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

描述(申请人提供)：这项提案的长期目标是提供对压力促进记忆形成的关键机制的洞察，或者换句话说，在压力条件下记忆的处理。两种与压力和记忆相关的障碍，创伤后应激障碍和严重抑郁障碍，是具有异常压力促进记忆处理的障碍的主要例子，据估计，这两种障碍在美国人的终生患病率都超过5%。在应激诱导的记忆过程中，一个关键的信号通路是丝裂原活化蛋白激酶/细胞外信号调节激酶(MAPK/ERK)通路。 这一途径的激活导致cAMP反应元件结合蛋白的下游激活，从而导致形成新记忆所需的转录变化。调节应激促进记忆的MAPK/ERK通路的激活物仍然没有很好的定义。然而，有证据表明，第二信使cAMP可能是上游启动者，因为cAMP的产生可以激活这一途径，导致记忆变化。此外，钙刺激的腺酰环化酶(AC)AC1和AC8结合神经元活动和细胞内钙离子增加cAMP的产生，从而暗示钙刺激的AC活性在调节应激促进的记忆变化中起作用。作为应激促进记忆的范式，我们将使用经典的条件测试，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活动都被证明在这个范式上影响学习。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的记忆。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AC1和AC8双基因敲除小鼠中AC8的表达，我们能够评估这一活动的时间特定的重要性。此外，通过使用基因治疗技术，我们可以通过慢病毒注射打开AC8表达来评估这一活动的区域特异性重要性。相关性：我们提议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障碍中的主要作用。更具体地说，它将着眼于这种压力促进的记忆机制调节记忆形成的特定时间和地区的方式。这项工作最终可能导致为因应激相关疾病而导致记忆异常变化的人开发治疗干预措施，因为全局的、非特定的治疗可能会导致一系列不想要的副作用。 公共卫生研究我们提议的这项研究将深入了解应激条件下记忆形成的机制，并可能揭示记忆相关症状在精神障碍中的主要作用。更具体地说，它将着眼于这种压力促进的记忆机制调节记忆形成的特定时间和地区的方式。这项工作最终可能导致为因应激相关疾病而导致记忆异常变化的人开发治疗干预措施，因为全局的、非特定的治疗可能会促进一系列不想要的副作用。

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.