Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior.
Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior.
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DOI：
10.1016/j.biopsych.2010.04.031
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发表时间：
2010-09-15
影响因子：
10.6
通讯作者：
McClung, Colleen A.
中科院分区：
文献类型：
--
作者：
Mukherjee, Shibani;Coque, Laurent;Cao, Jun-Li;Kumar, Jaswinder;Chakravarty, Sumana;Asaithamby, Aroumougame;Graham, Ami;Gordon, Elizabeth;Enwright, John F., III;DiLeone, Ralph J.;Birnbaum, Shari G.;Cooper, Donald C.;McClung, Colleen A.
昼夜节律异常与双相情感障碍密切相关，然而昼夜节律基因在情绪调节中的作用尚不清楚。之前，我们报道了Clock基因突变（ClockΔ19）的小鼠表现出与躁狂状态下的双相情感障碍患者惊人相似的行为特征。在这里，我们利用RNA干扰（RNAi）和病毒介导的基因转移敲低时钟表达，特别是在腹侧被盖区（VTA）的小鼠。然后，我们进行了各种行为，分子和生理措施。我们发现，在VTA中特异性敲低Clock会导致多动和焦虑相关行为的减少，这与ClockΔ19小鼠的表型相似。然而，VTA特异性敲除也导致抑郁样行为的大幅增加，从而产生整体混合躁狂状态。令人惊讶的是，VTA敲低Clock也改变了昼夜节律的周期和幅度，这表明VTA中的Clock在调节昼夜节律中的作用。此外，与对照组相比，表达Clock shRNA的VTA多巴胺能神经元的活性增加，并且这种敲低改变了VTA中多种离子通道和多巴胺相关基因的表达，这可能是这些小鼠生理和行为变化的原因。综上所述，这些结果表明腹侧被盖区的CLOCK在调节多巴胺能活性、躁狂和抑郁样行为以及昼夜节律中具有重要作用。
Circadian rhythm abnormalities are strongly associated with bipolar disorder, however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockΔ19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state. Here, we utilized RNA interference (RNAi) and viral-mediated gene transfer to knock-down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular and physiological measures. We found that knock-down of Clock specifically in the VTA results in hyperactivity and a reduction in anxiety-related behavior which is similar to the phenotype of the ClockΔ19 mice. However, VTA specific knock-down also results in a substantial increase in depression-like behavior, creating an overall mixed-manic state. Surprisingly, VTA knock-down of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock shRNA have increased activity compared to controls, and this knock-down alters the expression of multiple ion channels and dopamine-related genes in the VTA which could be responsible for the physiological and behavioral changes in these mice. Taken together, these results suggest an important role for CLOCK in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.
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影响因子：
10.6
作者：
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通讯作者：
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