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首页> 美国卫生研究院文献>Frontiers in Behavioral Neuroscience >GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology
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GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology

机译：GAD65单倍体缺乏症在应激诱导的精神病理学动物模型中传达弹性

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GABAergic mechanisms are critically involved in the control of fear and anxiety, but their role in the development of stress-induced psychopathologies, including post-traumatic stress disorder (PTSD) and mood disorders is not sufficiently understood. We studied these functions in two established mouse models of risk factors for stress-induced psychopathologies employing variable juvenile stress and/or social isolation. A battery of emotional tests in adulthood revealed the induction of contextually generalized fear, anxiety, hyperarousal and depression-like symptoms in these paradigms. These reflect the multitude and complexity of stress effects in human PTSD patients. With factor analysis we were able to identify parameters that reflect these different behavioral domains in stressed animals and thus provide a basis for an integrated scoring of affectedness more closely resembling the clinical situation than isolated parameters. To test the applicability of these models to genetic approaches we further tested the role of GABA using heterozygous mice with targeted mutation of the GABA synthesizing enzyme GAD65 [GAD65(+/−) mice], which show a delayed postnatal increase in tissue GABA content in limbic and cortical brain areas. Unexpectedly, GAD65(+/−) mice did not show changes in exploratory activity regardless of the stressor type and were after the variable juvenile stress procedure protected from the development of contextual generalization in an auditory fear conditioning experiment. Our data demonstrate the complex nature of behavioral alterations in rodent models of stress-related psychopathologies and suggest that GAD65 haplodeficiency, likely through its effect on the postnatal maturation of GABAergic transmission, conveys resilience to some of these stress-induced effects.
机译：GABA能机制关键地参与了恐惧和焦虑的控制，但是对它们在包括压力后精神障碍（PTSD）和情绪障碍在内的压力引起的精神病学发展中的作用还没有得到足够的了解。我们在两个建立的小鼠模型中研究了这些功能，这些模型使用可变的青少年应激和/或社会隔离来产生压力诱发的精神病理学危险因素。成年后的一系列情绪测试显示，在这些范式中诱发了上下文普遍的恐惧，焦虑，过度兴奋和抑郁样症状。这些反映了人类PTSD患者的应激效应的多样性和复杂性。通过因素分析，我们能够识别出反映压力动物中这些不同行为域的参数，从而为患病综合评分提供了基础，而不是单独的参数，更像是临床情况。为了测试这些模型对遗传学方法的适用性，我们使用具有目标突变性的GABA合成酶GAD65的杂合小鼠[GAD65（+/-）小鼠]进一步测试了GABA的作用，这些小鼠显示出生后组织中GABA含量的延迟增加。边缘和大脑皮层区域。出乎意料的是，GAD65（+/-）小鼠无论应激源的类型如何都没有显示出探索活动的变化，并且在听觉恐惧条件实验中保护了可变的青少年应激程序免受上下文概括的发展。我们的数据证明了与压力相关的精神病理学的啮齿动物模型中行为改变的复杂性质，并表明GAD65单倍体缺乏可能通过其对GABA能量传递的出生后成熟的影响传达了对这些压力诱导的某些影响的抵抗力。

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