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

大脑的许多区域会释放去甲肾上腺素，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的储存和消失，在某些情况下，对特别紧张事件的记忆会产生创伤后应激障碍（PTSD）等问题。海马体是接受去甲肾上腺素的大脑区域之一，是情境记忆的重要场所。去甲肾上腺素促进记忆储存的一种机制已被描述，但针对这种机制的PTSD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描述。拟议的研究将采用活细胞成像、生理学和计算模型来研究这种去甲肾上腺素改变记忆存储的替代机制。这一结果将通过为药物开发提供新的分子靶点，对开发新的治疗压力相关记忆障碍的方法具有重要意义。通过&amp；#946；肾上腺素能受体（&#946；AR）对海马体中长期突触可塑性（LTP）的记忆储存起着至关重要的作用。去甲肾上腺素能受体的激活通过经典信号通路导致第二信使cAMP和记忆激酶PKA的升高。最近，一种新的信号通路被&amp；#946；AR涉及记忆激酶ERK的激活，已被证明与记忆储存和突触可塑性有关。然而，海马体的机制尚不完全清楚，这阻碍了压力相关记忆障碍新疗法的发展。因此，这个项目的目标是描述&amp；#946；海马记忆储存中LTP的AR信号。本研究将通过&amp；#946；并证明了不同的时间刺激模式如何使用不同的下游信号通路&amp；#946；2基于“增大化现实”技术的激活。该研究使用信号通路的计算空间模型、脑切片活细胞成像、电生理学、生物化学和分子生物学来展示不同的时间刺激模式如何激活下游不同的信号通路。2基于“增大化现实”技术的信号。激酶活性的活细胞成像和模型开发之间的来回相互作用将产生一个实验约束和验证的信号通路模型。然后，模拟实验将用于设计刺激方案，并将通过电生理和生化实验进行测试。该研究包括开发软件工具（https://github.com/neurord/），以促进有助于解释活细胞成像结果的模型的创建。法国国家研究机构（ANR）正在资助一个伙伴项目。

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).