Enhanced contextual fear memory in central serotonin-deficient mice
Enhanced contextual fear memory in central serotonin-deficient mice
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中枢血清素缺乏小鼠的情境恐惧记忆增强
DOI：
10.1073/pnas.0801329105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Xu, Lin
中科院分区：
文献类型：
--
作者：
Dai, Jin-Xia;Han, Hui-Li;Xu, Lin
中枢5-羟色胺（5-HT）调节异常有助于精神障碍的易感性，包括抑郁症，焦虑症，创伤后应激障碍，以及学习和记忆缺陷。我们报告说，在中央5-HT缺陷小鼠中，依赖于大脑皮层的空间记忆的形成受到损害，但背景恐惧记忆的获得和检索得到增强。大脑中5-羟色胺的基因缺失是通过选择性地在脑干的中缝核中灭活Lmx 1b来实现的，导致整个大脑中5-HT几乎完全丧失。这些5-HT缺陷小鼠的脑结构没有明显异常，并且具有正常的运动活动。Morris水迷宫中的空间学习不受影响，但空间记忆的提取受损。相反，足电击条件反射引起的情境性恐惧学习和记忆显著增强，但这种增强作用可被脑室内注射5-HT所阻止。足电击损伤WT小鼠海马脑片的长时程增强和促进长时程抑制，但对5-HT缺陷小鼠无影响。此外，浴应用5-HT在5-HT缺陷小鼠恢复足休克引起的海马突触可塑性的改变。因此，中枢5-HT调节海马依赖的情境恐惧记忆，5-HT调节海马突触可塑性可能是其潜在机制。5-HT缺乏小鼠的恐惧记忆增强支持了5-HT缺乏使人类易患创伤后应激障碍的观点。
Central serotonin (5-HT) dysregulation contributes to the susceptibility for mental disorders, including depression, anxiety, and posttraumatic stress disorder, and learning and memory deficits. We report that the formation of hippocampus-dependent spatial memory is compromised, but the acquisition and retrieval of contextual fear memory are enhanced, in central 5-HT-deficient mice. Genetic deletion of serotonin in the brain was achieved by inactivating Lmx1b selectively in the raphe nuclei of the brainstem, resulting in a near-complete loss of 5-HT throughout the brain. These 5-HT-deficient mice exhibited no gross abnormality in brain structures and had normal locomotor activity. Spatial learning in the Morris water maze was unaffected, but the retrieval of spatial memory was impaired. In contrast, contextual fear learning and memory induced by foot-shock conditioning was markedly enhanced, but this enhancement could be prevented by intracerebroventricular administration of 5-HT. Foot shock impaired long-term potentiation and facilitated long-term depression in hippocampal slices in WT mice but had no effect in 5-HT-deficient mice. Furthermore, bath application of 5-HT in 5-HT-deficient mice restored foot shock-induced alterations of hippocampal synaptic plasticity. Thus, central 5-HT regulates hippocampus-dependent contextual fear memory, and 5-HT modulation of hippocampal synaptic plasticity may be the underlying mechanism. The enhanced fear memory in 5-HT-deficient mice supports the notion that 5-HT deficiency confers susceptibility to posttraumatic stress disorder in humans.