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Circuit-Wide Gene Network Analysis Reveals Sex-Specific Roles for Phosphodiesterase 1b in Cocaine Addiction.
Teague, Collin D; Markovic, Tamara; Zhou, Xianxiao; Martinez-Rivera, Freddyson J; Minier-Toribio, Angelica; Zinsmaier, Alexander; Pulido, Nathalia V; Schmidt, Kyra H; Lucerne, Kelsey E; Godino, Arthur; van der Zee, Yentl Y; Ramakrishnan, Aarthi; Futamura, Rita; Browne, Caleb J; Holt, Leanne M; Yim, Yun Young; Azizian, Corrine H; Walker, Deena M; Shen, Li; Dong, Yan; Zhang, Bin; Nestler, Eric J.
Afiliação
  • Teague CD; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Markovic T; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Zhou X; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Martinez-Rivera FJ; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Minier-Toribio A; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Zinsmaier A; Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
  • Pulido NV; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Schmidt KH; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Lucerne KE; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Godino A; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • van der Zee YY; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Ramakrishnan A; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Futamura R; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Browne CJ; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Holt LM; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Yim YY; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Azizian CH; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Walker DM; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Shen L; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Dong Y; Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239.
  • Zhang B; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
  • Nestler EJ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
J Neurosci ; 44(23)2024 Jun 05.
Article em En | MEDLINE | ID: mdl-38637154
ABSTRACT
Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b (Pde1b), a Ca2+/calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Caracteres Sexuais / Transtornos Relacionados ao Uso de Cocaína / Redes Reguladoras de Genes / Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 / Camundongos Endogâmicos C57BL / Núcleo Accumbens Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Caracteres Sexuais / Transtornos Relacionados ao Uso de Cocaína / Redes Reguladoras de Genes / Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 / Camundongos Endogâmicos C57BL / Núcleo Accumbens Idioma: En Ano de publicação: 2024 Tipo de documento: Article