Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex.
Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex.
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DOI：
10.1371/journal.pone.0030942
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shumyatsky GP
中科院分区：
文献类型：
--
作者：
Martel G;Hevi C;Wong A;Zushida K;Uchida S;Shumyatsky GP
灭绝是正常健康的恐惧反应的一个组成部分，而它在人类的几种与恐惧有关的精神状况中受到损害，例如创伤后应激障碍（PTSD）。尽管最近有很多研究都集中在恐惧消退上，但其分子和细胞基础仍然不清楚。灭绝动物模型的发展将极大地增强我们研究其神经回路及其机制的方法。在这里，我们描述了两个基因敲除小鼠品系，一个受损，另一个增强灭绝的学习恐惧。这些突变小鼠是基于恐惧记忆相关基因，stathmin和胃泌素释放肽受体（GRPR）。值得注意的是，这两个突变系都表现出了对线索的恐惧消退的变化，而不是对背景的变化。我们进行了间接成像的神经元活动的第二天的线索灭绝，使用即时早期基因c-Fos。GRPR基因敲除的小鼠比野生型小鼠熄灭得更慢（熄灭受损），这伴随着基底外侧杏仁核中c-Fos活性的增加和前额叶皮质的减少。相比之下，stathmin基因敲除小鼠的消退速度更快（消退增强），基底外侧杏仁核中的c-Fos活性降低，前额叶皮质中的c-Fos活性增加。与此同时，齿状回c-Fos活性在两个突变系中均增加。这些实验提供的遗传证据表明，杏仁核和前额叶皮层的神经元活动之间的平衡定义了一个障碍或促进灭绝的线索，而海马是参与灭绝的上下文特异性。
Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction.
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影响因子：
2
作者：
Knapska, Ewelina;Maren, Stephen
通讯作者：
Maren, Stephen
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作者：
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