title: CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.
abstract: The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.
authors.affiliation: Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA. michel.barrot@utsouthwestern.edu
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
authors.forename: Jocelien D A
authors.initials: JD
authors.lastname: Olivier
authors.forename: Linda I
authors.initials: LI
authors.lastname: Perrotti
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
authors.forename: Olivier
authors.initials: O
authors.lastname: Berton
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Storm
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Yin
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001362:Avoidance Learning / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000502:physiology*; D004644:Emotions / Q000502:physiology*; D017930:Genes, Reporter; D051379:Mice; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D051381:Rats; D013238:Stereotaxic Techniques; D019966:Substance-Related Disorders / Q000503:physiopathology; D014158:Transcription, Genetic; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D001616:beta-Galactosidase