Mouse hypothalamus and whole brain: control vs. sodium craving
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29451 | GEO | 2011/07/04
SECONDARY ACCESSION(S): PRJNA141569
REPOSITORIES: GEO
Similar Datasets
Project description:Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked ACTH and by reproduction. Genome-wide microarrays in sodium deficient mice, or following ACTH infusion, showed upregulation of hypothalamic genes, including DARPP-32, dopamine receptors-1 and -2, alpha-2C-adrenoceptor, and STEP. Both DARPP-32 and neural plasticity regulator, ARC were upregulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1- (SCH23390) and D2-receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1-receptor knockout mice had normal sodium appetite, indicating compensatory regulation. It was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100nM in 200nL) into rats? lateral hypothalamus greatly reduced sodium appetite. Gene Set Enrichment Analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates, cocaine). This finding of concerted gene regulation was attenuated upon gratification with perplexingly rapid kinetics of only 10 minutes, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over more than a hundred million years e.g. being present in Metatheria. Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a novel molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications. Transcripts were profiled in the hypothalamus and whole brain of control and salt craving animals to determine the gene expression profile corresponding to that behavioral state. We show an over-representation of addiction-related genes in the set that is common to different methods of salt craving. Mouse hypothalamus and whole brain under three conditions: control, furosemide treated, and ACTH treated. 4 or 5 biological replicated per group. Two channels - experimental and reference are used.
2011-07-04 | E-GEOD-29451 | biostudies-arrayexpress
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.
This model is hosted on
BioModels Database
and identified by:
MODEL1701170000.
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.
2017-08-16 | MODEL1701170000 | BioModels
Project description:Yapo2017 - A2AR/cAMP/PKA signalling in D2 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.
This model is hosted on
BioModels Database
and identified by:
MODEL1701170001.
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.
2017-08-16 | MODEL1701170001 | BioModels
Project description:Cell types are defined by their patterns of gene expression. Forebrain dopaminoceptive neurons play a key role in movement, action selection, and motivation, and are dysregulated in addiction, Parkinson’s disease, and many other medical conditions. To investigate similarities and differences between the main types of dopamine-sensitive neurons we compared the full ensemble of translated mRNAs in neurons expressing D1 or D2 dopamine receptors in the dorsal striatum and nucleus accumbens, and in D1 receptor-expressing neurons of the prefrontal cortex. We identified marked differences in mRNA profiles between these populations and distinct sets of genes that establish D1, D2, dorsal and ventral identities. Network analysis revealed transcription factors with known or putative role in these differences. Prostaglandin E2 appeared as a candidate upstream regulator of dorsal striatum and pharmacological experiments supported this hypothesis. Our study provides a powerful resource for the molecular studies of the striatum and new clues about its regional gene expression pattern.
2020-09-09 | GSE137153 | GEO
Project description:This is an SBML version of the model described in: A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.
Nakano T, Doi T, Yoshimoto J, Doya K. PLoS Comput Biol. 2010 Feb 12;6(2):e1000670. PMID: 20169176
; DOI: 10.1371/journal.pcbi.1000670
Abstract:
Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
The model was encoded from the supplemental material accompanying the article.
The stimuli used in the article are hard to implement in SBML, so right now the model does not reproduce the results given in the article. Originally created by libAntimony v1.4 (using libSBML 3.4.1)This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1101170000 | BioModels
Project description:Sex differences in behaviors relevant to nicotine addiction have been observed in rodent models and human subjects. Behavioral, imaging and epidemiological studies also suggest underlying sex differences in mesolimbic dopamine signaling pathways. In this study we evaluated the proteome in the ventral tegmental area (VTA) and nucleus accumbens (NAc) shell in male and female mice. Experimental groups included two mouse strains (C3H/HeJ and C57BL/6J) at baseline, a sub-chronic, rewarding regimen of nicotine in C3H/HeJ mice, and chronic nicotine administration and withdrawal in C57BL/6J mice. Isobaric labeling with a TMT 10-plex system, sample fractionation, and tandem mass spectrometry were used to quantify changes in protein abundance. Similar or greater numbers of differentially regulated proteins were found between sexes at baseline in C3H/HeJ or C57BL/6J mice than within sexes following their respective regimen of nicotine administration. Despite differences by sex, strain, and nicotine exposure parameters, glial fibrillary acidic protein (GFAP) and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32, Ppp1r1b) were repeatedly identified as significantly altered proteins, especially in the VTA. Further, network analyses showed sex- and nicotine-dependent regulation of a number of signaling pathways, including dopaminergic signaling. Sub-chronic nicotine exposure in female mice increased proteins related to dopaminergic signaling in the NAc shell but decreased them in the VTA, whereas the opposite pattern was observed in male mice. In contrast, dopaminergic signaling pathways were similarly upregulated in both male and female VTA after chronic nicotine and withdrawal. Overall, this study identifies significant sex differences in the proteome of the mesolimbic system, at baseline and after nicotine reward or withdrawal, which may help explain differential trajectories and susceptibility to nicotine addiction in males and females.
2021-06-28 | PXD023859 | Pride
Project description:The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here we implicate in this process a novel nuclear receptor transcription factor, Retinoid X Receptor Alpha (RXRα), which we identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that, while its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction, and paves the way for future studies of rexinoid signaling in psychiatric disease states.
2023-03-06 | GSE198527 | GEO
Project description:A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine’s rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2 MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.
2024-10-09 | GSE272458 | GEO
Project description:A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine’s rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2 MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.
2024-10-09 | GSE272369 | GEO
Project description:The mechanistic target of rapamycin (mTOR) is assembled into signaling complexes of mTORC1 or mTORC2, and plays key roles in cell metabolism, stress response, nutrient and growth factor sensing. Accumulating evidence from human and animal model studies has demonstrated a pathogenic role of hyperactive mTORC1 in age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) is a primary injury site in AMD. In mouse models of RPE-specific deletion of Tuberous sclerosis 1 (Tsc1), which encodes an upstream suppressor of mTORC1, the hyperactivated mTORC1 metabolically reprogrammed the RPE and led to the degeneration of the outer retina and choroid (CH). In the current study, we used single-cell RNA sequencing (scRNA-seq) to identify a novel RPE mTORC1 downstream protein, dopamine and cyclic AMP-regulated phosphoprotein of molecular weight 32,000 (DARPP-32). DARPP-32 was not found in healthy RPE but localized to drusen and basal linear deposits in human AMD eyes. In animal models, overexpressing DARPP-32 by adeno-associated virus (AAV) led to abnormal RPE structure and function. The data indicate that DARPP-32 is a previously unidentified signaling protein subjected to mTORC1 regulation and may contribute to RPE degeneration in AMD.
2022-07-29 | GSE209908 | GEO