Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression
Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression
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DOI：
10.1073/pnas.1034823100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Vaugeois, JM
中科院分区：
文献类型：
--
作者：
El Yacoubi, M;Bouali, S;Vaugeois, JM
抑郁症是一种多因素疾病，遗传因素在其病因中起作用。对其生理病理学的理解依赖于可能模拟该疾病的实验模型的可用性。在这里，我们描述了一个模型，建立了选择性繁殖的小鼠有显着不同的反应，在尾部悬挂试验，旨在筛选潜在的抗抑郁药的压力范例。事实上，“无助”小鼠在悬尾试验以及Porsolt强迫游泳试验中基本上是不动的，并且它们显示出可口的2%蔗糖溶液的消耗减少。此外，无助的小鼠表现出类似于抑郁症患者中典型观察到的睡眠-觉醒改变，特别是更轻和更碎片化的睡眠，快速眼动睡眠的压力增加。与“非无助”小鼠相比，它们在海马中显示出较高的基础血清皮质酮水平和较低的5-羟色胺代谢指数。值得注意的是，5-羟色胺（1A）自身受体刺激诱导更大的低温和抑制中缝背核中的多巴胺能神经元放电无助比nonhelpful小鼠。因此，无助的小鼠表现出肾上腺素能紧张度的降低，这引起了与人类内源性抑郁症相关的症状。最后，行为障碍和胆碱能功能障碍都可以通过抗抑郁药氟西汀的长期治疗得到改善。无助的小鼠品系可能提供了一个机会，以接近影响抑郁症易感性的基因，并研究抗抑郁作用的神经生理学和神经化学底物。
Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its physiopathology relies on the availability of experimental models potentially mimicking the disease. Here we describe a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increased pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal seric corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin(1A) autoreceptor stimulation induces larger hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.