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Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward

Abstract

Psychostimulant exposure alters the activity of ventral pallidum (VP) projection neurons. However, the molecular underpinnings of these circuit dysfunctions are unclear. We used RNA-sequencing to reveal alterations in the transcriptional landscape of the VP that are induced by cocaine self-administration in mice. We then probed gene expression in select VP neuronal subpopulations to isolate a circuit associated with cocaine intake. Finally, we used both overexpression and CRISPR-mediated knockdown to test the role of a gene target on cocaine-mediated behaviors as well as dendritic spine density. Our results showed that a large proportion (55%) of genes associated with structural plasticity were changed 24 h following cocaine intake. Among them, the transcription factor Nr4a1 (Nuclear receptor subfamily 4, group A, member 1, or Nur77) showed high expression levels. We found that the VP to mediodorsal thalamus (VP → MDT) projection neurons specifically were recapitulating this increase in Nr4a1 expression. Overexpressing Nr4a1 in VP → MDT neurons enhanced drug-seeking and drug-induced reinstatement, while Nr4a1 knockdown prevented self-administration acquisition and subsequent cocaine-mediated behaviors. Moreover, we showed that Nr4a1 negatively regulated spine dynamics in this specific cell subpopulation. Together, our study identifies for the first time the transcriptional mechanisms occurring in VP in drug exposure. Our study provides further understanding on the role of Nr4a1 in cocaine-related behaviors and identifies the crucial role of the VP → MDT circuit in drug intake and relapse-like behaviors.

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Fig. 1: Cocaine intake alters structural plasticity-related molecules in the ventral pallidum.
Fig. 2: Cocaine intake increases Nr4a1 expression specifically in VP neurons projecting to the MDT.
Fig. 3: Transcriptional characterization of VP neurons projecting to the MDT in controls and following cocaine intake.
Fig. 4: Overexpression of Nr4a1 in VP to MDT neurons enhanced relapse-like behaviors and reduced dendritic spine density.
Fig. 5: Knockdown of Nr4a1 in VP to MDT neurons blocks FR1 acquisition and alters dendritic spine density.

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Acknowledgements

This work was funded by NIH grants R01MH106500, R01DA038613, R01DA047843 and Israel-US Binational Science Foundation 201725 (to MKL), K99DA050575 (to MEF), F31DA052967 (to EC), T32DK098107 and F32DA052966 (to CAC). Data sharing and visualization via gEAR was supported by grants R24MH114815 and R01DC019370. SST and RJH were supported by the University of Maryland Scholars Program, an initiative of the University of Maryland: MPowering the State. The authors would like to thank Yang Song, Ronna Hertzano and the members of the UMSOM Institute for Genome Science (IGS) as well as Katherine Duarte for their technical help. We also thank Dr. Kristen Maynard and Dr. Keri Martinowich for their help with RNAscope protocols.

Funding

This work was funded by NIH grants R01MH106500, R01DA038613, R01DA047843 and Israel-US Binational Science Foundation 201725 (to MKL), K99DA050575 (to MEF), F31DA052967 (to EC), T32DK098107, and F32DA052966 (to CAC).

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ME and MKL designed the experiments. ME, MEF, HQ, SST, and RJH conducted behavioral experiments, MDT and VMR provided animal support. ME and HQ performed RAP2 assay. ME, EYC, RJH and VMR extracted RNA and/or performed qRT-PCR experiments. HN and ME performed in situ hybridization. MEF conducted cell-type specific RNA extraction. SST and ME performed in situ hybridization quantification. RC, EYC and CAC designed viral constructs. ME performed bioinformatic analyses. ME and MEF conducted neuronal morphology experiments. ME and MKL wrote the paper with contributions from all authors.

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Correspondence to Michel Engeln or Mary Kay Lobo.

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Engeln, M., Fox, M.E., Chandra, R. et al. Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01668-7

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