Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability.
Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability.
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DOI：
10.1073/pnas.0402208101
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发表时间：
2004-08
影响因子：
11.1
通讯作者：
Qiang Wei;Xin-Yun Lu;Li Liu;G. Schafer;K. Shieh;S. Burke;T. Robinson;S. Watson;A. Seasholtz;H. Akil
中科院分区：
文献类型：
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作者：
Qiang Wei;Xin-Yun Lu;Li Liu;G. Schafer;K. Shieh;S. Burke;T. Robinson;S. Watson;A. Seasholtz;H. Akil
控制情绪范围和稳定性的分子机制尚不清楚，但这一知识对于理解情绪障碍，特别是双相情感障碍至关重要。在这里，我们展示了糖皮质激素受体(GR)调节情绪反应的这些特征。我们培育了前脑特异高表达GR的转基因小鼠。与野生型相比，这些小鼠表现出焦虑和抑郁样行为的显著增加。然而，他们对抗抑郁剂也超敏感，对可卡因的敏感度也很高。因此，在前脑过度表达GR的小鼠在积极和消极情绪测试中的反应范围始终比正常范围大。在特定的大脑区域，这种表型与与情绪性相关的基因的表达增加有关：促肾上腺皮质激素释放激素、5-羟色胺、去甲肾上腺素和多巴胺转运体，以及5-羟色胺(1A)受体。因此，GR在前脑的过度表达导致更高的“情绪不稳定”，继而是一种独特的分子调控模式。这一发现表明，GR基因表达的自然变化有助于情绪稳定或不稳定的微调，并可能在双相情感障碍中发挥作用。
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.