Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain.
Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain.
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DOI：
10.1523/jneurosci.4904-07.2008
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发表时间：
2008-08-06
期刊：
影响因子：
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通讯作者：
Holmes A
中科院分区：
文献类型：
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作者：
Hefner K;Whittle N;Juhasz J;Norcross M;Karlsson RM;Saksida LM;Bussey TJ;Singewald N;Holmes A
恐惧消退是一种新的学习形式，它导致对条件性恐惧的抑制。恐惧消退的特质缺陷是焦虑症的危险因素。自然发生的物种灭绝受损动物模型的例子很少。本研究比较了一组近交系小鼠的恐惧消退。该菌株调查显示129/SvImJ（129 S1）的恐惧消退受损。通过比较129 S1和C57 BL/6 J的一次试验和多次试验的恐惧条件反射，伤害性感受，和条件性味觉厌恶（CTA）和食欲工具反应的消退来评估这种缺陷的表型特异性。测试129 S1对延长训练以及D-环丝氨酸和育亨宾治疗的预防促进作用的敏感性。为了阐明受损的129 S1恐惧消退的神经基础，c-Fos和Zif 268的表达被映射后灭绝回忆。结果表明，129 S1中受损的恐惧消退与改变的恐惧条件反射或伤害感受无关，并且与完整的食欲消退无关。育亨宾处理促进了129 S1的消退，但延长消退训练和D-环丝氨酸处理都不能改善129 S1的消退。与C57 BL/6 J相比，129 S1在消退回忆后，边缘下皮层和基底外侧杏仁核中的c-Fos和Zif 268表达减少，杏仁核中央核和内侧囊旁闰细胞团中的c-Fos或Zif 268表达升高。总的来说，这些数据表明，129 S1中的恐惧消退缺陷与未能正确参与皮质边缘消退电路有关。这种常见的近交系为研究焦虑症中受损的恐惧消退提供了一种新的模型。
Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally-occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multi-trial fear conditioning, nociception, and extinction of conditioned taste aversion (CTA) and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as D-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped following extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor D-cycloserine treatment improved 129S1 extinction. Following extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders.