The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several that exist only in a subset of species as well as substantial species-specific molecular differences across homologous neuronal, glial, and non-neural subtypes. The latter are exemplified by human-specific switching between expression of the neuropeptide somatostatin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine production in certain interneurons. The above molecular differences are also illustrated by expression of the neuropsychiatric risk gene FOXP2, which is human-specific in microglia and primate-specific in layer 4 granular neurons. We generated a comprehensive survey of the dlPFC cellular repertoire and its shared and divergent features in anthropoid primates. Description Primate brain diversity Primate brains benefit from an evolutionary specialization of the cortex that supports cognition. Ma et al. tracked transcriptomes from cellular nuclei sampled from human, chimpanzee, macaque, and marmoset brain cortices. The transcriptomes define groups of cell types, some of which are conserved and some that differ between these species. Several human-specific specializations were identified. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, group-specific patterns. —PJH Single-cell transcriptomics reveals prefrontal cell taxonomy and species differences in human, chimpanzee, macaque, and marmoset. INTRODUCTION The dorsolateral prefrontal cortex (dlPFC) lies at the center of high-order cognition and complex social behaviors, which are highly derived traits in anthropoid primates—particularly in humans. RATIONALE The granular dlPFC represents an evolutionary specialization found only in anthropoid primates, and alterations in the molecular and cellular mechanisms underlying its intricate circuitry have been implicated in myriad neuropsychiatric diseases. However, little is known about the full repertoire of cell types in the primate dlPFC and how conserved these cell types are between human and other primate species. RESULTS We generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets, thus spanning major primate phylogenetic groups. To study regulatory mechanisms underlying human-specific divergence, we generated single-nucleus multiome data (snATAC-seq and snRNA-seq) profiling the human dlPFC. Through cell clustering, marker gene expression, and integration with published multimodal and multispecies data we defined three levels of hierarchically organized taxonomy of transcriptomically defined neuronal, glial, and non-neural cell types in the four species, including four major cell classes, 29 subclasses and 114 subtypes. Most cell subtypes were conserved across the four species but we unraveled prominent species differences both at the molecular and cellular levels. We identified five cell subtypes detected in only a subset of species, including a layer (L) 2-3 intratelencephalic subtype absent in marmosets, an inhibitory neuron subtype exclusive to marmosets, and a microglial subtype detected only in humans. Cross-species comparisons of cell type proportions showed that L2-3 intratelencephalic neurons underwent substantial expansion in humans compared with other species as well as in Catarrhini as compared with marmosets. Gene expression entropy analysis revealed more transcriptomic heterogeneity among L2-3 intratelencephalic neurons in Catarrhini compared to marmosets. These results confirm and extend theories of primate cortical expansion. Within homologous cell subtypes across species, we identified prominent molecular changes. These are characterized by loss of expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine (including dopamine) biosynthesis, in the inhibitory neurons of chimpanzees that are homologous to TH-expressing inhibitory neurons in the other species studied. Among TH-expressing homologous cell subtypes in humans, macaques, and marmosets, we identified a human-specific posttranscriptional switch between the neuropeptide SST and TH, and the human-specific expression of genes involved in dopaminergic function. Through transcriptomic comparisons across the four primate species and immunohistochemistry across 51 mammal species, we found that the neuropsychiatric risk gene FOXP2 exhibited human-specific expression in microglia and primate-specific expression in L4 excitatory neurons. By integrating chromatin accessibility and gene coexpression, we identified cis-regulatory elements regulating FOXP2 expression and constructed FOXP2 regulatory networks including downstream targets mirroring the cell type- and species-specific FOXP2 expression patterns. CONCLUSION We produced a transcriptomic catalog of the primate dlPFC cell types, complemented with epigenomic characterization in the human dlPFC. Our analyses delineated cell type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Shared and species-divergent features were implicated in biological pathways and neuropsychiatric diseases. Our data may serve as a resource for future studies on prefrontal cortex function and disease. Transcriptomic taxonomy of the dlPFC in four anthropoid primates. (Top left) Homologous regions of the dlPFC dissected for snRNA-seq and sn-multiome analyses. (Top right) 114 hierarchically organized (dendrogram) transcriptomically defined cell subtypes distributed across the four species (bar plots; same color code as in the top left panel), with species-specific variations highlighted. (Bottom) Notable molecular changes across species featured by species-specific FOXP2 expression and the human-specific posttranscriptional switching between SST and TH.

Molecular and cellular evolution of the primate dorsolateral prefrontal cortex

Abstract As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions. 

Transcriptional and epigenetic decoding of the microglial aging process.

Microglia are resident immune cells in the central nervous system, playing critical roles in brain development and homeostasis. Increasing evidence has implicated microglia dysfunction in the pathogenesis of various brain disorders ranging from psychiatric disorders to neurodegenerative diseases. Using a human cell-based model to illuminate the functional mechanisms of microglia will promote pathological studies and drug development. The recently developed microglia-containing human brain organoids (MC-HBOs), in-vitro three-dimensional cell cultures that recapitulate key features of the human brain, have provided a new avenue to model brain development and pathology. However, MC-HBOs generated from different methods differ in the origin, proportion, and fidelity of microglia within the organoids, and may have produced inconsistent results. To help researchers to develop a robust and reproducible model that recapitulates in-vivo signatures of human microglia to study brain development and pathology, this review summarized the current methods used to generate MC-HBOs and provided opinions on the use of MC-HBOs for disease modeling and functional studies. 

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Microglia-containing human brain organoids for the study of brain development and pathology

Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6–23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain. 

Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain

The completion of the Human Genome Project has provided a foundational blueprint for understanding human life. Nonetheless, understanding the intricate mechanisms through which our genetic blueprint is involved in disease or orchestrates development across temporal and spatial dimensions remains a profound scientific challenge. Recent breakthroughs in cellular omics technologies have paved new pathways for understanding the regulation of genomic elements and the relationship between gene expression, cellular functions, and cell fate determination. The advent of spatial omics technologies, encompassing both imaging and sequencing-based methodologies, has enabled a comprehensive understanding of biological processes from a cellular ecosystem perspective. This review offers an updated overview of how spatial omics has advanced our understanding of the translation of genetic information into cellular heterogeneity and tissue structural organization and their dynamic changes over time. It emphasizes the discovery of various biological phenomena, related to organ functionality, embryogenesis, species evolution, and the pathogenesis of diseases. 

Spatiotemporal omics for biology and medicine

Decoding the temporal and regional specification of microglia in the developing human brain.

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Decoding the temporal and regional specification of microglia in the developing human brain.

Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain