Single-nucleus RNA-Seq
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246451 | GEO | 2024/01/22
REPOSITORIES: GEO
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Project description:We report the application of Bulk mRNA sequencing technology in mice for high-throughput profiling of brain tissue imprints of the orbitofrontal cortex (OFC) before addiction protocol and dissected OFC and medial prefrontal cortex after the application of an addiction protocol in the same mice. By obtaining about 21 reads per sample aftet next-generation sequencing (NGS), the goals of this study is to demonstrate compatibility of the brain tissue impriting method in mice with sequencing analysis and use the data obtained to compare differentially expressed genes before and after the developement of addiction and identify potential genes that could explain individual vulnerability to addiction.
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Project description:Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving), but the transcriptional mechanisms that contribute to this incubation are unknown. Here we used RNA-sequencing to analyze transcriptional profiles associated with incubation of Meth craving in central amygdala (CeA) and orbitofrontal cortex (OFC), two brain areas previously implicated in relapse to drug seeking. We trained rats to self-administer either saline (control condition) or Meth (10 days; 9 h/day, 0.1 mg/kg/infusion). Next, we collected brain tissue from CeA and OFC on withdrawal day 2 (when Meth seeking is low and non-incubated) and on day 35 (when Meth seeking is high and incubated), for subsequent RNA-sequencing. In CeA, we identified 10-fold more differentially expressed genes (DEGs) on withdrawal day 35 than day 2. These genes were enriched for several biological processes, including protein ubiquitination and histone methylation. In OFC, we identified many fewer expression changes than in CeA. Interestingly, there were more DEGs on withdrawal day 2 than on day 35. Several genes in OFC showed opposing expression changes on withdrawal day 2 (increase) when compared to withdrawal day 35 (decrease), which was further validated by qPCR. Our analyses highlight the CeA as a key region of transcriptional regulation associated with incubation of Meth seeking. In contrast, transcriptional regulation in OFC may contributes to Meth seeking during early withdrawal. Overall, these findings provide a unique resource of gene expression data for future studies examining transcriptional mechanisms in CeA that mediate Meth seeking after prolonged withdrawal.
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Project description:Due to the complexity and diversity of the cellular changes, our understanding of the exact molecular and cellular mechanisms underpinning behavioral sensitization remains incomplete. Therefore, the present study explored the single-cell transcriptional changes in the orbitofrontal cortex (OFC) — a region implicated in decision-making and reward-related behaviors15,16— in a rodent model of methamphetamine-induced sensitization. Our study provides insights into the molecular mechanisms cells associated with the development of drug addiction.
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2023-08-08 | GSE214920 | GEO
Project description:Overall risk for Major Depressive Disorder (MDD) is determined by complex interactions between genetic and environmental factors that influence epigenetic regulation of neuroplasticity and stress pathways1,2. These mechanisms are specific to the distinct regulatory context within regionally-defined brain cell-types3,4. Here, we employed genome-wide chromatin accessibility profiling of neuronal vs. non-neuronal cells in orbitofrontal cortex (OFC) to capture regulatory signatures of MDD. We mapped genetic risk for MDD to active promoters of non-neuronal cell-types in OFC and identified MDD-specific open chromatin regions, which were differentially accessible exclusively in non-neuronal cells. Characterization of these loci revealed a key role for astrocyte dysfunction, and implicated the chromatin remodeling protein ZBTB7A, which coordinates wide-ranging cellular activation programs, including NF-kB inflammatory transcription5. In mice, astrocyte-specific knockdown of Zbtb7a reversed chromatin remodeling, reactive astrocyte transcription, and behavioral deficits associated with chronic stress. Conversely, ZBTB7A overexpression in OFC astrocytes induced stress-related behavioral deficits, promoted widespread inflammatory gene expression, and drove pathophysiological OFC neuronal hyperactivity in response to a mild subthreshold stressor. Our data highlight a critical role for OFC astrocytes in the bidirectional regulation of stress vulnerability and pinpoint ZBTB7A as a key factor mediating maladaptive astrocyte plasticity and OFC neuronal hyperexcitability in MDD.
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Project description:Due to the complexity and diversity of the cellular changes, our understanding of the exact molecular and cellular mechanisms underpinning behavioral sensitization remains incomplete, particularly, the role of non-neuronal cells. Therefore, the present study explored the single-cell transcriptional changes in the orbitofrontal cortex (OFC) - a region implicated in decision-making and reward-related behaviors in a rodent model of methamphetamine-induced sensitization. Our study provides insights into the molecular mechanisms underlying dysfunction of microglial cells associated with the development of drug addiction.
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