To understand the cellular composition and region-specific specialization of white matter — a disease-relevant, glia-rich tissue highly expanded in primates relative to rodents — we profiled transcriptomes of ~500,000 nuclei from 19 tissue types of the central nervous system of healthy common marmoset and mapped 87 subclusters spatially onto a 3D MRI atlas. We performed cross-species comparison, explored regulatory pathways, modeled regional intercellular communication, and surveyed cellular determinants of neurological disorders. Here, we analyze this resource and find strong spatial segregation of microglia, oligodendrocyte progenitor cells, and astrocytes. White matter glia are diverse, enriched with genes involved in stimulus-response and biomolecule modification, and predicted to interact with other resident cells more extensively than their gray matter counterparts. Conversely, gray matter glia preserve the expression of neural tube patterning genes into adulthood and share six transcription factors that restrict transcriptome complexity. A companion Callithrix jacchus Primate Cell Atlas (CjPCA) is available through https://cjpca.ninds.nih.gov.

Cortical lesions are a primary driver of disability in multiple sclerosis (MS). However, noninvasive detection of cortical lesions with in vivo magnetic resonance imaging (MRI) remains challenging. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a relevant animal model of MS for investigating the pathophysiological mechanisms leading to brain damage. This study aimed to characterize cortical lesions in marmosets with EAE using ultrahigh-field (7 T) MRI and histological analysis. Tissue preparation was optimized to enable the acquisition of high-spatial resolution (50-μm isotropic) T2*-weighted images. A total of 14 animals were scanned in this study, and 70% of the diseased animals presented at least one cortical lesion on postmortem imaging. Cortical lesions identified on MRI were verified with myelin proteolipid protein immunostaining. An optimized T2*-weighted sequence was developed for in vivo imaging and shown to capture 65% of cortical lesions detected postmortem. Immunostaining confirmed extensive demyelination with preserved neuronal somata in several cortical areas of EAE animals. Overall, this study demonstrates the relevance and feasibility of the marmoset EAE model to study cortical lesions, among the most important yet least understood features of MS.

The microenvironments of the brain consist of specialized cell types that together influence physiological functions in health and pathological outcomes in disease. Despite apparent differences in the density of neurons and oligodendrocytes in various milieus, such as gray matter (GM) and white matter (WM), the extent of structural and functional heterogeneity of other resident cells remains unclear. We profiled RNA in ~500,000 nuclei from 19 tissue types across the central nervous system of the healthy adult common marmoset (Callithrix jacchus) and mapped 87 identified subclusters (including neurons, glia, and vasculature) spatially onto a 3D MRI atlas. We performed cross-species comparison, explored regulatory pathways, surveyed cellular determinants of neurological disorders, and modeled regional intercellular communication. We found spatially segregated microglia, oligodendrocyte lineage cells, and astrocytes in WM and GM. WM-glia are diverse, are enriched with genes involved in stimulus response and biomolecule modification, and interact with other resident cells more extensively than their GM counterparts. GM-glia preserve the expression of developmental morphogens into adulthood and share 6 differentially enriched transcription factors that restrict the transcriptome complexity. Our work in marmoset, an experimentally tractable animal model with >5 times more WM volume and complexity than mouse, identifies novel WM-glia subtypes and their contributions to different neurological disorders. A companion Callithrix jacchus Primate Cell Atlas (CjPCA) is available through an online portal https://cjpca.ninds.nih.gov to facilitate data exploration.

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