Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse
Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse
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DOI：
10.1073/pnas.0505407103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Tang, YP
中科院分区：
文献类型：
--
作者：
Chen, Q;Nakajima, A;Tang, YP
胆囊收缩素（Cholecystokinin， CCK）是大脑中最丰富的神经肽之一，通过激活CCK受体-2 （CCKR-2）在焦虑发生中起重要作用。然而，越来越多的证据表明，这一作用取决于内源性CCKergic“音调”，这在很大程度上取决于CCKR-2的表达水平。利用tTA/ teto诱导的转基因（tg）方法，我们在这里发现，与对照组相比，tg小鼠前脑神经元中CCKR-2的过表达显著增加了CCKR-2的结合能力。有趣的是，在一系列行为测试中，这些tg小鼠持续表现出增加的恐惧反应，这通常被解释为啮齿动物的焦虑样行为，这些行为测试代表了冲突情况或向受试者传递压力。多西环素处理对转基因表达的抑制完全减少了增加的受体结合活性和所有行为表型。此外，用安定治疗tg小鼠显著减轻了这些焦虑样行为。我们的研究结果直接表明，通过大脑中CCKR-2的过度表达而升高的CCKergic张力可能构成了焦虑表达的潜在分子/神经元机制。此外，我们的研究在小鼠的面部、建设性和预测有效性方面验证了一个强大的遗传焦虑模型。
Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic "tone," which is largely determined by the expression level of the CCKR-2. Using the tTA/tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular/neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity.