Preclinical Laboratory for Translational Research into Affective Disorders, Clinic for Affective Disorders & General Psychiatry, Psychiatric University Hospital Zürich, August Forel-Strasse 7, CH-8008 Zürich, Switzerland.
Neuropharmacology. 2012 Jan;62(1):358-72. doi: 10.1016/j.neuropharm.2011.08.012. Epub 2011 Aug 16.
Uncontrollability of major life events has been proposed to be central to depression onset and maintenance. The learned helplessness (LH) effect describes a deficit in terminating controllable aversive stimuli in individuals that experienced aversive stimuli as uncontrollable relative to individuals that experienced the same stimuli as controllable. The LH effect translates across species and therefore can provide an objective-valid readout in animal models of depression. Paradigms for a robust LH effect are established and currently applied in rat but there are few reports of prior and current study of the LH effect in mouse. This includes the C57BL/6 mouse, typically the strain of choice for application of molecular-genetic tools in pre-clinical depression research. The aims of this study were to develop a robust paradigm for the LH effect in BL/6 mice, provide evidence for underlying psychological processes, and study the effect of a depression-relevant genotype on the LH effect. The apparatus used for in/escapable electro-shock exposure and escape test was a two-way shuttle arena with continuous automated measurement of locomotion, compartment transfers, e-shock escapes, vertical activity and freezing. Brother-pairs of BL/6 mice were allocated to either escapable e-shocks (ES) or inescapable e-shocks (IS), with escape latencies of the ES brother used as e-shock durations for the IS brother. The standard two-way shuttle paradigm was modified: the central gate was replaced by a raised divider and e-shock escape required transfer to the distal part of the safe compartment. These refinements yielded reduced superstitious, pre-adaptive e-shock transfers in IS mice and thereby increased the LH effect. To obtain a robust LH effect in all brother pairs, pre-screening for minor between-brother ES differences was necessary and did not confound the LH effect. IS mice developed reduced motor responses to e-shock, consistent with a motivational deficit, and absence of a learning curve for escapes at escape test, consistent with a cognitive deficit. When a tone CS was used to predict e-shock, IS mice exhibited increased reactivity to the CS, consistent with hyper-emotionality. There was no ES-IS difference in pain sensitivity. Mice heterozygous knockout for the 5-HTT gene exhibited an increased LH effect relative to wildtype mice. This mouse model will allow for the detailed molecular study of the aetiology, psychology, neurobiology and neuropharmacology of uncontrollability of aversive stimuli, a potential major aetiological factor and state marker in depression. This article is part of a Special Issue entitled 'Anxiety and Depression'.
重大生活事件的不可控性被认为是抑郁发作和维持的核心。习得性无助（LH）效应描述了一种在经历令人痛苦的刺激时无法终止可控刺激的缺陷，这种缺陷存在于经历了不可控刺激的个体中，而不存在于经历了可控刺激的个体中。LH 效应在物种间具有转化性，因此可以为抑郁的动物模型提供客观有效的读数。目前已经在大鼠中建立了强大的 LH 效应范式，并得到了广泛应用，但在小鼠中，关于 LH 效应的先前和当前研究报告却很少。这包括 C57BL/6 小鼠，通常是应用于临床前抑郁研究的分子遗传工具的首选品系。本研究的目的是在 BL/6 小鼠中建立一个强大的 LH 效应范式，提供潜在心理过程的证据，并研究与抑郁相关的基因型对 LH 效应的影响。用于可逃避电击暴露和逃避测试的设备是一个双向穿梭竞技场，具有连续的自动运动、隔室转移、电击逃避、垂直活动和冻结的测量。BL/6 小鼠的兄弟对被分配到可逃避电击（ES）或不可逃避电击（IS），ES 兄弟的逃避潜伏期被用作 IS 兄弟的电击持续时间。对标准的双向穿梭范式进行了修改：中央门被一个升高的隔板取代，电击逃避需要转移到安全隔室的远端部分。这些改进减少了 IS 小鼠中迷信的、预先适应的电击转移，从而增加了 LH 效应。为了在所有兄弟对中获得强大的 LH 效应，需要对 ES 之间的微小差异进行预筛选，并且不能混淆 LH 效应。IS 小鼠对电击的运动反应减少，这与动机缺陷一致，在逃避测试中没有逃避学习曲线，这与认知缺陷一致。当一个音调 CS 用于预测电击时，IS 小鼠对 CS 的反应增强，这与过度情绪化一致。IS 与 ES 之间在疼痛敏感性上没有差异。5-羟色胺转运蛋白（5-HTT）基因杂合敲除的小鼠相对于野生型小鼠表现出更强的 LH 效应。这种小鼠模型将允许对厌恶刺激的不可控性的发病机制、心理学、神经生物学和神经药理学进行详细的分子研究，这是抑郁的一个潜在主要病因和状态标志物。本文是一个题为“焦虑和抑郁”的特刊的一部分。
