title: Early-life forebrain glucocorticoid receptor overexpression increases anxiety behavior and cocaine sensitization.
abstract: BACKGROUND
  Genetic factors and early-life adversity are critical in the etiology of mood disorders and substance abuse. Because of their role in the transduction of stress responses, glucocorticoid hormones and their receptors could serve as both genetic factors and mediators of environmental influences. We have shown that constitutive overexpression of the glucocorticoid receptor (GR) in forebrain results in increased emotional reactivity and lability in mice. Here, we asked whether there was a critical period for the emergence of this phenotype.
  
  
  METHODS
  We generated a mouse line with inducible GR overexpression specifically in forebrain. Anxiety-like behaviors and cocaine-induced sensitization were assessed in adult mice following GR overexpression during different periods in development. The molecular basis of the behavioral phenotype was examined using microarray analyses of dentate gyrus and nucleus accumbens.
  
  
  RESULTS
  Transient overexpression of GR during early life led to increased anxiety and cocaine sensitization, paralleling the phenotype of lifelong GR overexpression. This increased emotional reactivity was not observed when GR overexpression was induced after weaning. Glucocorticoid receptor overexpression in early life is sufficient to alter gene expression patterns for the rest of the animal's life, with dentate gyrus being more responsive than nucleus accumbens. The altered transcripts are implicated in GR and axonal guidance signaling in dentate gyrus and dopamine receptor signaling in nucleus accumbens.
  
  
  CONCLUSIONS
  Transient overexpression of GR early in life is both necessary and sufficient for inducing transcriptome-wide changes in the brain and producing a lifelong increase in vulnerability to anxiety and drugs of abuse.
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109, USA. qweis@umich.edu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Fentress
authors.forename: Mary T
authors.initials: MT
authors.lastname: Hoversten
authors.forename: Limei
authors.initials: L
authors.lastname: Zhang
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Hebda-Bauer
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Seasholtz
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology*; D003042:Cocaine / Q000494:pharmacology*; D003423:Critical Period, Psychological; D018891:Dentate Gyrus / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism* / Q000503:physiopathology*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000235:genetics; D059467:Transcriptome / Q000502:physiology
chemical_list: D011965:Receptors, Glucocorticoid; D003042:Cocaine