Merino Stephen M, Maren Stephen
Neuroscience Graduate Program, University of Michigan, 525 E. University Ave., Ann Arbor, MI 48109-1109, USA.
Eur J Neurosci. 2006 Jan;23(1):196-204. doi: 10.1111/j.1460-9568.2005.04546.x.
Several studies have implicated the Ras/mitogen-activated protein kinase (MAPK) pathway in Pavlovian fear conditioning. RasGRF1 knockout mice show significant deficits in acquisition of long-term fear memories and long-term potentaition (LTP) in the basolateral amygdala (BLA). MAPK kinase inhibition also impairs fear conditioning and amygdaloid LTP. However, there is no direct evidence to date for the involvement of Ras itself in fear conditioning. To address this issue, we examined the effects of intra-amygdala infusions of the selective Ras antagonist farnesylthiosalicylic acid (FTS) on the acquisition and expression of conditional freezing in rats. Micro-infusions of FTS into the BLA prior to contextual fear conditioning significantly impaired acquisition of long-term contextual fear memory in a dose-dependent manner. Post-training FTS infusions had no effect on acquisition of long-term fear memory. The effects of FTS on fear conditioning were specific for the BLA. Finally, intra-amygdala infusions of FTS inhibited MAPK activation in BLA. Collectively, these results provide further evidence for the involvement of amygdaloid Ras in the acquisition of long-term conditional fear memory.
多项研究表明，Ras/丝裂原活化蛋白激酶（MAPK）信号通路与巴甫洛夫式恐惧条件反射有关。RasGRF1基因敲除小鼠在获取长期恐惧记忆以及基底外侧杏仁核（BLA）的长时程增强（LTP）方面表现出显著缺陷。抑制MAPK激酶也会损害恐惧条件反射和杏仁核LTP。然而，迄今为止，尚无直接证据表明Ras本身参与恐惧条件反射。为解决这一问题，我们研究了向大鼠杏仁核内注射选择性Ras拮抗剂法尼基硫代水杨酸（FTS）对条件性僵住行为的获得和表达的影响。在情境恐惧条件反射之前向BLA微量注射FTS，会以剂量依赖的方式显著损害长期情境恐惧记忆的获得。训练后注射FTS对长期恐惧记忆的获得没有影响。FTS对恐惧条件反射的影响在BLA中具有特异性。最后，向杏仁核内注射FTS可抑制BLA中的MAPK激活。总体而言，这些结果为杏仁核Ras参与长期条件性恐惧记忆的获得提供了进一步的证据。
