Effect of bromodomain inhibitors on dopamine D1R induced gene expression in striatal neurons
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE179370 | GEO | 2021/07/05
REPOSITORIES: GEO
Shared Molecules
Only show the datasets with similarity scores above: 0.5
Threshold
0.5
Similar Datasets
Project description:This dataset contains single-nucleus RNA sequencing results from rat embryonic striatal neuronal cultures and serves as the basis for characterization of transcriptional response to dopamine (50µM), the Drd1 agonist SKF-38393 (1µM), and potassium chloride (25mM). The goal of this experiment was to define the transcriptional response to each of these stimulations across distinct cell types in cultured neurons. Single-cell sequencing was carried out on FACS-sorted nuclei isolated from these experiments using the 10X Genomics Chromium single cell sequencing platform.
2020-06-24 | GSE137759 | GEO
Project description:Nair2015 - Interaction between
neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D1
Neuron)
This model is described in the article:
Sensing Positive versus
Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs
in Direct and Indirect Pathway Striatal Medium Spiny
Neurons.
Nair AG, Gutierrez-Arenas O,
Eriksson O, Vincent P, Hellgren Kotaleski J.
J. Neurosci. 2015 Oct; 35(41):
14017-14030
Abstract:
Transient changes in striatal dopamine (DA) concentration
are considered to encode a reward prediction error (RPE) in
reinforcement learning tasks. Often, a phasic DA change occurs
concomitantly with a dip in striatal acetylcholine (ACh),
whereas other neuromodulators, such as adenosine (Adn), change
slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs
for these neuromodulators in striatal medium spiny neurons
(MSNs), which play important roles in plasticity. However,
little is known about the interaction between these
neuromodulators via GPCRs. The interaction between these
transient neuromodulator changes and the effect on cAMP/PKA
signaling via Golf- and Gi/o-coupled GPCR are studied here
using quantitative kinetic modeling. The simulations suggest
that, under basal conditions, cAMP/PKA signaling could be
significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an
ACh dip is required to gate a subset of D1R/Golf-dependent PKA
activation. Furthermore, the interaction between ACh dip and DA
peak, via D1R and M4R, is synergistic. In a similar fashion,
PKA signaling in D2+ MSNs is under basal inhibition via
D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting
A2aR/Golf, but D2+ MSNs could also respond to the DA peak via
other intracellular pathways. This study highlights the
similarity between the two types of MSNs in terms of high basal
AC inhibition by Gi/o and the importance of interactions
between Gi/o and Golf signaling, but at the same time predicts
differences between them with regard to the sign of RPE
responsible for PKA activation.Dopamine transients are
considered to carry reward-related signal in reinforcement
learning. An increase in dopamine concentration is associated
with an unexpected reward or salient stimuli, whereas a
decrease is produced by omission of an expected reward. Often
dopamine transients are accompanied by other neuromodulatory
signals, such as acetylcholine and adenosine. We highlight the
importance of interaction between acetylcholine, dopamine, and
adenosine signals via adenylyl-cyclase coupled GPCRs in shaping
the dopamine-dependent cAMP/PKA signaling in striatal neurons.
Specifically, a dopamine peak and an acetylcholine dip must
interact, via D1 and M4 receptor, and a dopamine dip must
interact with adenosine tone, via D2 and A2a receptor, in
direct and indirect pathway neurons, respectively, to have any
significant downstream PKA activation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000635.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000635 | BioModels
Project description:Nair2015 - Interaction between
neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D2
Neuron)
This model is described in the article:
Sensing Positive versus
Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs
in Direct and Indirect Pathway Striatal Medium Spiny
Neurons.
Nair AG, Gutierrez-Arenas O,
Eriksson O, Vincent P, Hellgren Kotaleski J.
J. Neurosci. 2015 Oct; 35(41):
14017-14030
Abstract:
Transient changes in striatal dopamine (DA) concentration
are considered to encode a reward prediction error (RPE) in
reinforcement learning tasks. Often, a phasic DA change occurs
concomitantly with a dip in striatal acetylcholine (ACh),
whereas other neuromodulators, such as adenosine (Adn), change
slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs
for these neuromodulators in striatal medium spiny neurons
(MSNs), which play important roles in plasticity. However,
little is known about the interaction between these
neuromodulators via GPCRs. The interaction between these
transient neuromodulator changes and the effect on cAMP/PKA
signaling via Golf- and Gi/o-coupled GPCR are studied here
using quantitative kinetic modeling. The simulations suggest
that, under basal conditions, cAMP/PKA signaling could be
significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an
ACh dip is required to gate a subset of D1R/Golf-dependent PKA
activation. Furthermore, the interaction between ACh dip and DA
peak, via D1R and M4R, is synergistic. In a similar fashion,
PKA signaling in D2+ MSNs is under basal inhibition via
D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting
A2aR/Golf, but D2+ MSNs could also respond to the DA peak via
other intracellular pathways. This study highlights the
similarity between the two types of MSNs in terms of high basal
AC inhibition by Gi/o and the importance of interactions
between Gi/o and Golf signaling, but at the same time predicts
differences between them with regard to the sign of RPE
responsible for PKA activation.Dopamine transients are
considered to carry reward-related signal in reinforcement
learning. An increase in dopamine concentration is associated
with an unexpected reward or salient stimuli, whereas a
decrease is produced by omission of an expected reward. Often
dopamine transients are accompanied by other neuromodulatory
signals, such as acetylcholine and adenosine. We highlight the
importance of interaction between acetylcholine, dopamine, and
adenosine signals via adenylyl-cyclase coupled GPCRs in shaping
the dopamine-dependent cAMP/PKA signaling in striatal neurons.
Specifically, a dopamine peak and an acetylcholine dip must
interact, via D1 and M4 receptor, and a dopamine dip must
interact with adenosine tone, via D2 and A2a receptor, in
direct and indirect pathway neurons, respectively, to have any
significant downstream PKA activation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000636.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000636 | BioModels
Project description:Effect of bromodomain inhibitors on dopamine D1R induced gene expression in striatal neurons
| PRJNA743352 | ENA
Project description:Nair2016 - Integration of calcium and
dopamine signals by D1R-expressing medium-sized spiny neurons
This model is described in the article:
Role of DARPP-32 and ARPP-21
in the Emergence of Temporal Constraints on Striatal Calcium
and Dopamine Integration.
Nair AG, Bhalla US, Hellgren
Kotaleski J.
PLoS Comput. Biol. 2016 Sep; 12(9):
e1005080
Abstract:
In reward learning, the integration of NMDA-dependent
calcium and dopamine by striatal projection neurons leads to
potentiation of corticostriatal synapses through CaMKII/PP1
signaling. In order to elicit the CaMKII/PP1-dependent
response, the calcium and dopamine inputs should arrive in
temporal proximity and must follow a specific (dopamine after
calcium) order. However, little is known about the cellular
mechanism which enforces these temporal constraints on the
signal integration. In this computational study, we propose
that these temporal requirements emerge as a result of the
coordinated signaling via two striatal phosphoproteins,
DARPP-32 and ARPP-21. Specifically, DARPP-32-mediated signaling
could implement an input-interval dependent gating function,
via transient PP1 inhibition, thus enforcing the requirement
for temporal proximity. Furthermore, ARPP-21 signaling could
impose the additional input-order requirement of calcium and
dopamine, due to its Ca2+/calmodulin sequestering property when
dopamine arrives first. This highlights the possible role of
phosphoproteins in the temporal aspects of striatal signal
transduction.
This model is hosted on
BioModels Database
and identified by:
MODEL1603270000.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-09-16 | MODEL1603270000 | BioModels
Project description:Parkinson’s (PD) is a multi-factorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal based cognitive function are common, appear early and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation in Lrrk2 also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of AMPA-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we used Lrrk2G2019S knockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs in dorsomedial striatum to favor incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D1R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD.
2024-06-16 | GSE246117 | GEO
Project description:Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.
2021-02-16 | GSE138802 | GEO
Project description:Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs. JQ1 (50-400 nM) increases insulin secretion from INS-1 cells in a concentration dependent manner. JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Overlapping yet discrete roles for individual BET proteins in metabolic regulation suggest new isoform-selective BET inhibitors may be useful to treat insulin resistant/diabetic patients. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.
2016-03-07 | GSE77450 | GEO
Project description:The goal of this experiment was to determine how dopamine receptor activation in medium spiny neurons alters rapid transcriptional programs. To identify genes altered by dopamine, we used a rat primary striatal neuronal culture system in which striatal neurons were removed from the rat brain at embryonic day 18, cultured for 11 days in vitro using standard neuronal conditions, and treated neurons with either vehicle (neurobasal media) or dopamine (at a concentration of 1µM) for 1hr. This dataset contains PolyA+ RNA-seq results from this experiment, in which we identified 100 upregulated genes and 3 downregulated genes after dopamine stimulation using DESeq2 pipelines.
2020-06-24 | GSE137568 | GEO
Project description:Three triple negative breast cancer cell lines (MDAMB231, SUM159, and HCC1806) were treated with small molecule inhibitors (JQ1, BET bromodomain inhibitor; GSK2801, BAZ2A/B bromodomain inhibitor) or BAZ siRNA alone and in combination with JQ1 for 48 hours
2019-07-09 | GSE116879 | GEO