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1.
Nature ; 630(8017): 587-595, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38898291

RESUMO

Advances in large-scale single-unit human neurophysiology, single-cell RNA sequencing, spatial transcriptomics and long-term ex vivo tissue culture of surgically resected human brain tissue have provided an unprecedented opportunity to study human neuroscience. In this Perspective, we describe the development of these paradigms, including Neuropixels and recent brain-cell atlas efforts, and discuss how their convergence will further investigations into the cellular underpinnings of network-level activity in the human brain. Specifically, we introduce a workflow in which functionally mapped samples of human brain tissue resected during awake brain surgery can be cultured ex vivo for multi-modal cellular and functional profiling. We then explore how advances in human neuroscience will affect clinical practice, and conclude by discussing societal and ethical implications to consider. Potential findings from the field of human neuroscience will be vast, ranging from insights into human neurodiversity and evolution to providing cell-type-specific access to study and manipulate diseased circuits in pathology. This Perspective aims to provide a unifying framework for the field of human neuroscience as we welcome an exciting era for understanding the functional cytoarchitecture of the human brain.


Assuntos
Encéfalo , Neurofisiologia , Neurociências , Análise de Célula Única , Humanos , Neurociências/métodos , Encéfalo/citologia , Encéfalo/fisiologia , Neurofisiologia/métodos , Fluxo de Trabalho , Mapeamento Encefálico/métodos , Transcriptoma
2.
Neurol Genet ; 10(2): e200142, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38586598

RESUMO

Objectives: Mosaic gain of chromosome 1q (chr1q) has been associated with malformation of cortical development (MCD) and epilepsy. Hyaline protoplasmic astrocytopathy (HPA) is a rare neuropathologic finding seen in cases of epilepsy with MCD. The cell-type specificity of mosaic chr1q gain in the brain and the molecular signatures of HPA are unknown. Methods: We present the case of a child with pharmacoresistant epilepsy who underwent epileptic focus resections at age 3 and 5 years and was found to have mosaic chr1q gain and HPA. We performed single-nuclei RNA sequencing (snRNA-seq) of brain tissue from the second resection. Results: snRNA-seq showed increased expression of chr1q genes specifically in subsets of neurons and astrocytes. Differentially expressed genes associated with inferred chr1q gain included AKT3 and genes associated with cell adhesion or migration. A subpopulation of astrocytes demonstrated marked enrichment for synapse-associated transcripts, possibly linked to the astrocytic inclusions observed in HPA. Discussion: snRNA-seq may be used to infer the cell-type specificity of mosaic chromosomal copy number changes and identify associated gene expression alterations, which in the case of chr1q gain may involve aberrations in cell migration. Future studies using spatial profiling could yield further insights on the molecular signatures of HPA.

3.
bioRxiv ; 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38328093

RESUMO

Introduction: Mosaic gain of chromosome 1q (chr1q) has been associated with malformation of cortical development (MCD) and epilepsy. Hyaline protoplasmic astrocytopathy (HPA) is a rare neuropathological finding seen in cases of epilepsy with MCD. The cell-type specificity of mosaic chr1q gain in the brain and the molecular signatures of HPA are unknown. Methods: We present a child with pharmacoresistant epilepsy who underwent epileptic focus resections at age 3 and 5 years and was found to have mosaic chr1q gain and HPA. We performed single-nuclei RNA-sequencing (snRNA-seq) of brain tissue from the second resection. Results: snRNA-seq showed increased expression of chr1q genes specifically in subsets of neurons and astrocytes. Differentially expressed genes associated with inferred chr1q gain included AKT3 and genes associated with cell adhesion or migration. A subpopulation of astrocytes demonstrated marked enrichment for synapse-associated transcripts, possibly linked to the astrocytic inclusions observed in HPA. Discussion: snRNA-seq may be used to infer the cell type-specificity of mosaic chromosomal copy number changes and identify associated gene expression alterations, which in the case of chr1q gain may involve aberrations in cell migration. Future studies using spatial profiling could yield further insights on the molecular signatures of HPA.

4.
J Neurosci ; 43(50): 8621-8636, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-37845031

RESUMO

Astrocytes play essential roles in the developing nervous system, including supporting synapse function. These astrocyte support functions emerge coincident with brain maturation and may be tailored in a region-specific manner. For example, gray matter astrocytes have elaborate synapse-associated processes and are morphologically and molecularly distinct from white matter astrocytes. This raises the question of whether there are unique environmental cues that promote gray matter astrocyte identity and synaptogenic function. We previously identified adrenergic receptors as preferentially enriched in developing gray versus white matter astrocytes, suggesting that noradrenergic signaling could be a cue that promotes the functional maturation of gray matter astrocytes. We first characterized noradrenergic projections during postnatal brain development in mouse and human, finding that process density was higher in the gray matter and increased concurrently with astrocyte maturation. RNA sequencing revealed that astrocytes in both species expressed α- and ß-adrenergic receptors. We found that stimulation of ß-adrenergic receptors increased primary branching of rodent astrocytes in vitro Conversely, astrocyte-conditional knockout of the ß1-adrenergic receptor reduced the size of gray matter astrocytes and led to dysregulated sensorimotor integration in female mice. These studies suggest that adrenergic signaling to developing astrocytes impacts their morphology and has implications for adult behavior, particularly in female animals. More broadly, they demonstrate a mechanism through which environmental cues impact astrocyte development. Given the key roles of norepinephrine in brain states, such as arousal, stress, and learning, these findings could prompt further inquiry into how developmental stressors impact astrocyte development and adult brain function.SIGNIFICANCE STATEMENT This study demonstrates a role for noradrenergic signaling in the development of gray matter astrocytes. We provide new evidence that the ß1-adrenergic receptor is robustly expressed by both mouse and human astrocytes, and that conditional KO of the ß1-adrenergic receptor from female mouse astrocytes impairs gray matter astrocyte maturation. Moreover, female conditional KO mice exhibit behavioral deficits in two paradigms that test sensorimotor function. Given the emerging interest in moving beyond RNA sequencing to probe specific pathways that underlie astrocyte heterogeneity, this study provides a foundation for future investigation into the effect of noradrenergic signaling on astrocyte functions in conditions where noradrenergic signaling is altered, such as stress, arousal, and learning.


Assuntos
Adrenérgicos , Astrócitos , Humanos , Camundongos , Animais , Feminino , Adrenérgicos/metabolismo , Astrócitos/metabolismo , Transdução de Sinais , Norepinefrina/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos
5.
Nature ; 622(7981): 112-119, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37704727

RESUMO

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.


Assuntos
Proteômica , Sinapses , Adolescente , Animais , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Camundongos , Adulto Jovem , Cognição/fisiologia , Espinhas Dendríticas , Idade Gestacional , Macaca , Neurônios/metabolismo , Densidade Pós-Sináptica/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Transdução de Sinais , Especificidade da Espécie , Sinapses/metabolismo , Sinapses/fisiologia
6.
Cell ; 185(20): 3753-3769.e18, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36179668

RESUMO

Interactions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester. These vascular cells follow distinct developmental trajectories and utilize diverse signaling mechanisms, including collagen, laminin, and midkine, to facilitate cell-cell communication and maturation. Interestingly, our results reveal that tip cells, a subtype of endothelial cells, are highly enriched near the ventricular zone, the site of active neurogenesis. Consistent with these observations, prenatal vascular cells transplanted into cortical organoids exhibit restricted lineage potential that favors tip cells, promotes neurogenesis, and reduces cellular stress. Together, our results uncover important mechanisms into vascular maturation during this critical period of human brain development.


Assuntos
Células Endoteliais , Neovascularização Fisiológica , Encéfalo , Colágeno , Humanos , Laminina , Midkina , Neovascularização Patológica/patologia , Neovascularização Fisiológica/fisiologia , Pericitos
7.
Science ; 376(6590): eabn8861, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35420933

RESUMO

Terreros-Roncal et al. investigated the impacts of human neurodegeneration on immunostainings assumed to be associated with neurogenesis. However, the study provides no evidence that putative proliferating cells are linked to neurogenesis, that multipolar nestin+ astrocytes are progenitors, or that mature-looking doublecortin+ neurons are adult-born. Their histology-marker expression differs from what is observed in species where adult hippocampal neurogenesis is well documented.


Assuntos
Hipocampo , Doenças Neurodegenerativas , Neurogênese , Adulto , Astrócitos , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Doenças Neurodegenerativas/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia
8.
Nature ; 603(7903): 871-877, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35322231

RESUMO

Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs)1, and recent studies have identified primate-specific neuronal populations at the molecular level2. However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution.


Assuntos
Evolução Biológica , Corpo Estriado , Desenvolvimento Embrionário , Macaca , Neurogênese , Neurônios , Bulbo Olfatório , Animais , Corpo Estriado/crescimento & desenvolvimento , Neurônios Dopaminérgicos , Feminino , Macaca/crescimento & desenvolvimento , Mamíferos , Camundongos , Neurogênese/fisiologia , Bulbo Olfatório/fisiologia , Gravidez , Primatas
9.
Science ; 375(6579): eabk2346, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35084970

RESUMO

The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.


Assuntos
Interneurônios/fisiologia , Eminência Mediana/embriologia , Células-Tronco Neurais/fisiologia , Neurogênese , Prosencéfalo/citologia , Animais , Animais Recém-Nascidos , Movimento Celular , Proliferação de Células , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/fisiologia , Perfilação da Expressão Gênica , Idade Gestacional , Humanos , Interneurônios/citologia , Eminência Mediana/citologia , Eminência Mediana/crescimento & desenvolvimento , Camundongos , Células-Tronco Neurais/transplante , Prosencéfalo/embriologia , Prosencéfalo/crescimento & desenvolvimento , Transplante Heterólogo
10.
Science ; 375(6579): eabf5546, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35084981

RESUMO

Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Interneurônios/citologia , Células-Tronco Neurais/fisiologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Encéfalo/embriologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Carcinogênese , Linhagem da Célula , Proliferação de Células , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Interneurônios/fisiologia , Perda de Heterozigosidade , Células-Tronco Neurais/citologia , Organoides , RNA-Seq , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
11.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066025

RESUMO

A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.


Assuntos
Interneurônios/metabolismo , Prosencéfalo/crescimento & desenvolvimento , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Idade Gestacional , Gravidez , Prosencéfalo/metabolismo
12.
J Neurosci ; 41(12): 2554-2565, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33762407

RESUMO

Adult hippocampal neurogenesis was originally discovered in rodents. Subsequent studies identified the adult neural stem cells and found important links between adult neurogenesis and plasticity, behavior, and disease. However, whether new neurons are produced in the human dentate gyrus (DG) during healthy aging is still debated. We and others readily observe proliferating neural progenitors in the infant hippocampus near immature cells expressing doublecortin (DCX), but the number of such cells decreases in children and few, if any, are present in adults. Recent investigations using dual antigen retrieval find many cells stained by DCX antibodies in adult human DG. This has been interpreted as evidence for high rates of adult neurogenesis, even at older ages. However, most of these DCX-labeled cells have mature morphology. Furthermore, studies in the adult human DG have not found a germinal region containing dividing progenitor cells. In this Dual Perspectives article, we show that dual antigen retrieval is not required for the detection of DCX in multiple human brain regions of infants or adults. We review prior studies and present new data showing that DCX is not uniquely expressed by newly born neurons: DCX is present in adult amygdala, entorhinal and parahippocampal cortex neurons despite being absent in the neighboring DG. Analysis of available RNA-sequencing datasets supports the view that DG neurogenesis is rare or absent in the adult human brain. To resolve the conflicting interpretations in humans, it is necessary to identify and visualize dividing neuronal precursors or develop new methods to evaluate the age of a neuron at the single-cell level.


Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Adulto , Diferenciação Celular/fisiologia , Criança , Humanos , Plasticidade Neuronal/fisiologia
13.
J Neurosci ; 41(14): 3105-3119, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33637558

RESUMO

Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6, and Dlx2 expression, in vitro differentiation into neurons expressing GABA, and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.SIGNIFICANCE STATEMENT Here we demonstrate that porcine medial ganglionic eminence, like rodents, exhibit a distinct transcriptional and interneuron-specific antibody profile, in vitro migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic interneuron origins in the pig; and because a rich neurodevelopmental literature on embryonic mouse medial ganglionic eminence exists (with some additional characterizations in other species, e.g., monkey and human), our work allows direct neurodevelopmental comparisons with this literature.


Assuntos
Gânglios/embriologia , Gânglios/transplante , Interneurônios/transplante , Eminência Mediana/embriologia , Eminência Mediana/transplante , Transplante Heterólogo/métodos , Animais , Feminino , Gânglios/citologia , Masculino , Eminência Mediana/citologia , Ratos , Ratos Sprague-Dawley , Suínos , Técnicas de Cultura de Tecidos/métodos
14.
Cell Rep ; 33(2): 108256, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33053356

RESUMO

Angiogenesis and neurogenesis are tightly coupled during embryonic brain development. However, little is known about how these two processes interact. We show that nascent blood vessels actively contact dividing neural stem cells by endothelial filopodia in the ventricular zone (VZ) of the murine ventral telencephalon; this association is conserved in the human ventral VZ. Using mouse mutants with altered vascular filopodia density, we show that this interaction leads to prolonged cell cycle of apical neural progenitors (ANPs) and favors early neuronal differentiation. Interestingly, pharmacological experiments reveal that ANPs induce vascular filopodia formation by upregulating vascular endothelial growth factor (VEGF)-A in a cell-cycle-dependent manner. This mutual relationship between vascular filopodia and ANPs works as a self-regulatory system that senses ANP proliferation rates and rapidly adjusts neuronal production levels. Our findings indicate a function of vascular filopodia in fine-tuning neural stem cell behavior, which is the basis for proper brain development.


Assuntos
Células-Tronco Neurais/metabolismo , Neurogênese , Pseudópodes/metabolismo , Telencéfalo/irrigação sanguínea , Animais , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Endotélio Vascular/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Neurônios/citologia , Pseudópodes/ultraestrutura , Telencéfalo/ultraestrutura , Imagem com Lapso de Tempo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Elife ; 92020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32452758

RESUMO

​Maf (c-Maf) and Mafb transcription factors (TFs) have compensatory roles in repressing somatostatin (SST+) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. Maf and Mafb conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) Mef2c and Snap25 are positively regulated by Maf and Mafb to drive IN morphological maturation; (2) Maf and Mafb promote Mef2c expression which specifies parvalbumin (PV+) INs; (3) Elmo1, Igfbp4 and Mef2c are candidate markers of immature PV+ hippocampal INs (HIN). Furthermore, Maf/Mafb neonatal cDKOs have decreased CINs and increased HINs, that express Pnoc, an HIN specific marker. Our findings not only elucidate key gene targets of Maf and Mafb that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.


Assuntos
Regulação da Expressão Gênica , Interneurônios/metabolismo , Fator de Transcrição MafB/fisiologia , Proteínas Proto-Oncogênicas c-maf/fisiologia , Animais , Feminino , Fatores de Transcrição MEF2/metabolismo , Camundongos , Doenças do Sistema Nervoso/etiologia , Gravidez , Precursores de Proteínas/genética , Receptores CXCR4/metabolismo , Receptores Opioides/genética , Análise de Célula Única , Proteína 25 Associada a Sinaptossoma/metabolismo , Transcriptoma
16.
Nat Neurosci ; 23(4): 500-509, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203496

RESUMO

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.


Assuntos
Astrócitos/citologia , Córtex Cerebral/citologia , Neurônios/citologia , Transcriptoma , Animais , Astrócitos/metabolismo , Mapeamento Encefálico , Córtex Cerebral/metabolismo , Humanos , Camundongos , Neurônios/metabolismo
17.
Front Cell Neurosci ; 13: 434, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611776

RESUMO

In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting.

18.
Nat Commun ; 10(1): 2748, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227709

RESUMO

The human amygdala grows during childhood, and its abnormal development is linked to mood disorders. The primate amygdala contains a large population of immature neurons in the paralaminar nuclei (PL), suggesting protracted development and possibly neurogenesis. Here we studied human PL development from embryonic stages to adulthood. The PL develops next to the caudal ganglionic eminence, which generates inhibitory interneurons, yet most PL neurons express excitatory markers. In children, most PL cells are immature (DCX+PSA-NCAM+), and during adolescence many transition into mature (TBR1+VGLUT2+) neurons. Immature PL neurons persist into old age, yet local progenitor proliferation sharply decreases in infants. Using single nuclei RNA sequencing, we identify the transcriptional profile of immature excitatory neurons in the human amygdala between 4-15 years. We conclude that the human PL contains excitatory neurons that remain immature for decades, a possible substrate for persistent plasticity at the interface of the hippocampus and amygdala.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Complexo Nuclear Basolateral da Amígdala/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Adolescente , Adulto , Idoso , Complexo Nuclear Basolateral da Amígdala/citologia , Núcleo Celular/genética , Criança , Pré-Escolar , Feto , Hipocampo/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Adulto Jovem
19.
Neuron ; 102(1): 143-158.e7, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30770253

RESUMO

In the developing human neocortex, progenitor cells generate diverse cell types prenatally. Progenitor cells and newborn neurons respond to signaling cues, including neurotransmitters. While single-cell RNA sequencing has revealed cellular diversity, physiological heterogeneity has yet to be mapped onto these developing and diverse cell types. By combining measurements of intracellular Ca2+ elevations in response to neurotransmitter receptor agonists and RNA sequencing of the same single cells, we show that Ca2+ responses are cell-type-specific and change dynamically with lineage progression. Physiological response properties predict molecular cell identity and additionally reveal diversity not captured by single-cell transcriptomics. We find that the serotonin receptor HTR2A selectively activates radial glia cells in the developing human, but not mouse, neocortex, and inhibiting HTR2A receptors in human radial glia disrupts the radial glial scaffold. We show highly specific neurotransmitter signaling during neurogenesis in the developing human neocortex and highlight evolutionarily divergent mechanisms of physiological signaling.


Assuntos
Cálcio/metabolismo , Células Ependimogliais/metabolismo , Neocórtex/embriologia , Neurogênese/genética , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Linhagem da Célula , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Neocórtex/citologia , Neocórtex/metabolismo , Neurogênese/fisiologia , Análise de Sequência de RNA , Serotonina/metabolismo , Análise de Célula Única
20.
Front Cell Neurosci ; 13: 576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32038172

RESUMO

Creating a functional cerebral cortex requires a series of complex and well-coordinated developmental steps. These steps have evolved across species with the emergence of cortical gyrification and coincided with more complex behaviors. The presence of diverse progenitor cells, a protracted timeline for neuronal migration and maturation, and diverse neuronal types are developmental features that have emerged in the gyrated cortex. These factors could explain how the human brain has expanded in size and complexity. However, their complex nature also renders new avenues of vulnerability by providing additional cell types that could contribute to disease and longer time windows that could impact the composition and organization of the cortical circuit. We aim to discuss the unique developmental steps observed in human corticogenesis and propose how disruption of these species-unique processes could lead to malformations of cortical development.

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