Reactive Oxygen Species Mediate Transcriptional Responses to Dopamine and Cocaine in Human Cerebral Organoids [Rudibaugh2022]
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PROVIDER: PRJNA982872 | ENA |
REPOSITORIES: ENA
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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: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:Reactive Oxygen Species Mediate Transcriptional Responses to Dopamine and Cocaine in Human Cerebral Organoids
| PRJNA982870 | ENA
Project description:Reactive Oxygen Species Mediate Transcriptional Responses to Dopamine and Cocaine in Human Cerebral Organoids [Rudibaugh2023]
| PRJNA982876 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-08-07 | GSE234769 | GEO
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:Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in VTA. By reducing H3Q5dop in VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated cue-induced dopamine release in nucleus accumbens and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in VTA.
2020-05-19 | GSE124055 | GEO
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.
2014-04-01 | GSE54839 | 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. 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: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