Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE94145 | GEO | 2020/03/16
REPOSITORIES: GEO
Similar Datasets
Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.
2022-03-17 | GSE185052 | GEO
Project description:We performed a study of gene expression changes that occur during mouse aging in the striatum and cortex in specific neuronal populations. Using translating ribosome afifnity purificaiton, we captured cell type-specific mRNAs from Drd1a-expressing cortical neurons, Drd1a-expressing striatal neurons, Drd2-expressing cortical neurons, and Drd2-expressing striatal neurons. 31 total samples were anlayzed. We generated the followinf pairwise comparisons: Old (2 years) vs young (6 weeks) Drd1a expressing cortical cells; old (2 years) vs young (6 weeks) Drd2 expressing cortical cells; old (2 years) vs young (6 weeks) Drd1a expressing striatal cells; old (2 years) vs young (6 weeks) Drd2 expressing striatal cells. We used a restriction of Benjamini-Hochberg FDR <0.05, and a fold-change restriction of 1.2-fold.
2014-12-13 | E-GEOD-64140 | biostudies-arrayexpress
Project description:The molecular mechanisms that underlie striatal development and organization remain largely unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and demonstrate that Foxp1 specifies a subpopulation of indirect pathway spiny projection neurons (iSPNs) while maintaining the striosome-matrix architecture through molecular mechanisms mediated by direct pathway spiny projection neurons (dSPNs). Functionally, Foxp1 alters striatal projection patterns both cell-autonomously and non-autonomously. We connect these changes in striatal circuitry to distinct behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. These data reveal novel cell-type specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development
2020-04-13 | GSE125290 | GEO
Project description:We performed a study of gene expression changes that occur during mouse aging in the striatum and cortex in specific neuronal populations. Using translating ribosome afifnity purificaiton, we captured cell type-specific mRNAs from Drd1a-expressing cortical neurons, Drd1a-expressing striatal neurons, Drd2-expressing cortical neurons, and Drd2-expressing striatal neurons.
2014-12-13 | GSE64140 | GEO
Project description:Selective degeneration of striatal projection neurons is one of the main features of Huntington’s disease (HD). The differences between vulnerable and resilient striatal cell types and cell type-specific molecular events associated with HD progression have not been established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of different cell types of the human striatum in HD and control donors.
2023-12-04 | GSE227729 | GEO
Project description:Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.
2018-07-18 | GSE116752 | 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:Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum
| PRJNA369081 | ENA
Project description:The mechanisms by which mutant Huntingtin leads to neuronal cell death in Huntington’s disease are not fully understood. To gain new molecular insights, we used snRNA-Seq and TRAP to conduct transcriptomic analyses of striatal cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons we observe a release of mitochondrial RNA and a concomitant upregulation of innate immune signaling in spiny projection neurons. We observe that the released mtRNAs can directly bind to the innate immune sensor PKR. We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis, and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.
2020-07-17 | GSE152058 | GEO