Molecular mechanisms of memrory retrieval

描述（由申请人提供）： 这个建议的目的是为了更好地了解陈述性/情景记忆的提取发生的分子机制。该提案的重点是去甲肾上腺素（NE）和1-肾上腺素能信号在海马体记忆提取过程中发挥的时间限制作用。第一个目标是确定哪些海马细胞的信号传导促进记忆检索。背景恐惧，这取决于NE和1信号，将被用来评估校园依赖的记忆。不依赖于NE或1信号的暗示（音调）恐惧将用于测试操纵是否影响表现或记忆。小鼠中的立即早期基因诱导的成像将被用作暴露于显著和中性环境后神经元活性的标志物。小鼠中的信号传导将被间接和遗传地操纵，使得其仅在背侧海马体中或在海马体的特定子区域中被全身阻断或激活。因为……1信号激活cAMP /蛋白激酶A通路，第二个目的将确定该通路是否是记忆提取所必需的。将在对照小鼠中进行阻断该途径的药剂的背海马输注，并且将在缺乏Δ 1信号传导的突变小鼠中进行刺激该途径的药剂的输注。NE和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，这也是所需的检索，将被确定。此外，在海马体中的信号传导的最突出的生理效应之一是介导放电调节的慢后超极化（sAHP）的减少。第三个目标将确定通过电压依赖性钙通道的钙内流是否会影响检索，以及sAHP的药理学阻断是否会挽救缺乏Δ 1信号传导的突变小鼠的检索。这一目标还将确定在恐惧条件反射而不是伪条件反射后的小鼠脑切片中是否可以观察到sAHP的短暂降低，如果是这样，这种降低是否取决于信号传导。最后，一个关键的假设解释了为什么NE是需要一些，但不是所有的记忆检索将在第四个目标进行测试。相关性：肾上腺素能信号传导功能障碍可能导致抑郁症和创伤后应激障碍的症状，包括前者的记忆检索困难和后者的创伤记忆的不必要的侵入性检索。这一提议的结果也可能与用阻断受体的药物治疗心力衰竭、高血压和表现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Ca++稳态失调如何导致记忆缺陷有关。

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.