US-French Research Proposal: Collaborative Research: Spatial and Temporal Aspects of Molecular Signaling in Synaptic Plasticity

美法研究提案：合作研究：突触可塑性分子信号传导的空间和时间方面

• 批准号: 1753700
• 负责人: Edwin (Ted) Abel
• 金额: $ 14.35万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1753700&HistoricalAwards=false
• 关键词: US; French; Research; Proposal; Collaborative

Noradrenaline is released in many regions of the brain in response to anxiety and stress. Its action on brain cells in several regions contributes to memory storage and extinction, and in some circumstances memory of particularly stressful events creates problems such as post-traumatic stress disorder (PTSD). The hippocampus is one of the brain regions receiving noradrenaline and is an important locus of contextual memory. One mechanism whereby noradrenaline facilitates memory storage has been characterized, but PTSD treatments aimed at this mechanism has not been successful. Recently, a non-standard action of noradrenaline on brain cells was discovered, but the implications for memory storage have not been characterized. The proposed research will employ live cell imaging, physiology and computational modeling to investigate this alternative mechanism whereby noradrenaline modifies memory storage. The results will have major implications for the development of novel treatments for stress-related memory disorders, by suggesting novel molecular targets for pharmaceutical development.Noradrenergic signaling through β adrenergic receptors (βAR) crucially contributes to the long term synaptic plasticity (LTP) underlying memory storage in the hippocampus. Activation of noradrenergic receptors leads to elevations in the second messenger cAMP and the memory kinase PKA through classical signaling pathways. Recently a novel signaling pathway activated by βAR, involving activation of the memory kinase ERK, has been shown to be involved in memory storage and synaptic plasticity. However, the mechanism employed in the hippocampus is not completely understood, which hinders development of novel treatments for stress-related memory disorders. Thus, the goal of this project is to delineate the role of βAR signaling in the LTP underlying hippocampal memory storage. This research will define the role of ERK recruitment by β2ARs in LTP, and demonstrate how different temporal patterns of stimulation use distinct signaling pathways downstream of β2AR activation. The research uses computational spatial modeling of signaling pathways, live cell imaging in brain slice, electrophysiology, biochemistry, and molecular biology to demonstrate how different temporal stimulation patterns activate distinct signaling pathways downstream of β2AR signaling. A back and forth interaction between live cell imaging of kinase activity and model development will produce an experimentally constrained and validated signaling pathway model. Then, simulation experiments will be used to design stimulation protocols that will be tested with electrophysiological and biochemical experiments. The research includes development of software tools (https://github.com/neurord/) to facilitate creation of models that help to interpret live cell imaging results.A companion project is being funded by the French National Research Agency (ANR).

去甲肾上腺素在大脑的许多区域被释放，以应对焦虑和压力。它对几个区域的脑细胞的作用有助于记忆存储和灭绝，在某些情况下，对特别应激事件的记忆会造成诸如创伤后应激障碍(PTSD)等问题。海马体是大脑接受去甲肾上腺素的区域之一，是语境记忆的重要场所。去甲肾上腺素促进记忆储存的一种机制已经确定，但针对这一机制的创伤后应激障碍治疗尚未成功。最近，去甲肾上腺素对脑细胞的非标准作用被发现，但其对记忆存储的影响尚未被表征。这项拟议的研究将利用活细胞成像、生理学和计算建模来研究去甲肾上腺素改变记忆存储的替代机制。通过为药物开发提供新的分子靶点，这一结果将对应激相关记忆障碍的新治疗方法的开发具有重要意义。通过肾上腺素能受体(AR)发出的去甲肾上腺素信号对海马体中潜在的记忆存储的长期突触可塑性(LTP)起着关键作用。去甲肾上腺素能受体的激活通过经典的信号通路导致第二信使cAMP和记忆激酶PKA的升高。最近，由AR激活的一条新的信号通路被证明与记忆存储和突触可塑性有关，该信号通路涉及记忆激酶ERK的激活。然而，海马体中使用的机制并不完全清楚，这阻碍了应激相关记忆障碍的新治疗方法的发展。因此，这个项目的目标是描述AR信号在LTP潜在的海马区记忆存储中的作用。这项研究将确定ERK在LTP中的作用，并展示不同的刺激时间模式如何使用激活2AR下游的不同信号通路。这项研究使用信号通路的计算空间模型、脑片活细胞成像、电生理学、生物化学和分子生物学来演示不同的时间刺激模式如何激活2AR信号下游的不同信号通路。活体细胞对激酶活性的成像和模型开发之间的来回交互作用将产生一个经过实验约束和验证的信号通路模型。然后，将使用模拟实验来设计刺激方案，并通过电生理和生化实验进行测试。这项研究包括开发软件工具(https://github.com/neurord/))，以促进创建有助于解释活细胞成像结果的模型。法国国家研究机构(ANR)正在资助一个配套项目。