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| Status |
Public on Jun 11, 2024 |
| Title |
Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences for which there are currently no FDA approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes related to protein folding, mRNA processing, immune signaling, and neurotransmission in striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analysis. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion did not alter methamphetamine-seeking behavior following 21 days of abstinence, highlighting the complexity of drug-seeking behaviors. Taken together, these results suggest that methamphetamine induces both short and long-term changes in striatal microglia that contribute to altered drug-taking behavior and may be leveraged for preclinical development of methamphetamine cessation therapeutics.
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| Overall design |
Mice were permitted to intravenously self-administer methamphetamine (0.05 mg/kg/inf dissolved in 0.9% saline) or saline during 15 daily 2-hr sessions. After 15 days of IVSA (Acquisition and Maintenance), mice underwent 21 days of forced home cage abstinence. Striatal microglia were isolated immediately after the final maintenance session (MN and SAL) and following abstinence (ABS).
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| Web link |
https://doi.org/10.1016/j.bbi.2024.05.038
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| Contributor(s) |
Vilca SJ, Margetts AV, Höglund L, Fleites I, Bystrom LL, Pollock TA, Bourgain-Guglielmetti F, Wahlestedt CR, Tuesta LM |
| Citation(s) |
38838836 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| F99 NS130871 |
Investigating the Role of Microglia in Methamphetamine Use Disorder |
University of Miami School of Medicine |
Samara Jo Vilca |
| DP1 DA051828 |
Microglia and Epigenetic Regulation in Opioid Addiction |
University of Miami School of Medicine |
Luis Miguel Tuesta |
| K01 DA045294 |
Role of Dopamine Neuron-Specific Gene Enhancers in Cocaine Relapse |
University of Miami School of Medicine |
Luis Miguel Tuesta |
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| Submission date |
Oct 20, 2023 |
| Last update date |
Jun 11, 2024 |
| Contact name |
Alexander Ve Margetts |
| E-mail(s) |
avm27@miami.edu
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| Phone |
7543666084
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| Organization name |
University of Miami
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| Department |
Psychiatry and Behavioral Sciences
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| Lab |
Luis Tuesta Lab
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| Street address |
1600 NW 10th Ave, Rosenstiel Med Sci 7014A
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| City |
Miami |
| State/province |
FL |
| ZIP/Postal code |
33136 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (23)
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| GSM7851860 |
Striatal Microglia, Saline, rep4 |
| GSM7851861 |
Striatal Microglia, Saline, rep5 |
| GSM7851862 |
Striatal Microglia, Saline, rep6 |
| GSM7851863 |
Striatal Microglia, Saline, rep7 |
| GSM7851864 |
Striatal Microglia, Saline, rep8 |
| GSM7851865 |
Striatal Microglia, Maintenance, rep1 |
| GSM7851866 |
Striatal Microglia, Maintenance, rep2 |
| GSM7851867 |
Striatal Microglia, Maintenance, rep3 |
| GSM7851868 |
Striatal Microglia, Maintenance, rep4 |
| GSM7851869 |
Striatal Microglia, Maintenance, rep5 |
| GSM7851870 |
Striatal Microglia, Maintenance, rep6 |
| GSM7851871 |
Striatal Microglia, Maintenance, rep7 |
| GSM7851872 |
Striatal Microglia, Maintenance, rep8 |
| GSM7851873 |
Striatal Microglia, Abstinence, rep1 |
| GSM7851874 |
Striatal Microglia, Abstinence, rep2 |
| GSM7851875 |
Striatal Microglia, Abstinence, rep3 |
| GSM7851876 |
Striatal Microglia, Abstinence, rep4 |
| GSM7851877 |
Striatal Microglia, Abstinence, rep5 |
| GSM7851878 |
Striatal Microglia, Abstinence, rep6 |
| GSM7851879 |
Striatal Microglia, Abstinence, rep7 |
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| Relations |
| BioProject |
PRJNA1030429 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE245951_MIVSA_gene_count_matrix.csv.gz |
1012.7 Kb |
(ftp)(http) |
CSV |
| GSE245951_MIVSA_normalized_counts_DESeq2.txt.gz |
821.4 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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