2-arachidonoylglycerol signaling impairs short-term fear extinction.
2-arachidonoylglycerol signaling impairs short-term fear extinction.
复制标题
2-芳基烯丙基甘油信号传导会损害短期恐惧灭绝。
DOI：
10.1038/tp.2016.26
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发表时间：
2016-03-01
影响因子：
6.8
通讯作者：
Patel S
中科院分区：
文献类型：
--
作者：
Hartley ND;Gunduz-Cinar O;Halladay L;Bukalo O;Holmes A;Patel S
恐惧消退障碍被认为是创伤后应激障碍的精神病理学的核心，内源性大麻素（eCB）信号传导与消退学习密切相关。在这里，我们利用单酰基甘油脂肪酶抑制剂JZL 184选择性地增加大脑2-AG水平结合听觉线索恐惧条件化范例来测试2-AG介导的eCB信号传导调节小鼠短期恐惧消退学习的假设。我们发现，全身JZL 184损害短期灭绝学习CB 1受体依赖的方式，而不影响非特异性冻结行为或收购条件性恐惧。在过度调节的小鼠中也观察到这种效应，这些小鼠在环境中被操纵以重新获得恐惧消退。累积起来，JZL 184的作用似乎部分是由于杏仁核（BLA）基底外侧核（BLA）中2-AG信号的增强，因为将JZL 184直接微输注到BLA中产生了类似的结果。此外，我们阐明了一个短的3天的时间窗口，在此期间，2-AG增强损害灭绝行为，这表明2-AG介导的eCB信号在短期行为后遗症的调制急性创伤应激暴露的优先作用。
Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure.