Repeated cocaine or methamphetamine treatment alters astrocytic CRF2 and GLAST expression in the ventral midbrain: RNA sequencing data
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ABSTRACT:
PROVIDER: PRJNA764771 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15988001_1.fastq.gz | Fastqsanger.gz | |||
| SRR15988001_2.fastq.gz | Fastqsanger.gz | |||
| SRR15988002_1.fastq.gz | Fastqsanger.gz | |||
| SRR15988002_2.fastq.gz | Fastqsanger.gz | |||
| SRR15988003_1.fastq.gz | Fastqsanger.gz |
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Project description:We describe the effects of cocaine and methamphetamine treatment on astrocytic expression of the corticotropin releasing factor 2 receptor and the excitatory amino acid transporter 1 in the ventral midbrain. The RNA-sequencing data confirms the expression of CRF2R on astrocytes using the Aldh1l1-NuTRAP model. This allowed for astrocyte mRNA isolation and characterization, confirming CRF2R expression on ventral midbrain astrocytes.
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Project description:Dopamine neurons in the substantia nigra (SN) and ventral tegmental area (VTA) play a central role in the reinforcing properties of abused drugs including methamphetamine and cocaine. Chronic effects of psychostimulants in the SN/VTA also involve non-dopaminergic transmitters, including glutamate and the stress-related peptide corticotropin-releasing factor (CRF). In the SN/VTA, astrocytes express a variety of membrane-bound neurotransmitter receptors and transporters that influence neurotransmission. CRF receptor type 2 (CRF2) activity in the VTA is important for stress-induced relapse and drug-seeking behaviour, but the localization of its effects is incompletely understood. Here, we first identified CRF2 transcript in astrocytes of the SN/VTA using RNA-Seq in Aldh1l1;NuTRAP mice and confirmed it using in situ hybridization (RNAscope) in wild-type mice. We then used immunofluorescence to quantify the astrocytic marker protein S100β, glial-specific glutamate/aspartate transporter GLAST, and CRF2 in the SN/VTA following 12 days of treatment (i.p.) with methamphetamine (3 mg/kg), cocaine (10 mg/kg), or saline. We observed a significant decrease in GLAST immunofluorescence in brains of psychostimulant treated mice compared with saline controls. In addition, we observed increased labelling of CRF2 in drug treated groups, a decrease in the number of S100β positive cells, and an increase of co-staining of CRF2 with both S100β and tyrosine hydroxylase (dopamine neurons). Our results suggest a significant interaction between CRF2, GLAST, and astrocytes in the midbrain that emerges with repeated exposure to psychostimulants. These findings provide rationale for future investigation of astrocyte-based strategies for altering cellular and circuit function in response to stress and drug exposure.
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Project description:Emerging evidence increasingly indicates that astrocytes are involved in neuropsychiatric disorders, including addiction, but the cocaine-induced astrocyte transcriptome has yet to be investigated. We performed RNA-sequencing on whole-cell sorted astrocytes from the nucleus accumbens and bioinformatically characterized the astrocyte transcriptome following cocaine self-administration in male mice. We found that astrocytes exhibit robust and contextually-specific transcriptional signatures that implicate CREB as a cocaine-induced transcriptional regulator in astrocytes. CUT&RUN-sequencing revealed increased astrocytic CREB DNA binding in response to cocaine. Viral-mediated manipulation of NAc astrocytic CREB activity in combination with addiction-related behaviors revealed that astrocytic CREB increases the rewarding and reinforcing properties of cocaine. Furthermore, we identified potential molecular mechanisms of astrocytic CREB’s influence through modulating astrocytic calcium dynamics and selectively increasing D1-type medium spiny neuronal activity.
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Project description:Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. We identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region. To identify whether changes in H3K9me2 correlated with genome-wide alterations in gene expression in the NAc, we employed microarray analyses to examine gene expression profiles induced by a challenge dose of cocaine in animals with or without a history of prior cocaine exposure. Animals that had received repeated cocaine displayed dramatically increased gene expression 1 hour after a cocaine challenge in comparison to acutely treated animals. This increased gene expression still occurred in response to a cocaine challenge given after 1 week of withdrawal from repeated cocaine. These data suggest that repeated, but not acute, cocaine exposure results in persistent sensitized genomic responses to a cocaine challenge, indicating that sensitized behavioral responses to repeated cocaine are likely the result of G9a-dependent alterations in global transcriptional responses to cocaine.
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