Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA.
Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA.
Neurobiol Learn Mem. 2019 May;161:26-36. doi: 10.1016/j.nlm.2019.03.001. Epub 2019 Mar 6.
The association of a sensory cue and an aversive footshock that are separated in time, as in trace fear conditioning, requires persistent activity in prelimbic cortex during the cue-shock interval. The activation of muscarinic acetylcholine receptors has been shown to facilitate persistent firing of cortical cells in response to brief stimulation, and muscarinic antagonists in the prefrontal cortex impair working memory. It is unknown, however, if the acquisition of associative trace fear conditioning is dependent on muscarinic signaling in the prefrontal cortex. Here, we delivered the muscarinic receptor antagonist scopolamine to the prelimbic cortex of rats prior to trace fear conditioning and tested their memories of the cue and training context the following day. The effect of scopolamine on working memory performance was also tested using a spatial delayed non-match to sample task. Male and female subjects were included to examine potential sex differences in the modulation of memory formation, as we have previously observed for pituitary adenylate cyclase-activating polypeptide signaling in the prefrontal cortex (Kirry et al., 2018). We found that pre-training administration of intra-prelimbic scopolamine impaired the formation of cued and contextual fear memories in males, but not females at a dose that impairs spatial working memory in both sexes. Fear memory formation in females was impaired by a higher dose of scopolamine and this impairment was gated by estrous cycle stage: scopolamine failed to impair memory in rats in the diestrus or proestrus stages of the estrous cycle. These findings add to the growing body of evidence that the prefrontal cortex is sexually dimorphic in learning and memory and additionally suggest that males and females differentially engage prefrontal neuromodulatory systems in support of learning.
时间上分离的感觉线索和厌恶性足底电击的关联，如痕迹恐惧条件反射，要求在线索-电击间隔期间在前扣带皮层中保持持续活动。已经表明，毒蕈碱乙酰胆碱受体的激活可促进皮质细胞对短暂刺激的持续放电，而前额叶皮层中的毒蕈碱拮抗剂会损害工作记忆。然而，尚不清楚关联的痕迹恐惧条件反射的获得是否依赖于前额叶皮层中的毒蕈碱信号。在这里，我们在进行痕迹恐惧条件反射之前，将毒蕈碱受体拮抗剂东莨菪碱递送至大鼠的前扣带皮层，并在第二天测试它们对线索和训练环境的记忆。还使用空间延迟非匹配样本任务测试了东莨菪碱对工作记忆性能的影响。包括雄性和雌性动物，以检查在记忆形成中的调制方面的潜在性别差异，正如我们之前在前额叶皮层中观察到的垂体腺苷酸环化酶激活多肽信号（Kirry 等人，2018 年）一样。我们发现，在雄性动物中，在预训练时在前扣带皮层内给予东莨菪碱可损害条件性和情境性恐惧记忆的形成，但在两性中都会损害空间工作记忆的剂量却不会损害。在雌性动物中，更高剂量的东莨菪碱会损害记忆形成，而这种损害是由发情周期阶段控制的：在发情周期的动情前期或动情前期阶段，东莨菪碱未能损害大鼠的记忆。这些发现增加了越来越多的证据，表明前额叶皮层在学习和记忆方面存在性别二态性，此外还表明雄性和雌性动物以不同的方式参与前额叶神经调节系统以支持学习。
