Circadian transcription factor NPAS2 and the NAD + -dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward.

Autor: Becker-Krail DD; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA., Parekh PK; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA., Ketchesin KD; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA., Yamaguchi S; Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Yoshino J; Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Hildebrand MA; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA., Dunham B; Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Ganapathiraju MK; Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Logan RW; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA., McClung CA; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Jazyk: angličtina
Zdroj: The European journal of neuroscience [Eur J Neurosci] 2022 Feb; Vol. 55 (3), pp. 675-693. Date of Electronic Publication: 2022 Jan 20.
DOI: 10.1111/ejn.15596
Abstrakt: Substance use disorders are associated with disruptions to both circadian rhythms and cellular metabolic state. At the molecular level, the circadian molecular clock and cellular metabolic state may be interconnected through interactions with the nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase, sirtuin 1 (SIRT1). In the nucleus accumbens (NAc), a region important for reward, both SIRT1 and the circadian transcription factor neuronal PAS domain protein 2 (NPAS2) are highly enriched, and both are regulated by the metabolic cofactor NAD + . Substances of abuse, like cocaine, greatly disrupt cellular metabolism and promote oxidative stress; however, their effects on NAD + in the brain remain unclear. Interestingly, cocaine also induces NAc expression of both NPAS2 and SIRT1, and both have independently been shown to regulate cocaine reward in mice. However, whether NPAS2 and SIRT1 interact in the NAc and/or whether together they regulate reward is unknown. Here, we demonstrate diurnal expression of Npas2, Sirt1 and NAD + in the NAc, which is altered by cocaine-induced upregulation. Additionally, co-immunoprecipitation reveals NPAS2 and SIRT1 interact in the NAc, and cross-analysis of NPAS2 and SIRT1 chromatin immunoprecipitation sequencing reveals several reward-relevant and metabolic-related pathways enriched among shared gene targets. Notably, NAc-specific Npas2 knock-down or a functional Npas2 mutation in mice attenuates SIRT1-mediated increases in cocaine preference. Together, our data reveal an interaction between NPAS2 and SIRT1 in the NAc, which may serve to integrate cocaine's effects on circadian and metabolic factors, leading to regulation of drug reward.
(© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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