SRA

The amygdala plays a key role in the negative emotional states associated with the relapse to drug seeking behavior. Neuroanatomical and functional observations have uncovered the role of discrete amygdala subregions in different aspects of these negative affective states. However, the underlying transcriptional regulatory programs driving the function of distinct amygdala cell types remains unknown. We generated an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of rats with low and high cocaine addiction-like behaviors after prolonged abstinence from extended access to cocaine intravenous self-administration. We identified thousands of cell type-specific differentially expressed genes, suggesting that negative affective states are associated with cell type-specific mechanisms which are enriched for molecular pathways, including energy metabolism and GABAergic synapses in excitatory and somatostatin neurons. We demonstrate that higher addiction severity is linked to excessive GABAergic inhibition and, using pharmacological inhibition, we find that addiction-like phenotypes are regulated by the metabolite methylglyoxal which is an agonist at GABA-A receptors. By analyzing differences in chromatin accessibility, we predict upstream transcriptional regulators associated with addiction-like behavior and find discordant regulation of key transcription factors among distinct cell populations. Overall, we provide a comprehensive characterization of cell type-specific transcriptional changes in the amygdala during protracted abstinence and use these insights to identify a novel target for pharmacological intervention. Overall design: snRNA-seq and snATAC-seq data generated using 10X Genomics Chromium Single Cell Multiome ATAC + Gene Expression