Yen Yi-Chun, Anderzhanova Elmira, Bunck Mirjam, Schuller Julia, Landgraf Rainer, Wotjak Carsten T
Department of Neuronal Plasticity, Max Planck Institute of Psychiatry Munich, Germany.
Front Behav Neurosci. 2013 Aug 15;7:103. doi: 10.3389/fnbeh.2013.00103. eCollection 2013.
We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field (OF) test with deficits in habituation, compared to mice bred for normal (NAB) and high anxiety-related behavior (HAB). Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition (PPI), implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles, and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD-like symptoms.
我们建立了特质焦虑极端情况的小鼠模型，该模型基于在高架十字迷宫中对低、正常、高开放臂探索进行选择性育种。经基因选择的低焦虑相关行为（LAB）小鼠与笼内多动现象一致。鉴于精神分裂症、躁狂症和注意力缺陷多动障碍（ADHD）等几种精神疾病都有多动症状这一事实，我们系统地研究了LAB小鼠是否具有这三种疾病独特且重叠的内表型。为此，维恩图被用作区分可能模型的工具。我们将内表型排列在维恩图中，并将其转化为不同的行为测试。与正常焦虑相关行为（NAB）和高焦虑相关行为（HAB）的小鼠相比，LAB小鼠在旷场（OF）试验中的运动水平升高，且习惯化存在缺陷。低活性的HAB小鼠与高活性的LAB小鼠杂交产生的后代运动水平较低，与HAB小鼠相当，这表明在决定运动水平方面，HAB等位基因比LAB等位基因更具显性。在洞板试验中，LAB小鼠在洞探索中花费的时间较少，这与精神分裂症和ADHD患者的情况相同；然而，LAB小鼠在社交互动和前脉冲抑制（PPI）方面没有受损，这意味着LAB不太可能作为精神分裂症的动物模型。尽管LAB小鼠表现出过度觉醒、积极的应对方式和认知缺陷，这些是躁狂症和ADHD共有的症状，但它们并未表现出典型的躁狂内表型，如享乐增加和物体互动增加。抗精神病药物氟哌啶醇降低了所有小鼠品系的运动活性。相比之下，情绪稳定剂锂和精神兴奋剂苯丙胺选择性地降低了LAB小鼠的多动。基于行为和药理学特征，LAB小鼠被认为是一种类似ADHD症状的新型啮齿动物模型。
