Inducible overexpression of the glucocorticoid receptor in forebrain during early life increases anxiety-like behavior and enhances cocaine sensitization.

Society for Neuroscience. 2009.


The glucocorticoid receptor (GR) modulates stress responsiveness, emotionality and cognitive function as well as responsiveness to drugs of abuse. To achieve control over the timing of the expression of GR, we generated a mouse line of inducible GR overexpression in the forebrain using the Tet-Off regulatory system. We carried out studies with the following conditions: a) Induction of GR throughout the lifetime of the animal (Lifetime GRov), b) Induction of GR only during the first 3 weeks of life (Early Life GRov), c) Induction of GR only after 3 weeks of age and throughout adulthood (Adulthood GRov), d) No induction of GR in the forebrain (None GRov). In the anxiety-like behavior tests, both Lifetime and Early Life GRov mice displayed increased anxiety compared to None GRov animals. By contrast, Adulthood GRov mice showed normal anxiety-like behaviors. These results suggest that overexpression of GR in the forebrain during early life plays a critical role in triggering increased anxiety-like behavior in mice. In a pilot study of cocaine-induced sensitization, Early Life GRov mice not only showed the enhancement of sensitization that is induced by GR overexpression, but the effect was even greater than the one seen in Lifetime GRov mice. These findings indicates that transient overexpression of GR in the forebrain early in life is sufficient to produce a lifelong increase in the vulnerability to cocaine-induced sensitization. In an expression profiling study using laser capture microdissection combined with microarray, we evaluate the global change in basal gene expression in Ammon's horn and the dentate gyrus of the hippocampal formation in inducible GRov mice. Results suggest that short term overexpression of GR during early life is sufficient to change the gene expression profile for the rest of the animal's life and the dentate gyrus is more vulnerable to enhanced GR activation relative to Ammon's horn. The majority of the genes that were significantly altered are implicated in growth, synaptogenesis, axonal guidance, neurotransmitter signaling, and learning and memory.Some of these changes are shared between Early Life and Lifetime GRov while others are not. A number of genes in differential expression have been confirmed by real-time PCR. This body of work demonstrates that early manipulation of the glucocorticoid receptor is sufficient to produce a lifelong change in emotional responses and cocaine sensitization, coupled with profound expression changes in genes related to neuroplasticity, growth, and signaling in the hippocampus.