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