Gene expression profile of 2-D or 3-D neural cultures derived from an H1 hESC cell line
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE225497 | GEO | 2023/04/14
REPOSITORIES: GEO
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Project description:Enduring patterns of epigenomic and transcriptional plasticity within the mesolimbic dopamine system contribute importantly to persistent behavioral adaptations that characterize substance use disorders (SUD). While drug addiction has long been thought of as a disorder of dopamine (DA) neurotransmission, therapeutic interventions targeting receptor mediated DA-signaling have not yet resulted in efficacious treatments. Our laboratory recently identified a non-canonical, neurotransmission-independent signaling moiety for DA in brain, termed dopaminylation, whereby DA itself acts as a donor source for the establishment of post-translational modifications (PTM) on substrate proteins (e.g., histone H3 at glutamine 5; H3Q5dop). In our previous studies, we demonstrated that H3Q5dop plays a critical role in the regulation of neuronal transcription and, when perturbed within monoaminergic neurons of the ventral tegmental area (VTA), critically contribute to pathological states, including relapse vulnerability to both psychostimulants (e.g., cocaine) and opiates (e.g., heroin). Importantly, H3Q5dop is also observed throughout the mesolimbic DA reward pathway (e.g., in nucleus accumbens/NAc and medial prefrontal cortex/mPFC, which receive DA input from VTA). As such, we investigated whether H3Q5dop may similarly be altered in its expression in response to drugs of abuse in these non-dopamine-producing regions. In rats undergoing extended abstinence from cocaine self-administration (SA), we observed both acute and prolonged accumulation of H3Q5dop in NAc, but not mPFC. Attenuation of H3Q5dop in NAc during drug abstinence reduced cocaine-seeking and affected cocaine-induced gene expression programs associated with altered dopamine signaling and neuronal function. These findings thus establish H3Q5dop in NAc, but not mPFC, as an important mediator of cocaine-induced behavioral and transcriptional plasticity during extended cocaine abstinence.
2023-06-14 | GSE221177 | GEO
Project description:Dopamine signaling in the adult ventral forebrain regulates behavior, stress response, and memory formation and in neurodevelopment regulates neural differentiation and cell migration. Excessive dopamine levels including due to cocaine use both in utero and in adults could lead to long-term adverse consequences. The mechanisms underlying both homeostatic and pathological changes remain unclear, partly due to the diverse cellular responses elicited by dopamine and the reliance on animal models that exhibit species-specific differences in dopamine signaling. To address these limitations, 3-D cerebral organoids have emerged as human-derived models, recapitulating salient features of human cell signaling and neurodevelopment. Organoids have demonstrated responsiveness to external stimuli, including substances of abuse, making them valuable investigative models. In this study we utilize the Xiang-Tanaka ventral forebrain organoid model and characterize their response to acute and chronic dopamine or cocaine exposure. The findings revealed a robust immune response, novel response pathways, and a potential critical role for reactive oxygen species (ROS) in the developing ventral forebrain. These results highlight the potential of cerebral organoids as in vitro human models for studying complex biological processes in the brain.
2023-08-07 | GSE234766 | GEO
Project description:Dopamine signaling in the adult ventral forebrain regulates behavior, stress response, and memory formation and in neurodevelopment regulates neural differentiation and cell migration. Excessive dopamine levels including due to cocaine use both in utero and in adults could lead to long-term adverse consequences. The mechanisms underlying both homeostatic and pathological changes remain unclear, partly due to the diverse cellular responses elicited by dopamine and the reliance on animal models that exhibit species-specific differences in dopamine signaling. To address these limitations, 3-D cerebral organoids have emerged as human-derived models, recapitulating salient features of human cell signaling and neurodevelopment. Organoids have demonstrated responsiveness to external stimuli, including substances of abuse, making them valuable investigative models. In this study we utilize the Xiang-Tanaka ventral forebrain organoid model and characterize their response to acute and chronic dopamine or cocaine exposure. The findings revealed a robust immune response, novel response pathways, and a potential critical role for reactive oxygen species (ROS) in the developing ventral forebrain. These results highlight the potential of cerebral organoids as in vitro human models for studying complex biological processes in the brain.
2023-08-07 | GSE234767 | GEO
Project description:Maintenance of the drug-addicted state involves changes in gene expression in different neuronal cell types and neural circuits. Midbrain dopamine neurons in particular mediate numerous responses to drugs of abuse. Long noncoding RNAs (lncRNAs) regulate CNS gene expression through a variety of mechanisms, but very little is known about their role in drug abuse. The proportion of lncRNAs that are primate-specific provides a strong rationale for their study in human drug abusers. We examined the profile of lncRNA expression in postmortem human midbrain specimens from chronic cocaine abusers and well-matched control subjects (n=11 subject pairs) using a custom lncRNA microarray. Differential expression was validated by quantitative PCR, and cellular localization investigated by in situ hybridization histochemistry.A profile of lncRNAs significantly dysregulated in chronic cocaine abusers was determined. LncRNAs with dopamine cell-specific expression, differential subcellular distribution, covariance with protein-coding genes, and tissue-specific drug-responsiveness were identified. Dysregulation of midbrain lncRNA expression may reflect pathophysiological processes associated with chronic cocaine abuse. LncRNAs may be central mediators of cellular responses to drug abuse.
2015-07-04 | GSE67281 | GEO
Project description:Substance use disorders (SUDs) are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based (LC-MS/MS) quantitative proteomics, along with a data-independent acquisition (DIA) analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveals cocaine and morphine differentially alters diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome.
2023-07-20 | PXD042043 | Pride
Project description:Maintenance of the drug-addicted state involves changes in gene expression in different neuronal cell types and neural circuits. Midbrain dopamine neurons in particular mediate numerous responses to drugs of abuse. Long noncoding RNAs (lncRNAs) regulate CNS gene expression through a variety of mechanisms, but very little is known about their role in drug abuse. The proportion of lncRNAs that are primate-specific provides a strong rationale for their study in human drug abusers. We examined the profile of lncRNA expression in postmortem human midbrain specimens from chronic cocaine abusers and well-matched control subjects (n=11 subject pairs) using a custom lncRNA microarray. Differential expression was validated by quantitative PCR, and cellular localization investigated by in situ hybridization histochemistry.A profile of lncRNAs significantly dysregulated in chronic cocaine abusers was determined. LncRNAs with dopamine cell-specific expression, differential subcellular distribution, covariance with protein-coding genes, and tissue-specific drug-responsiveness were identified. Dysregulation of midbrain lncRNA expression may reflect pathophysiological processes associated with chronic cocaine abuse. LncRNAs may be central mediators of cellular responses to drug abuse. cRNAs were generated from postmortem human midbrain specimens from chronic cocaine abusers and well-matched control subjects and hybridized to a custom Agilent 4 x 44,000-feature high-density oligonucleotide microarray platform using 60-mer probes. Cocaine control pairs were run together in a dye-flip two-color design, meaning each sample was run in quadruplicate, twice with each dye (Alexa-647 and Alexa-555; Invitrogen, Carlsbad, CA). Microarray slides were scanned with the default Agilent protocol and the intensity of fluorescence between dyes was normalized using a Loess correction. There are 7 probes per gene. Data across all cases and quadruplicates were quantile-normalized.
2015-07-04 | E-GEOD-67281 | biostudies-arrayexpress
Project description:Midbrain dopamine (DA)-synthesizing neurons play a key role in the addiction process, providing a compelling rationale for determining drug-induced molecular changes arising in these cells. This microarray-based study determined the profiles of midbrain gene expression in chronic cocaine abusers (n = 10) and well-matched drug-free control subjects (n = 10). Array-related procedures were performed in triplicate for each subject. Data analysis revealed that 98 array probes (corresponding to 91 genes) exhibited robust, statistically significant expression differences between chronic cocaine abusers and matched control subjects (p ? 0.05, FDR = 5%; with ? 1.4 fold-change cut-off applied). Changes in transcript abundance identified by microarray were validated by qPCR analysis in every instance examined (n = 11), regardless of the direction or magnitude of change, supporting the validity of the larger dataset of genes differentially expressed in cocaine abusers. Many of the genes exhibiting robust differential expression were associated with the regulation of transcription, chromatin function, or dopamine cell phenotype. For approximately one-half of these genes, transcript abundance was significantly predictive for subject assignment to the cocaine-abusing versus control cohort. The findings suggest that there is a molecular signature associated with core pathophysiological changes in the DA neurons of chronic cocaine abusers that can be exploited for the development of potential biomarkers and novel therapeutic targets for addiction. Human post-mortem midbrain gene expression derived from cocaine-related deaths are compared to midbrain gene expression of non-cocaine related deaths. Each subject was was arrayed in triplicates.
2014-04-01 | E-GEOD-54839 | biostudies-arrayexpress
Project description:Histone acetylation and other modifications of the chromatin are important regulators of gene expression and, consequently, may contribute to drug-induced behaviors and neuroplasticity. Previous studies have shown that a reduction on histone deacetylase (HDAC) activity results on the enhancement of some psychostimulant-induced behaviors. In the present study, we extend those seminal findings by showing that the administration of the HDAC inhibitor sodium butyrate enhances morphine-induced locomotor sensitization and conditioned place preference. In contrast, this compound has no effects on the development of morphine tolerance and dependence. Similar effects were observed for cocaine and ethanol-induced behaviors. These behavioral changes were accompanied by a selective boosting of a component of the transcriptional program activated by chronic morphine administration that included circadian clock genes and other genes relevant in addictive behavior. Our results support an specific role for histone acetylation and the epigenetic modulation of transcription at a reduced number of biologically relevant loci on non-homeostatic, long lasting, drug-induced behavioral plasticity. To further investigate the molecular bases of sodium butyrate action on long-lasting behavioral responses to morphine, we screened for potential substrates of their interaction by performing a genome-wide comparison of the striatal transcriptome after chronic administration of morphine in the absence or presence of sodium butyrate. Striatal tissue was dissected from two months-old Swiss-Albino male mice subjected to behavioral sensitization. Behavioural sensitization: Locomotor sensitization induced by morphine was evaluated using a protocol divided into two phases: induction and challenge. The induction phase involved six trials on alternate days, one trial per day. On each one of these trials, mice received and injection of saline or sodium butyrate (300 mg/kg) immediatedly followed by a second injection of morphine (20 mg/kg). The challenge phases consisted of a single trial conducted 7 days after the last test of the induction phase. In this case, all animals received a single injection of morphine (20 mg/kg). Striatal RNA was extracted 1h after the morphine challenge in groups of four animals that received either saline (N=6) or morphine (N=3), or the sodium butyrate-morphine (N=3) co-treatment during the sensitization induction phase.
2010-09-17 | E-GEOD-17731 | biostudies-arrayexpress
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