title: Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.
abstract: Learned associations between environmental stimuli and rewards play a critical role in addiction. Associative learning requires alterations in sparsely distributed populations of strongly activated neurons, or neuronal ensembles. Until recently, assessment of functional alterations underlying learned behavior was restricted to global neuroadaptations in a particular brain area or cell type, rendering it impossible to identify neuronal ensembles critically involved in learned behavior.
  
  
  
  We used Fos-GFP transgenic mice that contained a transgene with a Fos promoter driving expression of green fluorescent protein (GFP) to detect neurons that were strongly activated during associative learning, in this case, context-independent and context-specific cocaine-induced locomotor sensitization. Whole-cell electrophysiological recordings were used to assess synaptic alterations in specifically activated GFP-positive (GFP+) neurons compared with surrounding nonactivated GFP-negative (GFP-) neurons 90 min after the sensitized locomotor response.
  
  
  
  After context-independent cocaine sensitization, cocaine-induced locomotion was equally sensitized by repeated cocaine injections in two different sensitization contexts. Correspondingly, silent synapses in these mice were induced in GFP+ neurons, but not GFP- neurons, after sensitization in both of these contexts. After context-specific cocaine sensitization, cocaine-induced locomotion was sensitized exclusively in mice trained and tested in the same context (paired group), but not in mice that were trained in one context and then tested in a different context (unpaired group). Silent synapses increased in GFP+ neurons, but not in GFP- neurons from mice in the paired group, but not from mice in the unpaired group.
  
  
  
  Our results indicate that silent synapses are formed only in neuronal ensembles of the nucleus accumbens shell that are related to associative learning.
authors.affiliation: Behavioral Neuroscience Branch, National Institutes of Health National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Whitaker
authors.affiliation: Laboratório de Neuropsicofarmacologia, PANT, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, San Paulo, Brazil.
authors.forename: Paulo E
authors.initials: PE
authors.lastname: Carneiro de Oliveira
authors.affiliation: Behavioral Neuroscience Branch, National Institutes of Health National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
authors.forename: Kylie B
authors.initials: KB
authors.lastname: McPherson
authors.affiliation: Behavioral Neuroscience Branch, National Institutes of Health National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
authors.forename: Rebecca V
authors.initials: RV
authors.lastname: Fallon
authors.affiliation: Laboratório de Neuropsicofarmacologia, PANT, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, San Paulo, Brazil.
authors.forename: Cleopatra S
authors.initials: CS
authors.lastname: Planeta
authors.affiliation: Behavioral Neuroscience Branch, National Institutes of Health National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.affiliation: Behavioral Neuroscience Branch, National Institutes of Health National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland. Electronic address: bhope@intra.nida.nih.gov.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Hope
mesh_terms: D000818:Animals; D001245:Association Learning / Q000502:physiology*; D059333:Central Nervous System Sensitization / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine
keywords: Addiction; Electrophysiology; Glutamate; Memory; Psychostimulant; Transgenic