Calcium-Stimulated Adenylyl Cyclase Activity's Role in Stress-Facilitated Memory

描述（由申请人提供）：本提案的长期目标是深入了解压力促进记忆形成的关键机制，或者换句话说，在压力条件下处理记忆。 两种与压力和记忆相关的障碍，创伤后应激障碍和重度抑郁症，是异常压力促进记忆处理障碍的主要例子，它们在美国人中的估计终生患病率都超过5%。 有丝分裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路是应激诱导的记忆过程中的一个关键信号通路。 该途径的激活导致下游cAMP反应元件结合蛋白的激活，这导致形成新记忆所需的转录变化。 MAPK/ERK通路的激活剂，调节应激促进记忆仍然没有得到很好的定义。 然而，有证据表明，第二信使cAMP可能是上游启动子，因为cAMP的产生可以激活这一途径，导致记忆的变化。 此外，钙刺激的腺苷酸环化酶（AC），AC 1和AC 8，耦合神经元的活动和细胞内钙增加cAMP的生产，因此，牵连钙刺激的AC活动在调节应激促进记忆的变化。 作为应激促进记忆的范例，我们将使用经典的条件反射测试，这是一个很好的模型来研究我们的假设，因为MAPK/ERK信号通路和钙刺激的AC活性都被证明会影响这种范例的学习。 因此，我们的目标是研究这种活动如何激活MAPK/ERK通路来调节应激促进记忆。 通过使用一种新的转基因小鼠模型，该模型使用四环素诱导系统来取代AC 1和AC 8双敲除小鼠中的AC 8表达，我们能够评估该活性的时间特异性重要性。 此外，通过使用基因治疗技术，我们可以通过启动AC 8表达的慢病毒给药来评估这种活性的区域特异性重要性。 相关性：我们提出的研究将深入了解在压力条件下记忆形成的机制，并可能揭示记忆相关症状在精神疾病中的主要作用。 更具体地说，它将着眼于时间和区域的具体方式，这种压力促进记忆机制调节记忆的形成。这项工作最终可能会导致开发针对因压力相关疾病而导致记忆异常变化的人的治疗干预措施，因为全球性的非特异性治疗可能会促进许多不必要的副作用。 公共卫生宣传我们提出的研究将深入了解在压力条件下记忆形成的机制，并可能揭示记忆相关症状在精神疾病中的主要作用。更具体地说，它将着眼于时间和区域的具体方式，这种压力促进记忆机制调节记忆的形成。这项工作可能最终导致开发针对因压力相关疾病而导致记忆异常变化的人的治疗干预措施，因为全球性的非特异性治疗可能会促进许多不必要的副作用。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to provide insight into mechanisms critical for stress-facilitated memory formation, or in other words, the processing of memories under stressful conditions. Two stress- and memory-associated disorders, posttraumatic stress disorder and major depressive disorder, are prime examples of disorders with abnormal stress-facilitated memory processing, and they both have an estimated lifetime prevalence of over 5% among Americans. A key signaling pathway implicated in stress-induced memory processing is the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Activation of this pathway leads to downstream activation of cAMP response element-binding protein, which results in transcriptional changes needed to form new memories. The activator of the MAPK/ERK pathway that modulates stress-facilitated memory is still not well defined. However, evidence suggests the second messenger, cAMP, may be the upstream initiator as cAMP production can activate this pathway to cause changes in memory. Moreover, calcium-stimulated adenylyl cyclases (AC), AC1 and AC8, couple neuronal activity and intracellular calcium increases to the production of cAMP, thus, implicating calcium-stimulated AC activity in modulating stress-facilitated memory changes. As a paradigm for stress-facilitated memory, we will use a classical conditioning test, which serves as a good model to investigate our hypothesis as both the MAPK/ERK signaling pathway and calcium-stimulated AC activity have been shown to effect learning on this paradigm. Therefore, we aim to examine how this activity may activate the MAPK/ERK pathway to modulate stress-facilitated memory. Through use of a novel transgenic mouse model, which uses a tetracycline-inducible system to replace AC8 expression in AC1 and AC8 double knock-out mice, we are able to assess the time-specific importance of this activity. Moreover, through the use of gene therapy techniques, we can assess the region-specific importance of this activity via lentivirus administration that turns on AC8 expression. Relevance: The research we are proposing will give insight into a mechanism of memory formation under stressful conditions and may reveal a primary role of memory-related symptoms in psychiatric disorders. More specifically, it will look at the time- and region-specific manner in which this stress-facilitated memory mechanism modulates memory formation. This work may eventually lead to the development of therapeutic interventions for people with abnormal memory changes from stress-related disorders as global, non-specific treatments can facilitate a host of unwanted side-effects. PUBLIC HEALTH RELVENCE The research we are proposing will give insight into a mechanism of memory formation under stressful conditions and may reveal a primary role of memory-related symptoms in psychiatric disorders. More specifically, it will look at the time- and region-specific manner in which this stress-facilitated memory mechanism modulates memory formation. This work may eventually lead to the development of therapeutic interventions for people with abnormal memory changes from stress-related disorders as global, non- specific treatments can facilitate a host of unwanted side-effects.