Molecular mechanisms of memrory retrieval

描述(申请人提供)：这项建议的目标是更好地理解声明性/情景记忆提取的分子机制。该提案着重于去甲肾上腺素(NE)和1-肾上腺素能信号在记忆提取过程中在海马区发挥的限时作用。第一个目标将确定在哪个海马细胞(S)信号中起促进记忆恢复的作用。情境恐惧依赖于NE和？1信号，将被用来评估海马体依赖的记忆。线索(音调)恐惧不依赖于NE或？1信号，将被用来测试操作是否会影响表现或记忆。小鼠即刻早期基因诱导的成像将被用作暴露在显著和中性环境中的神经元活动的标志，小鼠中的信号将受到药理学和遗传学的操纵，以便仅在背侧海马区或在海马区的特定亚区被系统性地阻断或激活。因为1信号激活cAMP/蛋白激酶A途径，第二个目的将决定记忆恢复是否需要该途径。在对照组小鼠的背侧海马区注入阻断这一途径的药物，而在缺乏信号转导的突变小鼠中注入刺激这一途径的药物。去甲肾上腺素与细胞外信号调节激酶和磷脂酰肌醇3-激酶的激活之间的关系将被确定，这也是恢复所必需的。此外，海马区信号最显著的生理效应之一是减少了调节放电的慢后超极化(SAHP)。第三个目标将确定通过电压依赖性钙通道的钙内流是否影响恢复，以及SAHP的药理阻断是否拯救缺乏信号的突变小鼠的恢复。这一目标还将确定在恐惧条件作用后小鼠的脑片中是否存在暂时性的SAHP减少，但不能观察到假条件作用，如果是的话，这种减少是否依赖于信号。最后，在第四个目标中，将检验一个关键假设，该假说解释了为什么某些记忆提取需要去甲肾上腺素，而不是所有记忆提取都需要NE。相关性：肾上腺素能信号功能障碍可能导致抑郁症和创伤后应激障碍的症状，包括前者记忆提取困难，后者创伤记忆不受欢迎的侵入性提取。这一建议的结果也可能与使用阻断受体的药物治疗心力衰竭、高血压和绩效焦虑时可能出现的潜在认知副作用有关。最后，研究结果也应该与了解老年人神经元钙离子稳态失调如何导致记忆障碍有关。

DESCRIPTION (provided by applicant): The goal of this proposal is to better understand the molecular mechanisms by which the retrieval of declarative/episodic memory occurs. The proposal focuses on the time-limited role that norepinephrine (NE) and ¿1-adrenergic signaling play in the hippocampus during memory retrieval. The first aim will determine in which hippocampal cell(s) ¿1 signaling acts to promote memory retrieval. Contextual fear, which depends to NE and ¿1 signaling, will be used to assess hippocampus-dependent memory. Cued (tone) fear, which does not depend on NE or ¿1 signaling, will be used to test whether manipulations affect performance or memory. Imaging of immediate-early gene induction in mice will be employed as a marker of neuronal activity following exposure to salient and neutral contexts, ¿1 signaling in the mice will be manipulated pharmacologically and genetically so that it is blocked or activated either, systemically, only in the dorsal hippocampus, or in specific subfields of the hippocampus. Because ¿1 signaling activates the cAMP / protein kinase A pathway, the second aim will determine whether this pathway is required for memory retrieval. Dorsal hippocampal infusions of agents that block this pathway will be performed in control mice, and infusions of agents that stimulate this pathway will be performed in mutant mice that lack ¿1 signaling. The relationship between NE and activation of extracellular signal-regulated kinase and phosphatidylinositol 3- kinase, which are also required for retrieval, will be determined. Further, one of the most prominent physiological effects of ¿1 signaling in the hippocampus is reduction of the slow afterhyperpolarization (sAHP) that mediates accommodation of firing. The third aim will determine whether calcium influx through voltage-dependent calcium channels influences retrieval, and whether pharmacologic block of the sAHP rescues retrieval in mutant mice lacking ¿1 signaling. This aim will also determine whether there is a transient reduction in the sAHP that can be observed in brain slices of mice after fear conditioning but not pseudoconditioning and, if so, whether the reduction depends on ¿1 signaling. Finally, a key hypothesis explaining why NE is required for some but not all memory retrieval will be tested in the fourth aim. Relevance: Dysfunction of adrenergic signaling may contribute to symptoms of depression and post- traumatic stress disorder that include difficulties with memory retrieval in the former and unwanted, intrusive retrieval of traumatic memories in the latter. Results from this proposal may also be relevant to potential cognitive side effects that might arise when treating heart failure, hypertension and performance anxiety with drugs that block ¿ receptors. Finally, results should also be relevant to understanding how dysregulation of neuronal Ca++ homeostasis in the elderly may lead to memory deficits.