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The neocortex is disproportionately expanded in human compared with mouse 1 , 2 , both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth 3 . Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer’s disease 4 , 5 . Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease. Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey ( Macaca mulatta ) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey. A high-resolution gene expression atlas of prenatal and postnatal brain development of rhesus monkey charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex. Gene expression in the primate brain Following the publication of the mouse and human brain gene expression atlases in recent years, Ed Lein and colleagues now present a high-resolution transcriptional atlas of pre- and post-natal brain development for the rhesus monkey — the dominant non-human primate model for human brain development and disease. The data charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex.

The evolutionary increase in size and complexity of the primate neocortex is thought to underlie the higher cognitive abilities of humans. ARHGAP11B is a human-specific gene that, based on its expression pattern in fetal human neocortex and progenitor effects in embryonic mouse neocortex, has been proposed to have a key function in the evolutionary expansion of the neocortex. Here, we study the effects of ARHGAP11B expression in the developing neocortex of the gyrencephalic ferret. In contrast to its effects in mouse, ARHGAP11B markedly increases proliferative basal radial glia, a progenitor cell type thought to be instrumental for neocortical expansion, and results in extension of the neurogenic period and an increase in upper-layer neurons. Consequently, the postnatal ferret neocortex exhibits increased neuron density in the upper cortical layers and expands in both the radial and tangential dimensions. Thus, human-specific ARHGAP11B can elicit hallmarks of neocortical expansion in the developing ferret neocortex. The human brain owes its characteristic wrinkled appearance to its outer layer, the cerebral cortex. All mammals have a cerebral cortex, but its size varies greatly between species. As the brain evolved, the neocortex, the evolutionarily youngest part of the cerebral cortex, expanded dramatically and so had to fold into wrinkles to fit inside the skull. The human neocortex is roughly three times bigger than that of our closest relatives, the chimpanzees, and helps support advanced cognitive skills such as reasoning and language. But how did the human neocortex become so big? The answer may lie in genes that are unique to humans, such as ARHGAP11B. Introducing ARHGAP11B into the neocortex of mouse embryos increases its size and can induce folding. It does this by increasing the number of neural progenitors, the cells that give rise to neurons. But there are two types of neural progenitors in mammalian neocortex: apical and basal. A subtype of the latter – basal radial glia – is thought to drive neocortex growth in human development. Unfortunately, mice have very few basal radial glia. This makes them unsuitable for testing whether ARHGAP11B acts via basal radial glia to enlarge the human neocortex. Kalebic et al. therefore introduced ARHGAP11B into ferret embryos in the womb. Ferrets have a larger neocortex than mice and possess more basal radial glia. Unlike in mice, introducing this gene into the ferret neocortex markedly increased the number of basal radial glia. It also extended the time window during which the basal radial glia produced neurons. These changes increased the number of neurons, particularly of a specific subtype found mainly in animals with large neocortex and thought to be involved in human cognition. Introducing human-specific ARHGAP11B into embryonic ferrets thus helped expand the ferret neocortex. This suggests that this gene may have a similar role in human brain development. Further experiments are needed to determine whether ferrets with the ARHGAP11B gene, and thus a larger neocortex, have enhanced cognitive abilities. If they do, testing these animals could provide insights into human cognition. The animals could also be used to model human brain diseases and to test potential treatments.

To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type–specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.

Key Points In spite of its stereotypic laminar and columnar organization, the cerebral neocortex displays numerous species-specific adaptations of old and acquired new traits that subserve specific functions introduced during 100 million years of mammalian evolution. The human neocortex, a substrate of our unique cognitive abilities, has many distinct traits in addition to a larger surface, including different places of neuronal origin, distinct migratory pathways and acquisition of new cell types that were traditionally studied by comparative anatomists. The contemporary, evo–devo approach uses developmental principles and mechanisms uncovered by experiments in embryos of living species to obtain a glimpse into how the human neocortex may have developed at the cellular and molecular level in extinct common ancestors. The radial unit model of cortical evolution provides insight into how mutation of genes that control the transition from the symmetric to asymmetric mode of cell division in the proliferative ventricular zone subjected to radial constraint during migration can generate neocortical expansion in surface rather than in thickness. The protomap hypothesis of differential enlargement of the existing and introduction of new cytoarchitectonic areas has been tested in mouse embryos by mutation and/or changes of gene expression and transcriptional factors in the neural stem cells of the proliferative ventricular and subventricular zones. Understanding of the species-specific difference in tempo and sequence of cortical development as well as genesis of new cell subtypes, functional columns and synaptic connectivity is essential for design of therapies for trauma, congenital malformations, neurodegenerative disorders and ageing of the human cerebral neocortex. Focusing on mammalian species, Pasko Rakic uses evo–devo studies to model how gene mutations may have affected neuron number and neuronal migration, which in turn may have contributed to the species-specific expansion and elaboration of the cerebral cortex. The enlargement and species-specific elaboration of the cerebral neocortex during evolution holds the secret to the mental abilities of humans; however, the genetic origin and cellular mechanisms that generated the distinct evolutionary advancements are not well understood. This article describes how novelties that make us human may have been introduced during evolution, based on findings in the embryonic cerebral cortex in different mammalian species. The data on the differences in gene expression, new molecular pathways and novel cellular interactions that have led to these evolutionary advances may also provide insight into the pathogenesis and therapies for human-specific neuropsychiatric disorders.

Non-pial neocortical astrocytes have historically been thought to comprise largely a nondiverse population of protoplasmic astrocytes. Here we show that astrocytes of the mouse somatosensory cortex manifest layer-specific morphological and molecular differences. Two- and three-dimensional observations revealed that astrocytes in the different layers possess distinct morphologies as reflected by differences in cell orientation, territorial volume, and arborization. The extent of ensheathment of synaptic clefts by astrocytes in layer II/III was greater than that by those in layer VI. Moreover, differences in gene expression were observed between upper-layer and deep-layer astrocytes. Importantly, layer-specific differences in astrocyte properties were abrogated in reeler and Dab1 conditional knockout mice, in which neuronal layers are disturbed, suggesting that neuronal layers are a prerequisite for the observed morphological and molecular differences of neocortical astrocytes. This study thus demonstrates the existence of layer-specific interactions between neurons and astrocytes, which may underlie their layer-specific functions. Several studies have suggested that astrocytes in the neocortex are more diverse than previously thought. Here, the authors describe layer-specific differences in morphology and molecular characteristics of astrocytes that depend on the neurons within those layers.

Key Points The subplate zone is a highly dynamic structure that contains diverse cell populations that are derived from cortical (ventricular and subventricular zones) and extracortical (rostro-medial telencephalic wall and ganglionic eminence) sources. Interneurons may be underrepresented in the postnatal subplate. Subplate cells in rodents and primates share similarities, such as an early birth date and their location below the cortical plate, but they exhibit marked differences in relative cell survival times, molecular expression profiles and cell morphologies. Subplate cells pioneer axonal projections from the cortex to subcortical targets, but there are species differences in the targets that they innervate. Ablation of the subplate by excitotoxicity or immunotoxicity impairs circuit-level maturation of the primary sensory cortex, and an absence of subplate neurons prevents thalamic afferents from crossing the pallial–subpallial boundary and invading the cortex. Transcriptomic evidence highlights the relative maturity of embryonic and fetal subplate cells and suggests novel roles for subplate neurons in the secretion of various extracellular molecules involved in axon pathfinding, cell survival or differentiation, and synaptic plasticity. Histological, MRI and transcriptomic evidence points towards a role for the subplate in schizophrenia and autism. Whether this is causal or a consequence of earlier malformations remains unclear. The subplate is a transient cortical zone that forms during mammalian brain development and has a crucial role in the formation of intracortical and extracortical circuits. Here, Hoerder-Suabedissen and Molnár review the changing architecture and cellular diversity of this zone in developing mouse and primate brains. Subplate neurons have an essential role in cortical circuit formation. They are among the earliest formed neurons of the cerebral cortex, are located at the junction of white and grey matter, and are necessary for correct thalamocortical axon ingrowth. Recent transcriptomic studies have provided opportunities for monitoring and modulating selected subpopulations of these cells. Analyses of mouse lines expressing reporter genes have demonstrated novel, extracortical subplate neurogenesis and have shown how subplate cells are integrated under the influence of sensory activity into cortical and extracortical circuits. Recent studies have revealed that the subplate is involved in neurosecretion and modification of the extracellular milieu.

Key Points Unlike in other organs, changes in cell numbers in the brain cannot be compensated by changes in cell size. This explains why the brain is particularly sensitive to defects in cell division and requires specific proliferation control mechanisms. Drosophila melanogaster neural stem cells and mammalian cortical progenitors have emerged as the key model systems to study proliferation control in the brain. In D. melanogaster , the segregating determinants NUMB, Prospero (PROS) and Brain tumour (BRAT) establish differential proliferation control in the two daughter cells of neural progenitors. In mammals, the asymmetric inheritance of apical and basal processes, asymmetry between the two centrosomes and interactions between the daughter cells through Notch signalling act redundantly to establish unequal cell fates. D. melanogaster neural stem cells pass through distinct temporal stages, starting with their activation by insulin receptor signalling through the expression of a temporal transcription factor cascade to a switch in metabolic activity that ultimately triggers their shrinkage and differentiation. In mammals, homologues of the D. melanogaster temporal cascade seem to act in conjunction with distinct events, such as the switch from neurogenesis to gliogenesis, which is dependent on the JAK–STAT (Janus kinase–signal transducer and activation of transcription) and Notch pathways. Metabolic regulation plays a crucial role in proliferation control in both D. melanogaster neural stem cells and in adult mammalian neurogenesis. Defects in proliferation control can lead to diseases such as microcephaly or megalencephaly. The brain is particularly sensitive to changes in cell number, which can acutely affect neural function. Here, Knoblich and colleagues describe the proliferation control mechanisms that exist in Drosophila melanogaster and mammals, and their regulation by developmental age and by metabolic and nutritional status. Neural circuit function can be drastically affected by variations in the number of cells that are produced during development or by a reduction in adult cell number owing to disease. For this reason, unique cell cycle and cell growth control mechanisms operate in the developing and adult brain. In Drosophila melanogaster and in mammalian neural stem and progenitor cells, these mechanisms are intricately coordinated with the developmental age and the nutritional, metabolic and hormonal state of the animal. Defects in neural stem cell proliferation that result in the generation of incorrect cell numbers or defects in neural stem cell differentiation can cause microcephaly or megalencephaly.

The activity of neuronal circuits of the neocortex underlies our ability to perceive the world and interact with our environment. During development, these circuits emerge from dynamic interactions between cell-intrinsic, genetically determined programs and input/activity-dependent signals, which together shape these circuits into adulthood. Building on a large body of experimental work, several recent technological developments now allow us to interrogate these nature–nurture interactions with single gene/single input/single-cell resolution. Focusing on excitatory glutamatergic neurons, this review discusses the genetic and input-dependent mechanisms controlling how individual cortical neurons differentiate into specialized cells to assemble into stereotypical local circuits within global, large-scale networks. Proper functioning of the neocortex – the center of higher-order brain functions – depends on the correct assembly of neocortical neural circuits during development. Here the author discusses how cell-intrinsic developmental programs and activity-dependent signals together shape the formation of neocortical circuits.

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. Recent studies have revealed a remarkable molecular diversity across the prenatal cortex but little is known about how this diversity translates into the differential rates of cortical expansion observed during gestation. We present a digital resource, μBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal brain. Using μBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions, quantified in utero using magnetic resonance imaging. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of neocortical expansion during gestation. We identify genes, upregulated from mid-gestation, that are highly expressed in rapidly expanding neocortex and implicated in genetic disorders with cognitive sequelae. The μBrain atlas provides a tool to comprehensively map early brain development across domains, model systems and resolution scales. The third trimester of human gestation is characterised by rapid increases in cortical surface area. Here, authors show that increased rates of cortical expansion are associated with differences in the timing of neurogenesis.