Expression data from 9 and 13 weeks old TIFIAD1Cre mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29647 | GEO | 2011/06/01
SECONDARY ACCESSION(S): PRJNA141231
REPOSITORIES: GEO
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Project description:We have investigated the p53-dependent stress response in medium spiny neurons (MSNs) that degenerate in Huntington’s disease. To induce p53 signaling cascade, we have genetically inactivated by the Cre/loxP system the essential RNA polymerase I (Pol I) transcription factor TIF-IA, leading to stabilization of p53 and induction of p53-dependent apoptosis. In the present study, we selectively ablated the TIF-IA gene in MSNs by crossing TIF-IAflox/flox mice, homozygous for the floxed TIF-IA allele with transgenic mice expressing the Cre recombinase under the control of the D1 dopamine receptor (D1R) promoter. To explore the molecular mechanisms underlying survival and death we profiled global gene expression in 9 and 13 week old control and TIF-IAD1RCre mutant mice (3 mice/each timepoint For each of the four conditions, five GeneChips were used each )
2011-06-01 | E-GEOD-29647 | biostudies-arrayexpress
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Project description:Variations in the human FTO gene have been linked to obesity and altered connectivity and function of the dopaminergic neurocircuitry. Here we report that FTO in D2 medium spiny neurons (MSNs) of mice regulates the excitability of these cells in vitro and in vivo as well as controls D2 MSN globus pallidus external projections. Lack of FTO in D2 MSNs translates into increased locomotor responses to novelty, associated with altered timing behavior without affecting reward responses to drugs of abuse and highly palatable food, or the ability to discount rewards. Pharmacological manipulation of D1R- and D2R-dependent pathways in these animals reveals an altered balance between D1 MSN- and D2 MSN-mediated control of motor output. These findings hold the potential to target a novel avenue for control of basal ganglia motor function, where modulation of FTO-dependent signaling in D2 MSNs may promote D1 MSN regulated locomotor behavior without altering reward signaling or inciting impulsivity.
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Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.
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Project description:Direct neuronal conversion of fibroblasts from Huntington’s disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD.
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Project description:Direct neuronal conversion of fibroblasts from Huntington’s disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD.
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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:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.
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