Glucocorticoid receptor overexpression in forebrain: A mouse model of increased emotional lability

Qiang Wei, Xinyun Lu, Li Liu, Gwen Schafer, Kun Ruey Shieh, Sharon Burke, Terry E. Robinson, Stanley J. Watson, Audrey F. Seasholtz, Huda Akil

Research output: Contribution to journalArticlepeer-review

216 Scopus citations


The molecular mechanisms that control the range and stability of emotions are unknown, yet this knowledge is critical for understanding mood disorders, especially bipolar illness. Here, we show that the glucocorticoid receptor (GR) modulates these features of emotional responsiveness. We generated transgenic mice overexpressing GR specifically in forebrain. These mice display a significant increase in anxiety-like and depressant-like behaviors relative to wild type. Yet, they are also supersensitive to antidepressants and show enhanced sensitization to cocaine. Thus, mice overexpressing GR in forebrain have a consistently wider than normal range of reactivity in both positive and negative emotionality tests. This phenotype is associated, in specific brain regions, with increased expression of genes relevant to emotionality: corticotropin-releasing hormone, serotonin, norepinephrine and dopamine transporters, and 5-hydroxytryptamine1A receptor. Thus, GR overexpression in forebrain causes higher "emotional lability" secondary to a unique pattern of molecular regulation. This finding suggests that natural variations in GR gene expression can contribute to the fine-tuning of emotional stability or lability and may play a role in bipolar disorder.

Original languageEnglish (US)
Pages (from-to)11851-11856
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
StatePublished - Aug 10 2004
Externally publishedYes

ASJC Scopus subject areas

  • General


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