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Generation of Locus Coeruleus Norepinephrine Neurons from Human Pluripotent Stem Cells [snRNA-seq]

ABSTRACT: Generation of Locus Coeruleus Norepinephrine Neurons from Human Pluripotent Stem Cells [snRNA-seq]

PROVIDER: PRJNA917198 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22944234_1.fastq.gz	Fastqsanger.gz
	SRR22944234_2.fastq.gz	Fastqsanger.gz
	SRR22944235_1.fastq.gz	Fastqsanger.gz
	SRR22944235_2.fastq.gz	Fastqsanger.gz
	SRR22944236_1.fastq.gz	Fastqsanger.gz

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Generation of Locus Coeruleus Norepinephrine Neurons from Human Pluripotent Stem Cells [snRNA-seq]

Project description:Central norepinephrine (NE) neurons, mainly located in the Locus coeruleus (LC), play roles in a wide range of behavioral and physiological processes. How the human LC-NE neurons develop and what roles they play in the pathophysiology of human diseases is poorly understood, partly due to the unavailability of functional human LC-NE neurons. Here we established a technology for efficient generation of LC-NE neurons from human pluripotent stem cells by identifying a novel role of ACTIVIN A in regulating the LC-NE transcription factors in the dorsal rhombomere 1 (r1) progenitors. The in vitro generated human LC-NE neurons not only display extensive axonal arborization and release/uptake NE, but also exhibit the pacemaker activity, calcium oscillation, and in particular chemoreceptor activity in response to CO2. Multiple timepoint single nucleus RNA-Seq (snRNA-Seq) analysis captured the dynamic NE differentiation process, confirmed the NE cell population and revealed the differentiation trajectory from hindbrain progenitors to NE neurons via ASCL1 expressing precursor stage. The LC-NE neurons engineered with a NE sensor reliably reported the extracellular NE level. The availability of functional human LC-NE neurons enables investigation of their roles in the pathogenesis of and development of therapeutics for neural psychiatric and degenerative diseases.

2023-08-24 | GSE221988 | GEO

Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells.

Project description: Not available

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Cellular Signatures of Melanocortin Pathway Genes Across the Locus Coeruleus [snRNA-seq]

Project description:Cellular Signatures of Melanocortin Pathway Genes Across the Locus Coeruleus [snRNA-seq]

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Cellular Signatures of Melanocortin Pathway Genes Across the Locus Coeruleus [snRNA-seq]

Project description:Obesity and Alzheimer’s disease (AD) are epidemiologically associated. The locus coeruleus (LC) – the brain’s primary and most significant source of norepinephrine – is one of the earliest sites of neurodegeneration in AD. The LC participates in feeding behavior through connections with the hypothalamus. The cellular composition of the LC has been characterized at single-cell resolution. However, the constituent cellular signatures of genes related to energy homeostasis – such as the melanocortin pathway genes – in the LC are unclear. We performed single-nucleus RNA sequencing and spatial transcriptomics (Visium) in the human LC, and HiPlex RNAscope in the LC of mice. The melanocortin pathway gene MRAP2 was expressed in the majority of DBH neurons across the LC. Mrap2 was also co-expressed with AD-associated genes such as App, Psen1, Psen2, and Sorl1. More than 20% of Dbh neurons in the LC were positive for Mrap2, App, Psen1, and Psen2. Mrap2 is expressed in the central nervous system and modulates the trafficking and signaling of all five G-protein coupled receptors (GPCRs) of the melanocortin receptor family: Mc1r, Mc2r, Mc3r, Mc4r, and Mc5r. In mice, among the melanocortin receptors, Mc5r showed the highest co-expression with Mrap2, accounting for 17.9% of Mrap2-positive cells, followed by Mc2r with 10.9% of Mrap2-positive cells. Mc1r, Mc3r, and Mc4r showed very limited co-expression with Mrap2. Our study reveals that many Mrap2-positive cells do not express any melanocortin receptor genes, warranting future studies into metabolically relevant GPCRs downstream of MRAP2 in the LC. In summary, our study characterizes melanocortin molecular substrates in the human and mouse LC and highlights MRAP2 as a potential link between pathways of energy homeostasis and neurodegeneration.

2026-04-20 | GSE327442 | GEO

Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy.

Project description: Not available

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Single-nuclei RNA sequencing of the locus coeruleus and pericoerulear brain regions

Project description:As the primary source of norepinephrine (NE) in the brain, the locus coeruleus (LC) regulates both arousal and stress responses, but how neuromodulatory inputs contribute to LC modulation remains incompletely understood. In this study, we isolated a network of transcriptionally diverse inhibitory pericoerulear (peri-LC) GABAergic neurons that integrate distant stimuli and modulate modes of LC firing. To define the peri-LC anatomy, we used viral tracing, single-nuclei and high-resolution spatial RNA transcriptomics to molecularly characterize both LC and peri-LC cell types. We complemented this approach with techniques in electrophysiology, photometry, optogenetics, and chemogenetics to probe the function of peri-LC neurons in behaving mice. These findings indicate that LC and peri-LC neurons comprise transcriptionally heterogenous neuronal groups which integrate diverse inputs to influence behavioral arousal states and avoidance. We used snRNAseq to characterize the peri-LC and LC brain regions. Our dataset contains 30,838 cells, of which 12,278 are neurons.

2025-01-31 | GSE201998 | GEO

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The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

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