Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability.
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-hydroxytryptamine(1A) 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.
Wei
Qiang
Q
Mental Health Research Institute, University of Michigan, Ann Arbor, MI 48109, USA. qweis@umich.edu
Lu
Xin-Yun
XY
Liu
Li
L
Schafer
Gwen
G
Shieh
Kun-Ruey
KR
Burke
Sharon
S
Robinson
Terry E
TE
Watson
Stanley J
SJ
Seasholtz
Audrey F
AF
Akil
Huda
H
D000342:Affective Symptoms / Q000209:etiology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001007:Anxiety / Q000209:etiology; D003042:Cocaine / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D003863:Depression / Q000209:etiology; D005786:Gene Expression Regulation / Q000502:physiology; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D019964:Mood Disorders / Q000209:etiology; D016548:Prosencephalon / Q000737:chemistry* / Q000503:physiopathology; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000502:physiology*
D000928:Antidepressive Agents; D026901:Membrane Transport Proteins; D011965:Receptors, Glucocorticoid; D044282:Receptor, Serotonin, 5-HT1A; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine