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Cell Jul 2011The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated... (Review)
Review
The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated human neocortex involves a lineage of neural stem and transit-amplifying cells that forms the outer subventricular zone (OSVZ), a proliferative region outside the ventricular epithelium. We discuss how proliferation of cells within the OSVZ expands the neocortex by increasing neuron number and modifying the trajectory of migrating neurons. Relating these features to other mammalian species and known molecular regulators of the mouse neocortex suggests how this developmental process could have emerged in evolution.
Topics: Animals; Biological Evolution; Cell Movement; Humans; Neocortex; Neural Stem Cells; Neurogenesis; Receptors, Notch; Signal Transduction
PubMed: 21729779
DOI: 10.1016/j.cell.2011.06.030 -
Nature Neuroscience Feb 2015Similarities in neocortical circuit organization across areas and species suggest a common strategy to process diverse types of information, including sensation from... (Review)
Review
Similarities in neocortical circuit organization across areas and species suggest a common strategy to process diverse types of information, including sensation from diverse modalities, motor control and higher cognitive processes. Cortical neurons belong to a small number of main classes. The properties of these classes, including their local and long-range connectivity, developmental history, gene expression, intrinsic physiology and in vivo activity patterns, are remarkably similar across areas. Each class contains subclasses; for a rapidly growing number of these, conserved patterns of input and output connections are also becoming evident. The ensemble of circuit connections constitutes a basic circuit pattern that appears to be repeated across neocortical areas, with area- and species-specific modifications. Such 'serially homologous' organization may adapt individual neocortical regions to the type of information each must process.
Topics: Animals; Humans; Interneurons; Neocortex; Nerve Net
PubMed: 25622573
DOI: 10.1038/nn.3917 -
Nature Oct 2021The human brain is subdivided into distinct anatomical structures, including the neocortex, which in turn encompasses dozens of distinct specialized cortical areas....
The human brain is subdivided into distinct anatomical structures, including the neocortex, which in turn encompasses dozens of distinct specialized cortical areas. Early morphogenetic gradients are known to establish early brain regions and cortical areas, but how early patterns result in finer and more discrete spatial differences remains poorly understood. Here we use single-cell RNA sequencing to profile ten major brain structures and six neocortical areas during peak neurogenesis and early gliogenesis. Within the neocortex, we find that early in the second trimester, a large number of genes are differentially expressed across distinct cortical areas in all cell types, including radial glia, the neural progenitors of the cortex. However, the abundance of areal transcriptomic signatures increases as radial glia differentiate into intermediate progenitor cells and ultimately give rise to excitatory neurons. Using an automated, multiplexed single-molecule fluorescent in situ hybridization approach, we find that laminar gene-expression patterns are highly dynamic across cortical regions. Together, our data suggest that early cortical areal patterning is defined by strong, mutually exclusive frontal and occipital gene-expression signatures, with resulting gradients giving rise to the specification of areas between these two poles throughout successive developmental timepoints.
Topics: Atlases as Topic; Base Sequence; Biomarkers; Gene Expression Regulation, Developmental; Humans; Neocortex; Neurogenesis; Neuroglia; Neurons; Reproducibility of Results; Single-Cell Analysis; Time Factors
PubMed: 34616070
DOI: 10.1038/s41586-021-03910-8 -
Cold Spring Harbor Perspectives in... Aug 2015Conscious memory for a new experience is initially dependent on information stored in both the hippocampus and neocortex. Systems consolidation is the process by which... (Review)
Review
Conscious memory for a new experience is initially dependent on information stored in both the hippocampus and neocortex. Systems consolidation is the process by which the hippocampus guides the reorganization of the information stored in the neocortex such that it eventually becomes independent of the hippocampus. Early evidence for systems consolidation was provided by studies of retrograde amnesia, which found that damage to the hippocampus-impaired memories formed in the recent past, but typically spared memories formed in the more remote past. Systems consolidation has been found to occur for both episodic and semantic memories and for both spatial and nonspatial memories, although empirical inconsistencies and theoretical disagreements remain about these issues. Recent work has begun to characterize the neural mechanisms that underlie the dialogue between the hippocampus and neocortex (e.g., "neural replay," which occurs during sharp wave ripple activity). New work has also identified variables, such as the amount of preexisting knowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools (e.g., optogenetics) can be expected to further improve understanding of the neural mechanisms underlying consolidation.
Topics: Animals; Hippocampus; Humans; Memory; Neocortex
PubMed: 26238360
DOI: 10.1101/cshperspect.a021766 -
Science (New York, N.Y.) Jun 2022Progenitors of the developing human neocortex reside in the ventricular and outer subventricular zones (VZ and OSVZ, respectively). However, whether cells derived from...
Progenitors of the developing human neocortex reside in the ventricular and outer subventricular zones (VZ and OSVZ, respectively). However, whether cells derived from these niches have similar developmental fates is unknown. By performing fate mapping in primary human tissue, we demonstrate that astrocytes derived from these niches populate anatomically distinct layers. Cortical plate astrocytes emerge from VZ progenitors and proliferate locally, while putative white matter astrocytes are morphologically heterogeneous and emerge from both VZ and OSVZ progenitors. Furthermore, via single-cell sequencing of morphologically defined astrocyte subtypes using Patch-seq, we identify molecular distinctions between VZ-derived cortical plate astrocytes and OSVZ-derived white matter astrocytes that persist into adulthood. Together, our study highlights a complex role for cell lineage in the diversification of human neocortical astrocytes.
Topics: Astrocytes; Cell Lineage; Humans; Neocortex; Neural Stem Cells; Neurogenesis; Primary Cell Culture; Stem Cell Niche
PubMed: 35587512
DOI: 10.1126/science.abm5224 -
Nature Oct 2021Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types, yet our knowledge of its diversity remains limited....
Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.
Topics: Atlases as Topic; Biomarkers; Brain; Cell Shape; Gene Expression Regulation, Developmental; Humans; Neocortex; Neurogenesis; Neuroglia; Neurons; RNA-Seq; Reproducibility of Results; Single-Cell Analysis
PubMed: 34616072
DOI: 10.1038/s41586-021-03941-1 -
Cell Sep 2015Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone...
Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex.
Topics: Animals; Cell Cycle; Humans; Macaca; Mice; Neocortex; Neural Stem Cells; Neurogenesis; Neuroglia; STAT3 Transcription Factor; Signal Transduction; Single-Cell Analysis; Stem Cell Niche
PubMed: 26406371
DOI: 10.1016/j.cell.2015.09.004 -
Nature Aug 2022Microglia are specialized macrophages in the brain parenchyma that exist in multiple transcriptional states and reside within a wide range of neuronal environments....
Microglia are specialized macrophages in the brain parenchyma that exist in multiple transcriptional states and reside within a wide range of neuronal environments. However, how and where these states are generated remains poorly understood. Here, using the mouse somatosensory cortex, we demonstrate that microglia density and molecular state acquisition are determined by the local composition of pyramidal neuron classes. Using single-cell and spatial transcriptomic profiling, we unveil the molecular signatures and spatial distributions of diverse microglia populations and show that certain states are enriched in specific cortical layers, whereas others are broadly distributed throughout the cortex. Notably, conversion of deep-layer pyramidal neurons to an alternate class identity reconfigures the distribution of local, layer-enriched homeostatic microglia to match the new neuronal niche. Leveraging the transcriptional diversity of pyramidal neurons in the neocortex, we construct a ligand-receptor atlas describing interactions between individual pyramidal neuron subtypes and microglia states, revealing rules of neuron-microglia communication. Our findings uncover a fundamental role for neuronal diversity in instructing the acquisition of microglia states as a potential mechanism for fine-tuning neuroimmune interactions within the cortical local circuitry.
Topics: Animals; Cell Count; Mice; Microglia; Neocortex; Pyramidal Cells; Single-Cell Analysis; Somatosensory Cortex; Transcriptome
PubMed: 35948630
DOI: 10.1038/s41586-022-05056-7 -
Nature Oct 2021The neocortex is disproportionately expanded in human compared with mouse, both in its total volume relative to subcortical structures and in the proportion occupied by...
The neocortex is disproportionately expanded in human compared with mouse, 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. 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. 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.
Topics: Alzheimer Disease; Animals; Cell Shape; Collagen; Electrophysiology; Extracellular Matrix Proteins; Female; Glutamic Acid; Humans; Lysine; Male; Mice; Neocortex; Neurons; Patch-Clamp Techniques; Transcriptome
PubMed: 34616067
DOI: 10.1038/s41586-021-03813-8 -
Trends in Neurosciences Jan 2020Although classically thought of as a motor circuit, the cerebellum is now understood to contribute to a wide variety of cognitive functions through its dense... (Review)
Review
Although classically thought of as a motor circuit, the cerebellum is now understood to contribute to a wide variety of cognitive functions through its dense interconnections with the neocortex, the center of brain cognition. Recent investigations have shed light on the nature of cerebellar cognitive processing and information exchange with the neocortex. We review findings that demonstrate widespread reward-related cognitive input to the cerebellum, as well as new studies that have characterized the codependence of processing in the neocortex and cerebellum. Together, these data support a view of the neocortex-cerebellum circuit as a joint dynamic system both in classical sensorimotor contexts and reward-related, cognitive processing. These studies have also expanded classical theory on the computations performed by the cerebellar circuit.
Topics: Cerebellum; Cognition; Humans; Neocortex
PubMed: 31787351
DOI: 10.1016/j.tins.2019.11.002