Browse
Submit Data
Databases
API
Help

Dataset Information

11 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds.

ABSTRACT: Astrocytes play central roles in normal brain function and are critical components of synaptic networks that oversee behavioral outputs. Despite their close affiliation with neurons, how neuronal-derived signals influence astrocyte function at the gene expression level remains poorly characterized, largely due to difficulties associated with dissecting neuron- versus astrocyte-specific effects. Here, we use an in vitro system of stem cell-derived astrocytes to identify gene expression profiles in astrocytes that are influenced by neurons and regulate astrocyte development. Furthermore, we show that neurotransmitters and neuromodulators induce distinct transcriptomic and chromatin accessibility changes in astrocytes that are unique to each of these neuroactive compounds. These findings are highlighted by the observation that noradrenaline has a more profound effect on transcriptional profiles of astrocytes compared to glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and serotonin. This is demonstrated through enhanced noradrenaline-induced transcriptomic and chromatin accessibility changes in vitro and through enhanced calcium signaling in vivo. Taken together, our study reveals distinct transcriptomic and chromatin architecture signatures in astrocytes in response to neuronal-derived neuroactive compounds. Since astrocyte function is affected in all neurological disorders, this study provides a new entry point for exploring genetic mechanisms of astrocyte-neuron communication that may be dysregulated in disease.

SUBMITTER: Sardar D

PROVIDER: S-EPMC8069033 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-07 | GSE171595 | GEO

Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds

Project description:Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds

| PRJNA720144 | ENA

Profiling astrocyte transcriptional signatures in response to neurons and neuroactive compounds [RNA-seq]

Project description:The goal of the study is to profile molecular signature of astrocytes in response to neuronal contact and neuroactive chemicals. We performed RNA-seq on (1) mouse embryonic stem cell derived astrocytes (mES_astrocytes) from different time points of culture to determine transcriptomic changes as astrocytes mature over time in culture, (2) mES_astrocytes cocultured with human neurons to determine how neurons affect astrocyte gene expression and (3) mES_astrocytes cultured in presence of neuroactive chemicals (glutamate, gamma-aminobutyric acid, acetylcholine, noradrenaline, and serotonin) to determine transcriptomic changes induced by different types of neuronal signaling.

2021-04-07 | GSE171590 | GEO

Profiling astrocyte transcriptional signatures in response to neurons and neuroactive compounds [RNA-seq]

Project description:Profiling astrocyte transcriptional signatures in response to neurons and neuroactive compounds [RNA-seq]

| PRJNA720140 | ENA

Astrocytic chromatin remodeling in response to neuroactive compounds [ATAC-seq]

Project description:The goal of the study is to profile chromatin landscape of astrocytes in response to neuroactive chemicals. We performed ATAC-seq on mES_astrocytes induced for 30 minutes in presence of neuroactive chemicals (glutamate, gamma-aminobutyric acid, acetylcholine, noradrenaline, and serotonin) to understand how induction from different types of neuronal signaling remodels chromatin in astrocytes.

2021-04-07 | GSE171594 | GEO

Simultaneous analysis of neuroactive compounds in zebrafish

Project description: Not available

| S-BSST1123 | biostudies-other

Determination of minimal transcriptional signatures of compounds for target prediction.

Project description:The identification of molecular target and mechanism of action of compounds is a key hurdle in drug discovery. Multiplexed techniques for bead-based expression profiling allow the measurement of transcriptional signatures of compound-treated cells in high-throughput mode. Such profiles can be used to gain insight into compounds' mode of action and the protein targets they are modulating. Through the proxy of target prediction from such gene signatures we explored important aspects of the use of transcriptional profiles to capture biological variability of perturbed cellular assays. We found that signatures derived from expression data and signatures derived from biological interaction networks performed equally well, and we showed that gene signatures can be optimised using a genetic algorithm. Gene signatures of approximately 128 genes seemed to be most generic, capturing a maximum of the perturbation inflicted on cells through compound treatment. Moreover, we found evidence for oxidative phosphorylation to be one of the most general ways to capture compound perturbation.

| S-EPMC3386022 | biostudies-literature

Astrocytic chromatin remodeling in response to neuroactive compounds [ATAC-seq]

Project description:Astrocytic chromatin remodeling in response to neuroactive compounds [ATAC-seq]

| PRJNA720146 | ENA

In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds.

Project description:Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. In vitro experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by l-glutamate (l-Glu), l-aspartate, ?-aminobutyric acid, and acetylcholine, with l-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation. We also found that l-Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which differs from the EFV-binding site. The other principal differences between EFV and l-Glu in CYP46A1 activation include an apparent lack of l-Glu binding to the P450 active site and different pathways of signal transduction from the allosteric site to the active site. EFV and l-Glu similarly increased the CYP46A1 kcat, the rate of the "fast" phase of the enzyme reduction by the redox partner NADPH-cytochrome P450 oxidoreductase, and the amount of P450 reduced. Spectral titrations with cholesterol, in the presence of EFV or l-Glu, suggest that water displacement from the heme iron can be affected in activator-bound CYP46A1. Moreover, EFV and l-Glu synergistically activated CYP46A1. Collectively, our in vitro data, along with those from previous cell culture and in vivo studies by others, suggest that l-Glu-induced CYP46A1 activation is of physiological relevance.

| S-EPMC5546033 | biostudies-literature

Multidimensional chemobehavior analysis of flavonoids and neuroactive compounds in zebrafish.

Project description:The comparative analysis of complex behavioral phenotypes is valuable as a reductionist tool for both drug discovery and defining chemical bioactivity. Flavonoids are a diverse class of chemicals that elicit robust neuroactive and hormonal actions, though bioactivity information is limited for many, particularly for neurobehavioral endpoints. Here, we used a zebrafish larval chemomotor response (LCR) bioassay to comparatively evaluate a suite of 24 flavonoids, and in addition a panel of 30 model neuroactive compounds representing diverse modes of action (e.g. caffeine, chlorpyrifos, methamphetamine, nicotine, picrotoxin). Naïve larval zebrafish were exposed to concentration ranges of each compound at 120 hour post-fertilization (hpf) and locomotor activity measured for 5 h. The model neuroactive compounds were largely behaviorally bioactive (20 of 30) with most effects phenotypic of their known modes of action. Flavonoids rapidly and broadly elicited hyperactive locomotor effects (22 of 24). Multidimensional analyses compared responses over time and identified three distinct bioactive groups of flavonoids based on efficacy and potency. Using GABAergics to modulate hyperactive responses, two flavonoids, (S)-equol and kaempferol were tested for GABAA receptor antagonism, as well as a known GABAA receptor antagonist, picrotoxin. Pharmacological intervention with positive allosteric modulators of the GABAA receptor, alfaxalone and chlormethiazole, ameliorated the hyperactive response to picrotoxin, but not for (S)-equol or kaempferol. Taken together, these studies demonstrate that flavonoids are differentially bioactive and that the chemobehavioral effects likely do not involve a GABAA receptor mediated mode of action. Overall, the integrative zebrafish platform provides a useful framework for comparatively evaluating high-content chemobehavioral data for sets of structurally- and mechanistically-related flavonoids and neuroactive compounds.

| S-EPMC5912343 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data