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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression
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Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression

机译：抑郁症的遗传小鼠模型的行为，神经化学和电生理特征

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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―wakeful ness 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.
机译：抑郁症是一种多因素疾病，遗传因素在其病因中起作用。对其生理病理学的了解取决于可能模拟该疾病的实验模型的可用性。在这里，我们描述了一种通过选择性繁殖小鼠而建立的模型，该小鼠在尾部悬吊测试中具有显着不同的反应，这是一种旨在筛选潜在抗抑郁药的应激范例。实际上，“无助”小鼠在尾部悬吊测试以及Porsolt强迫游泳测试中基本上是无法移动的，并且它们显示出可口的2％蔗糖溶液的消耗量减少。此外，无助的小鼠表现出睡眠觉醒性改变，类似于抑郁症患者的经典观察，特别是睡眠较轻，更零碎的睡眠，而眼动快速睡眠的压力增加。与“无助”小鼠相比，它们在海马体中显示出较高的基础浆液性皮质酮水平和较低的5-羟色胺代谢指数。值得注意的是，与无助的小鼠相比，无助的小鼠中背核中的5-羟色胺_（1A）自身受体刺激引起更大的体温降低和5-羟色胺能神经元放电的抑制。因此，无助的小鼠表现出5-羟色胺能的降低，这引起了与人类内源性抑郁相关的现象。最后，通过抗抑郁药氟西汀的长期治疗，可以改善行为障碍和5-羟色胺能功能障碍。无助的小鼠系可能提供机会来研究影响抑郁症易感性的基因，并研究潜在的抗抑郁作用的神经生理和神经化学底物。

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