Specific Role of VTA Dopamine Neuronal Firing Rates and Morphology in the Reversal of Anxiety-Related, but not Depression-Related Behavior in the ClockΔ19 Mouse Model of Mania
Specific Role of VTA Dopamine Neuronal Firing Rates and Morphology in the Reversal of Anxiety-Related, but not Depression-Related Behavior in the ClockΔ19 Mouse Model of Mania
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DOI：
10.1038/npp.2011.33
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发表时间：
2011-06-01
影响因子：
7.6
通讯作者：
McClung, Colleen A.
中科院分区：
文献类型：
--
作者：
Coque, Laurent;Mukherjee, Shibani;McClung, Colleen A.
锂已广泛用于稳定情绪，并且在治疗双相躁狂方面特别有效。与其他用于治疗精神疾病的药物一样，它对健康人的情绪影响不大。我们之前的研究发现，时钟基因（Clock Delta 19）发生突变的小鼠具有与人类躁狂症非常相似的完整行为特征，可以通过长期锂治疗来逆转。然而，其靶向治疗功效背后的细胞和生理效应仍然未知。在这里，我们发现 Clock Delta 19 小鼠腹侧被盖区 (VTA) 的多巴胺能活性增加，并且锂治疗选择性地降低了突变型小鼠的放电率，而对野生型小鼠的活动没有影响。此外，锂治疗选择性地降低了突变小鼠的伏隔核（NAc）多巴胺水平。 Clock突变体中多巴胺能活性的增加与多巴胺神经元的细胞体积变化有关，这也可以通过锂治疗来挽救。为了确定多巴胺能活性和多巴胺神经元形态变化在躁狂样行为中的作用，我们使用病毒介导的基因转移，通过在 Clock Delta 19 小鼠和野生型小鼠的 VTA 中选择性过度表达内向整流钾通道亚基 (Kir2.1) 来操纵这些神经元的兴奋性。该通道的引入模拟了锂治疗对 Clock Delta 19 小鼠多巴胺神经元放电率的影响，并导致多巴胺细胞体积发生类似的变化。此外，Clock Delta 19 动物的多巴胺能放电率降低会导致运动和焦虑相关行为正常化，这与锂治疗非常相似。然而，这还不足以扭转与抑郁症相关的行为。这些结果表明，多巴胺细胞放电和相关形态的异常是双相躁狂中焦虑相关行为改变的基础，而锂的治疗作用来自于这些异常表型的逆转。神经精神药理学 (2011) 36, 1478-1488; doi：10.1038/npp.2011.33； 2011 年 3 月 23 日在线发布
Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (Clock Delta 19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that Clock Delta 19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of Clock Delta 19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in Clock Delta 19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in Clock Delta 19 animals results in a normalization of locomotor-and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes. Neuropsychopharmacology (2011) 36, 1478-1488; doi:10.1038/npp.2011.33; published online 23 March 2011