 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Feb 20, 2022 |
| Title |
Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced maladaptive plasticity |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder (SUD). Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. By attenuating H3Q5dop during abstinence, we both altered gene expression programs associated with heroin withdrawal and reduced heroin-primed reinstatement behavior. These findings thus establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in opioid-induced plasticity in VTA.
|
| |
|
| Overall design |
To explore the functional consequences of H3Q5dop accumulation during heroin abstinence, we used a lentiviral vector that expresses the H3 variant, H3.3, with a glutamine-to-alanine substitution at position 5 (H3.3Q5A), which cannot be dopaminylated. This H3.3Q5A vector has previously been shown to strongly express the mutant H3.3Q5A protein in a nuclear-specific manner in adult neurons, resulting in downregulation of H3Q5dop. We delivered this H3.3QA vector into rodent VTA vs. H3.3 wildtype (WT) vs. empty vector controls in order to evaluate the impact of reducing H3Q5dop accumulation on gene expression programs during prolonged abstinence. After 10 d of heroin SA, rats were infected intra-VTA with one of the three viruses (on day 11), followed by a 30 d period of enforced abstinence to ensure maximal expression of viral transgenes. Following 30 d of forced abstinence, infected VTA tissues were microdissected and processed for RNA-seq.
|
| |
|
| Contributor(s) |
Fulton SL, Maze I |
| Citation(s) |
35094023 |
| Submission date |
Mar 25, 2021 |
| Last update date |
Feb 20, 2022 |
| Contact name |
Sasha Leilani Fulton |
| E-mail(s) |
sasha.fulton@icahn.mssm.edu
|
| Organization name |
Icahn School of Medicine at Mount Sinai
|
| Street address |
1470 Madison Avenue
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL25947 |
Illumina NovaSeq 6000 (Rattus norvegicus) |
|
| Samples (45)
|
|
| Relations |
| BioProject |
PRJNA717243 |
| SRA |
SRP312141 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE169628_VST-Normalized_counts_file_NPPNovember2021.txt.gz |
4.8 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...