Profiling transcriptomic responses of human stem cell-derived medium spiny neuron-like cells to exogenous phasic and tonic neurotransmitters
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA992014 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25181000_1.fastq.gz | Fastqsanger.gz | |||
| SRR25181000_2.fastq.gz | Fastqsanger.gz | |||
| SRR25181100_1.fastq.gz | Fastqsanger.gz | |||
| SRR25181100_2.fastq.gz | Fastqsanger.gz | |||
| SRR25181001_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptomic responses to neurotransmitters contribute to the complex processes driving memory and addiction. Advances in both measurement methods and experimental models continue to improve our understanding of this regulatory layer. Here we focus on the experimental potential of stem cell derived neurons, currently the only ethical model that can be used in reductionist and experimentally perturbable studies of human cells. Prior work has focused on generating distinct cell types from human stem cells, and has also shown their utility in modeling development and cellular phenotypes related to neurodegeneration. Here we seek an understanding of how stem cell derived neural cultures respond to perturbations experienced during development and disease progression. This work profiles transcriptomic responses of human medium spiny neuron-like cells with three specific goals. We first characterize transcriptomic responses to dopamine and dopamine receptor agonists and antagonists presented in dosing patterns mimicking acute, chronic, and withdrawal regimens. We also assess transcriptomic responses to low and persistent tonic levels of dopamine, acetylcholine, and glutamate to better mimic the in vivo environment. Finally, we identify similar and distinct responses between hMSN-like cells derived from H9 and H1 stem cell lines, providing some context for the extent of variability these types of systems will likely pose for experimentalists. The results here suggest future optimizations of human stem cell derived neurons to increase their in vivo relevance and the biological insights that can be garnered from these models.
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Project description:The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using Bacterial Artificial Chromosome (BAC) transgenic mice which express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology to affinity purify polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neuron display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted Translating Ribosome Affinity Purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations. Keywords: Cell Type Comparison
2008-11-14 | GSE13384 | GEO
Project description:The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using Bacterial Artificial Chromosome (BAC) transgenic mice which express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology to affinity purify polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neuron display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted Translating Ribosome Affinity Purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations. Keywords: Cell Type Comparison For each cell population, D1 and D2, three independent TRAP replicates were collected, and total RNA from the immunoprecipitates were amplified and hybridized. Data were normalized with the GC-RMA algorithm, and expression values on each chip were normalized to that chip’s 50th percentile. Data were then converted to log2 scale. We recommend that only genes where more than one sample has a normalized intensity larger than 16 (4 in log2 scale) should be kept in the analysis.
2008-11-14 | E-GEOD-13384 | biostudies-arrayexpress
Project description:The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using Bacterial Artificial Chromosome (BAC) transgenic mice which express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology to affinity purify polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neuron display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted Translating Ribosome Affinity Purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations. Keywords: Cell Type Comparison
2008-11-14 | GSE13386 | GEO
Project description:The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using Bacterial Artificial Chromosome (BAC) transgenic mice which express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology to affinity purify polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neuron display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted Translating Ribosome Affinity Purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations. Keywords: Cell Type Comparison For each cell type and treatment (cell = D1 or D2, treatment = acute or chronic, saline or cocaine) three independent TRAP replicates were collected, and total RNA from the immunoprecipitates were amplified and hybridized. Data were normalized with the GC-RMA algorithm, and expression values on each chip were normalized to that chip’s 50th percentile. Data were then converted to log2 scale. We recommend that only genes where more than one sample has a normalized intensity larger than 16 (4 in log2 scale) should be kept in the analysis.
2008-11-14 | E-GEOD-13386 | biostudies-arrayexpress
Project description:The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using Bacterial Artificial Chromosome (BAC) transgenic mice which express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology to affinity purify polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neuron display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted Translating Ribosome Affinity Purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations. Keywords: Cell Type Comparison
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2018-09-01 | GSE103345 | GEO
Project description:Yapo2017- cAMP/PKA signalling in D1 dopamine receptor expressing medium-spiny neurons
This model is described in the article:
Detection of phasic dopamine
by D1 and D2 striatal medium spiny neurons.
Yapo C, Nair AG, Clement L, Castro
LR, Hellgren Kotaleski J, Vincent P.
J. Physiol. (Lond.) 2017 Aug; :
Abstract:
The phasic release of dopamine in the striatum determines
various aspects of reward and action selection, but the
dynamics of dopamine effect on intracellular signalling remains
poorly understood. We used genetically-encoded FRET biosensors
in striatal brain slices to quantify the effect of transient
dopamine on cAMP or PKA-dependent phosphorylation level, and
computational modelling to further explore the dynamics of this
signalling pathway. Medium-sized spiny neurons (MSNs), which
express either D1 or D2 dopamine receptors, responded to
dopamine by an increase or a decrease in cAMP, respectively.
Transient dopamine showed similar sub-micromolar efficacies on
cAMP in both D1 and D2 MSNs, thus challenging the commonly
accepted notion that dopamine efficacy is much higher on D2
than on D1 receptors. However, in D2 MSNs, the large decrease
in cAMP level triggered by transient dopamine did not translate
in a decrease in PKA-dependent phosphorylation level, owing to
the efficient inhibition of Protein Phosphatase 1 by DARPP-32.
Simulations further suggested that D2 MSNs can also operate in
a "tone-sensing" mode, allowing them to detect transient dips
in basal dopamine. Overall, our results show that D2 MSNs may
sense much more complex patterns of dopamine than previously
thought. This article is protected by copyright. All rights
reserved.
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2017-08-16 | MODEL1701170000 | BioModels