Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition.

Autor: Zhou JL; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, USA.; Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA., de Guglielmo G; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Ho AJ; Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA., Kallupi M; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Pokhrel N; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Li HR; Department of Medicine, University of California San Diego, La Jolla, CA, USA., Chitre AS; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Munro D; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA., Mohammadi P; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA.; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.; Department of Genome Sciences, University of Washington, Seattle, WA, USA., Carrette LLG; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., George O; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Palmer AA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA., McVicker G; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, USA. gmcvicker@salk.edu.; Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. gmcvicker@salk.edu., Telese F; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. ftelese@health.ucsd.edu.; Department of Medicine, University of California San Diego, La Jolla, CA, USA. ftelese@health.ucsd.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2023 Nov; Vol. 26 (11), pp. 1868-1879. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1038/s41593-023-01452-y
Abstrakt: The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABA A receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats.
(© 2023. The Author(s).)
Databáze: MEDLINE
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