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.
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: H M Reichardt; K H Kaestner; J Tuckermann; O Kretz; O Wessely; R Bock; P Gass; W Schmid; P Herrlich; P Angel; G Schütz Journal: Cell Date: 1998-05-15 Impact factor: 41.582
Authors: A Montkowski; N Barden; C Wotjak; I Stec; J Ganster; M Meaney; M Engelmann; J M Reul; R Landgraf; F Holsboer Journal: J Neuroendocrinol Date: 1995-11 Impact factor: 3.627
Authors: F Tronche; C Kellendonk; O Kretz; P Gass; K Anlag; P C Orban; R Bock; R Klein; G Schütz Journal: Nat Genet Date: 1999-09 Impact factor: 38.330
Authors: Qiang Wei; Elaine K Hebda-Bauer; Amy Pletsch; Jie Luo; Mary T Hoversten; Andrew J Osetek; Simon J Evans; Stanley J Watson; Audrey F Seasholtz; Huda Akil Journal: J Neurosci Date: 2007-08-15 Impact factor: 6.167
Authors: Chase H Bourke; Madiha Q Raees; Sanjana Malviya; Cory A Bradburn; Elisabeth B Binder; Gretchen N Neigh Journal: Psychoneuroendocrinology Date: 2012-05-29 Impact factor: 4.905
Authors: Sarah M Clinton; Cortney A Turner; Shelly B Flagel; Danielle N Simpson; Stanley J Watson; Huda Akil Journal: Pharmacol Biochem Behav Date: 2012-11 Impact factor: 3.533
Authors: Vivek Kumar; David M Krolewski; Elaine K Hebda-Bauer; Aram Parsegian; Brian Martin; Matthew Foltz; Huda Akil; Stanley J Watson Journal: Brain Struct Funct Date: 2021-01-02 Impact factor: 3.270