Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward
Mol Psychiatry. 2022-06-28; 27(10): 3980-3991
DOI: 10.1038/s41380-022-01668-7
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https://www.bordeaux-neurocampus.fr/11857
Engeln M(1)(2), Fox ME(3)(4), Chandra R(3), Choi EY(3), Nam H(3), Qadir H(3),
Thomas SS(3), Rhodes VM(3), Turner MD(3), Herman RJ(3), Calarco CA(3), Lobo
MK(5).
Author information:
(1)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, MD, USA. .
(2)Univ. Bordeaux, CNRS, INCIA, UMR 5287, F-33000, Bordeaux, France.
.
(3)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, MD, USA.
(4)Department of Anesthesiology & Perioperative Medicine, Penn State College of
Medicine, Hershey, PA, USA.
(5)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, MD, USA. .
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.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41380-022-01668-7
PMCID: PMC9722585
PMID: 35764708 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest: The authors declare they
have no conflicts of interest.