Elsevier

Biological Psychiatry

Volume 71, Issue 3, 1 February 2012, Pages 224-231
Biological Psychiatry

Archival Report
Early-Life Forebrain Glucocorticoid Receptor Overexpression Increases Anxiety Behavior and Cocaine Sensitization

https://doi.org/10.1016/j.biopsych.2011.07.009Get rights and content

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.

Section snippets

Generation of Inducible Glucocorticoid Receptor Overexpression in Forebrain Mice

The codons encoding the influenza hemagglutinin (HA) epitope were added to 5'-end of the full length mouse GR complementary DNA (19). The HA-GR complementary DNA was cloned into the response plasmid tetracycline-response element (TRE) of the Tet-Off inducible system. Founder TRE-HA-GR mice were crossed with CaMKIIα-tTA mice (The Jackson Laboratory, Bar Harbor, Maine) to produce bigenic mice that were treated ± doxycycline (Dox) for various stages of lifetime. The bigenic mice express the

Generation of Inducible Glucocorticoid Receptor Overexpression in Forebrain Mice

To produce an animal model where we could not only target GR overexpression to the forebrain but also achieve control over the timing of the overexpression, we generated transgenic mice expressing HA-GR under the control of the TRE of the Tet-Off inducible system. In this bigenic system, Dox inhibits expression of transgene and removal of the drug allows overexpression to take place (Figure S1A in Supplement 1). To achieve forebrain-specific expression of the GR protein, the TRE-GR transgenic

Discussion

In this study, transient early-life GR overexpression in forebrain causes lifelong alterations in reactivity to the environment as indexed by increased anxiety behavior and enhanced sensitization to cocaine. Enhanced GR expression before weaning sets in motion a cascade of molecular and neural events that cause profound changes in the transcriptome, in a region-specific manner. The existence of a critical time window is consistent with the notion that GR activity is involved in a highly

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