maps gene expression, epigenetic regulation, and protein abundance across postnatal brain regions and during neuroinflammation.
A: By measuring RNA, chromatin state, and proteins in the same anatomical locations, the method links regulatory changes to functional protein outcomes, enabling a more complete view of cellular states and interregional communication.
A: Inflammation can spread beyond the lesion site and reactivate developmental gene programs, particularly those tied to myelination, which has implications for diseases like multiple sclerosis.
About this research on brain mapping, genetics and inflammation
Author: Press Office
Source: Karolinska Institute
Contact: Press Office, Karolinska Institute
Image credit: Neuroscience News
Original Research (open access): Spatial dynamics of brain development and neuroinflammation; Gonçalo Castelo-Branco et al., Nature. DOI: 10.1038/s41586-025-09663-y
Abstract
Spatial dynamics of brain development and neuroinflammation
Mapping multiple omics layers across developmental time enables investigation of mechanisms that drive brain differentiation, arealization and disease-related alterations. The authors applied spatial ATAC–RNA–protein and spatial CUT&Tag–RNA–protein sequencing together with multiplexed immunofluorescence imaging to profile dynamic spatial remodelling during postnatal brain development and in a lysolecithin-induced neuroinflammation model.
They generated a spatiotemporal tri-omic atlas of the mouse brain from postnatal day 0 to day 21 and compared corresponding regions with the human developing brain. In cortex, they observed persistent and spreading chromatin accessibility patterns for a subset of layer-defining transcription factors. In the corpus callosum, they detected chromatin priming of myelin genes across subregions and implicated layer-specific projection neurons in coordinating axonogenesis and myelination.
In the neuroinflammation model, the study identified molecular programs shared with developmental processes. Microglia displayed both conserved and distinct programs for inflammation and resolution, with transient activation at lesion cores and at distal sites. Overall, the work highlights common and divergent mechanisms underlying normal brain development and neuroinflammatory responses and provides a resource for further exploration of brain function and disease.