title: Transcriptomics of Environmental Enrichment Reveals a Role for Retinoic Acid Signaling in Addiction.
abstract: There exists much variability in susceptibility/resilience to addiction in humans. The environmental enrichment paradigm is a rat model of resilience to addiction-like behavior, and understanding the molecular mechanisms underlying this protective phenotype may lead to novel targets for pharmacotherapeutics to treat cocaine addiction. We investigated the differential regulation of transcript levels using RNA sequencing of the rat nucleus accumbens after environmental enrichment/isolation and cocaine/saline self-administration. Ingenuity Pathways Analysis and Gene Set Enrichment Analysis of 14,309 transcripts demonstrated that many biofunctions and pathways were differentially regulated. New functional pathways were also identified for cocaine modulation (e.g., Rho GTPase signaling) and environmental enrichment (e.g., signaling of EIF2, mTOR, ephrin). However, one novel pathway stood out above the others, the retinoic acid (RA) signaling pathway. The RA signaling pathway was identified as one likely mediator of the protective enrichment addiction phenotype, an interesting result given that nine RA signaling-related genes are expressed selectively and at high levels in the nucleus accumbens shell (NAcSh). Subsequent knockdown ofCyp26b1(an RA degradation enzyme) in the NAcSh of rats confirmed this role by increasing cocaine self-administration as well as cocaine seeking. These results provide a comprehensive account of enrichment effects on the transcriptome and identify RA signaling as a contributing factor for cocaine addiction.
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, GalvestonTX, USA; Biomedical Informatics Program, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Fanping
authors.initials: F
authors.lastname: Kong
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Crofton
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Dragosljvich
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, GalvestonTX, USA; Biomedical Informatics Program, The University of Texas Medical Branch, GalvestonTX, USA; Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Mala
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Dingge
authors.initials: D
authors.lastname: Li
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Fan
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Shyny
authors.initials: S
authors.lastname: Koshy
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hommel
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, GalvestonTX, USA; Biomedical Informatics Program, The University of Texas Medical Branch, GalvestonTX, USA; Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch, GalvestonTX, USA; Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Spratt
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, GalvestonTX, USA; Biomedical Informatics Program, The University of Texas Medical Branch, GalvestonTX, USA; Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Luxon
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, GalvestonTX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, GalvestonTX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, GalvestonTX, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
keywords: RNA-seq; differential rearing; drug dependence; regionally enhanced gene expression; self-administration; stimulants