title: Environmental enrichment produces a behavioral phenotype mediated by low cyclic adenosine monophosphate response element binding (CREB) activity in the nucleus accumbens.
abstract: BACKGROUND
  Previous research has shown that rats reared in an enriched condition (EC) are more sensitive to the acute effects of amphetamine than rats reared in an isolated condition (IC); yet, EC rats self-administer less amphetamine than IC rats. The present study used cocaine to further explore this environmental enrichment behavioral phenotype, as well as the underlying molecular mechanisms involved.
  
  
  METHODS
  Enriched condition and IC rats were studied in a broad battery of behavioral tests, including cocaine conditioned place preference (CPP) and self-administration and several measures of anxiety- and depression-related behavior. The involvement of the transcription factor, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), in mediating EC versus IC differences was investigated.
  
  
  RESULTS
  Enriched condition rats exhibited less cocaine self-administration, despite showing enhanced cocaine CPP. Enriched condition rats also displayed less depression-like behavior but higher levels of anxiety-like behavior. This behavioral phenotype is consistent with low CREB activity in the nucleus accumbens, a key brain reward region. Indeed, EC rats have less phospho-CREB (the transcriptionally active form of the protein) in the nucleus accumbens than IC rats, and a selective knockdown of CREB in this brain region of normally reared rats, by use of a novel viral vector expressing a short hairpin RNA (shRNA) directed against CREB, reproduced the EC behavioral phenotype.
  
  
  CONCLUSIONS
  These studies identify a potential molecular mechanism for how rearing environment-a nonpharmacological, nonsurgical manipulation-can modify a wide range of complex emotional behaviors.
authors.affiliation: Departments of Psychiatry and Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. tom.green@utmb.edu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
authors.forename: Imran N
authors.initials: IN
authors.lastname: Alibhai
authors.forename: C Nathaniel
authors.initials: CN
authors.lastname: Roybal
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Winstanley
authors.forename: David E H
authors.initials: DE
authors.lastname: Theobald
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.forename: Ami R
authors.initials: AR
authors.lastname: Graham
authors.forename: Stephen
authors.initials: S
authors.lastname: Unterberg
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Graham
authors.forename: Vincent
authors.initials: V
authors.lastname: Vialou
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bass
authors.forename: Ernest F
authors.initials: EF
authors.lastname: Terwilliger
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology; D001526:Behavioral Symptoms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005518:Food Preferences / Q000502:physiology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050882:CREB-Binding Protein; D003042:Cocaine