title: Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2.
abstract: Early life stress is a major risk factor for cocaine addiction; however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors.
  
  
  
  We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex.
  
  
  
  Male BALB/c mice subjected to MS (3 h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment.
  
  
  
  MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS.
  
  
  
  Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.
authors.affiliation: Postgraduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.|Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre, 90619-900, RS, Brazil.
authors.forename: Thiago Wendt
authors.initials: TW
authors.lastname: Viola
authors.affiliation: Postgraduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.|Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre, 90619-900, RS, Brazil.
authors.forename: Luis Eduardo
authors.initials: LE
authors.lastname: Wearick-Silva
authors.affiliation: Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre, 90619-900, RS, Brazil.|Postgraduate Program in Medicine and Health Sciences, PUCRS, Porto Alegre, RS, Brazil.
authors.forename: Lucas Araújo
authors.initials: LA
authors.lastname: De Azeredo
authors.affiliation: Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre, 90619-900, RS, Brazil.
authors.forename: Anderson
authors.initials: A
authors.lastname: Centeno-Silva
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: Conor
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California-Irvine, Irvine, 92697, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Marshall
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California-Irvine, Irvine, 92697, CA, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.affiliation: Department of Psychiatry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Frederico
authors.initials: F
authors.lastname: Garcia
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California-Irvine, Irvine, 92697, CA, USA.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Bredy
authors.affiliation: Postgraduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. rodrigo.grassi@pucrs.br.|Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre, 90619-900, RS, Brazil. rodrigo.grassi@pucrs.br.
authors.forename: Rodrigo
authors.identifier: 0000-0001-9911-5921
authors.initials: R
authors.lastname: Grassi-Oliveira
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000235:genetics*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders; D003214:Conditioning, Classical / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D008426:Maternal Deprivation; D051783:Methyl-CpG-Binding Protein 2 / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; C554518:MIRN212 microRNA, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D003042:Cocaine
keywords: Adolescence; Brain-derived neurotrophic factor; Cocaine; Conditioned place preference; Maternal separation; microRNAs