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Cell-type specific transcriptional adaptations of nucleus accumbens interneurons to amphetamine

Molecular Psychiatry volume 28, pages 3414–3428 (2023)Cite this article

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Abstract

Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we assessed expression of PV-enriched, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants to explore the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.

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Fig. 1: INTACT-mediated isolation of PV+ and SST+ GABAergic interneuron nuclei from mouse NAc.
Fig. 2: AMPH induces an overlapping program of rapid PRGs in distinct populations of NAc GABAergic neurons.
Fig. 3: Cell-type specific programs of gene expression regulated 3 h after AMPH administration in different populations of NAc GABAergic neurons.
Fig. 4: Cell-type specific and post-AMPH chromatin accessibility in NAc neurons.
Fig. 5: Single-nucleus RNA-seq reveals molecular heterogeneity of PV+ interneurons in the NAc.
Fig. 6: Motif analysis of differentially accessible chromatin near AMPH-regulated genes suggests transcriptional mechanisms of gene regulation in NAc neurons.
Fig. 7: Gene regulation in NAc PV+ neurons of MeCP2 Ser421Ala knockin mice.

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Data availability

RNA and ATAC sequencing data have been deposited at GEO (GSE181421). All primary data are stored on a secure server at Duke University and are available from the corresponding author.

Code availability

Full coding implementation of all analysis tools can be found in complete alignment/analysis pipelines available at https://github.com/WestLabDuke/Psychostimulant-NAcInterneuron.

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Acknowledgements

We thank Xiaoting Wang, Alexias Safi, and Greg Crawford for assistance with experiments. We thank Chris McGinnis for assistance in disambiguating Multi-seq LMOs. The Duke University School of Medicine Sequencing and Genomic Technologies Shared Resource provided sequencing services and the Duke University Mouse Behavioral and Neuroendocrine Analysis Core Facility provided equipment and support for the mouse behavioral studies. FANS was performed in the Immunology Unit of the Regional Biocontainment Laboratory at Duke, which receives support from NIH grant UC6-AI058607. This work was supported by NIH grants R01DA047115 and R33DA041878 (AEW).

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  1. Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

    David A. Gallegos, Melyssa Minto, Fang Liu, Mariah F. Hazlett, S. Aryana Yousefzadeh, Luke C. Bartelt & Anne E. West

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  1. David A. Gallegos
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Contributions

DAG and AEW conceived of and designed the study. DAG, MM, FL, MFH, SAY, and LCB acquired and analyzed data. DAG and AEW wrote the paper with feedback from other authors. All authors read and approved the submitted version of the study.

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Correspondence to Anne E. West.

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Gallegos, D.A., Minto, M., Liu, F. et al. Cell-type specific transcriptional adaptations of nucleus accumbens interneurons to amphetamine. Mol Psychiatry 28, 3414–3428 (2023). https://doi.org/10.1038/s41380-022-01466-1

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