Transcriptomic correlates of neuron electrophysiological diversity

Tripathy, Shreejoy J.; Toker, Lilah; Li, Brenna; Crichlow, Cindy-Lee; Tebaykin, Dmitry; Mancarci, B. Ogan; Pavlidis, Paul

doi:10.1101/134791

Cited by 3 publications

(1 citation statement)

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“…Differences in cell capacitance and membrane resistance hinted at distinct morphology and indeed cell body diameter measurements confirmed a significantly smaller soma size for Cartpt + as compared to surrounding Cartptneurons. Higher membrane resistance indicates that Cartpt + neurons are more electrotonically compact, which could be mediated by differential potassium channel expression (Tripathy et al, 2017). Finally, Cartpt + neurons displayed prominent voltage sag, in accordance with predictions from the DevHb dataset regarding the presence Hcn3 and Hcn4 ion channels in Cartpt + cell clusters.…”

Section: Linking Molecular and Functional Properties Of Habenular Sub...supporting

confidence: 82%

Molecular Signatures and Cellular Diversity During Mouse Habenula Development

Haar

Riga

Boer

et al. 2022

Preprint

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The habenula plays a key role in various motivated and pathological behaviors and is composed of molecularly distinct neuron subtypes. Despite progress in identifying mature habenula neuron subtypes, how these subtypes develop and organize into functional brain circuits remains largely unknown. Here we performed single-cell transcriptional profiling of mouse habenular neurons at critical developmental stages instructed by detailed three-dimensional anatomical data. Our data reveal cellular and molecular trajectories during embryonic and postnatal development leading to different habenular subtypes. Further, based on this analysis our work establishes the distinctive functional properties and projection target of a previously uncharacterized subtype of Cartpt+ habenula neurons. Finally, we show how comparison of single-cell transcriptional profiles and GWAS data links specific developing habenular subtypes to psychiatric disease. Together, our study begins to dissect the mechanisms underlying habenula neuron subtype-specific development and creates a framework for further interrogation of habenular development in normal and disease states.

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Section: Linking Molecular and Functional Properties Of Habenular Sub...supporting

confidence: 82%

Molecular Signatures and Cellular Diversity During Mouse Habenula Development

Haar

Riga

Boer

et al. 2022

Preprint

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Cross-laboratory analysis of brain cell type transcriptomes with applications to interpretation of bulk tissue data

Mancarci

Toker

Tripathy

et al. 2016

Preprint

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Establishing the molecular diversity of cell types is crucial for the study of the nervous system. We compiled a cross-laboratory database of mouse brain cell type-specific transcriptomes from 36 major cell types from across the mammalian brain using rigorously curated published data from pooled cell type microarray and single cell RNA-sequencing studies. We used these data to identify cell type-specific marker genes, discovering a substantial number of novel markers, many of which we validated using computational and experimental approaches. We further demonstrate that summarized expression of marker gene sets in bulk tissue data can be used to estimate the relative cell type abundance across samples. To facilitate use of this expanding resource, we provide a user-friendly web interface at Neuroexpresso.org.Significance StatementCell type markers are powerful tools in the study of the nervous system that help reveal properties of cell types and acquire additional information from large scale expression experiments. Despite their usefulness in the field, known marker genes for brain cell types are few in number. We present NeuroExpresso, a database of brain cell type specific gene expression profiles, and demonstrate the use of marker genes for acquiring cell type specific information from whole tissue expression. The database will prove itself as a useful resource for researchers aiming to reveal novel properties of the cell types and aid both laboratory and computational scientists to unravel the cell type specific components of brain disorders.

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Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles

Logan

Arzua

Yan

et al. 2020

Cells

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Background: The development of 3D cerebral organoid technology using human-induced pluripotent stem cells (iPSCs) provides a promising platform to study how brain diseases are appropriately modeled and treated. So far, understanding of the characteristics of organoids is still in its infancy. The current study profiled, for the first time, the electrophysiological properties of organoids at molecular and cellular levels and dissected the potential age equivalency of 2-month-old organoids to human ones by a comparison of gene expression profiles among cerebral organoids, human fetal and adult brains. Results: Cerebral organoids exhibit heterogeneous gene and protein markers of various brain cells, such as neurons, astrocytes, and vascular cells (endothelial cells and smooth muscle cells) at 2 months, and increases in neural, glial, vascular, and channel-related gene expression over a 2-month differentiation course. Two-month organoids exhibited action potentials, multiple channel activities, and functional electrophysiological responses to the anesthetic agent propofol. A bioinformatics analysis of 20,723 gene expression profiles showed the similar distance of gene profiles in cerebral organoids to fetal and adult brain tissues. The subsequent Ingenuity Pathway Analysis (IPA) of select canonical pathways related to neural development, network formation, and electrophysiological signaling, revealed that only calcium signaling, cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling in neurons, glutamate receptor signaling, and synaptogenesis signaling were predicted to be downregulated in cerebral organoids relative to fetal samples. Nearly all cerebral organoid and fetal pathway phenotypes were predicted to be downregulated compared with adult tissue. Conclusions: This novel study highlights dynamic development, cellular heterogeneity and electrophysiological activity. In particular, for the first time, electrophysiological drug response recapitulates what occurs in vivo, and neural characteristics are predicted to be highly similar to the human brain, further supporting the promising application of the cerebral organoid system for the modeling of the human brain in health and disease. Additionally, the studies from these characterizations of cerebral organoids in multiple levels and the findings from gene comparisons between cerebral organoids and humans (fetuses and adults) help us better understand this cerebral organoid-based cutting-edge platform and its wide uses in modeling human brain in terms of health and disease, development, and testing drug efficacy and toxicity.

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Transcriptomic correlates of neuron electrophysiological diversity

Cited by 3 publications

References 70 publications

Molecular Signatures and Cellular Diversity During Mouse Habenula Development

Molecular Signatures and Cellular Diversity During Mouse Habenula Development

Cross-laboratory analysis of brain cell type transcriptomes with applications to interpretation of bulk tissue data

Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles

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