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: 1515458
• 负责人: Edwin (Ted) Abel
• 金额: $ 22.5万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1515458&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).

北肾上腺素在大脑的许多区域释放，以应对焦虑和压力。 它对几个地区的脑细胞的作用有助于记忆存储和灭绝，在某些情况下，对特别压力事件的记忆会引起创伤后应激障碍（PTSD）等问题。海马是接受去甲肾上腺素的大脑区域之一，是上下文记忆的重要轨迹。 去甲肾上腺素促进记忆存储的一种机制已被表征，但是针对该机制的PTSD处理尚未成功。 最近，发现去甲肾上腺素对脑细胞的非标准作用，但尚未表征对记忆存储的影响。 拟议的研究将采用活细胞成像，生理和计算建模来研究这种替代机制，北肾上腺素可以修饰存储器的存储。结果将通过提出新型的药物开发分子靶标，对与应力相关记忆障碍的新处理有重大影响。通过＆＃946;非肾上腺素能信号传导；肾上腺素能受体（＆＃946; ar）至关重要地有助于海马中的长期突触可塑性（LTP）。去甲肾上腺素能受体的激活导致第二信使训练营和通过经典信号通路的记忆激酶PKA升高。 最近，涉及记忆激酶ERK激活的＆＃946; AR激活的新型信号通路已被证明参与了记忆存储和突触可塑性。 但是，海马中采用的机制尚未完全理解，这阻碍了与压力相关的记忆障碍的新型治疗方法。因此，该项目的目的是描述＆＃946; ar信号在LTP下面的海马记忆存储中的作用。这项研究将定义LTP中ERK募集的作用，并证明刺激的不同时间模式如何使用＆＃946; 2AR激活下游的不同信号通路。该研究使用信号通路的计算空间建模，脑切片中的活细胞成像，电生理学，生物化学和分子生物学来证明不同的时间刺激模式如何激活＆＃946; 2AR信号下游的不同信号通路。 激酶活性和模型开发的活细胞成像之间的后退相互作用将产生实验约束和经过验证的信号通路模型。然后，模拟实验将用于设计将通过电生理和生化实验测试的刺激方案。该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。伴侣项目由法国国家研究机构（ANR）资助。