Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety

The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcr iption of target genes both directly by interaction with DNA regulatory ele ments and indirectly by cross-talk with other transcription factors(1, 2). In response to various stimuli, including stress, glucocorticoids coordinat e metabolic, endocrine, immune and nervous system responses and ensure an a dequate profile of transcription. In the brain, Gr has been proposed to mod ulate emotional behaviour, cognitive functions and addictive states(3-5). P reviously, these aspects were not studied in the absence of functional Gr b ecause inactivation of Grl1 in mice causes lethality at birth(6) (F.T., C.K , and G.S., unpublished data), Therefore, we generated tissue-specific muta tions of this gene using the Cre/loxP-recombination system(7). This allowed us to generate viable adult mice with loss of Gr function in selected tiss ues. Loss of Gr function in the nervous system impairs hypothalamus-pituita ry-adrenal (HPA)-axis regulation, resulting in increased glucocorticoid (GC ) levels that lead to symptoms reminiscent of those observed in Gushing syn drome, Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour becaus e mutant animals show an impaired behavioural response to stress and displa y reduced anxiety.