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

去甲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。海马是接受去甲肾上腺素的脑区之一，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经被描述，但针对这种机制的创伤后应激障碍治疗并不成功。 最近，去甲肾上腺素对脑细胞的非标准作用被发现，但对记忆储存的影响还没有被描述。 拟议的研究将采用活细胞成像，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。这些结果将对开发新的治疗应激相关记忆障碍的药物具有重要意义，为药物开发提供了新的分子靶点。通过#946;肾上腺素能受体（#946;AR）的去甲肾上腺素能信号传导对海马中的长期突触可塑性（LTP）至关重要。去甲肾上腺素能受体的激活通过经典信号传导途径导致第二信使cAMP和记忆激酶PKA升高。 最近，一个新的信号通路激活的#946;AR，涉及激活的记忆激酶ERK，已被证明参与记忆储存和突触可塑性。 然而，海马中的机制尚未完全了解，这阻碍了开发新的治疗应激相关记忆障碍的方法。因此，本项目的目标是描绘#946;AR信号在海马记忆储存的LTP中的作用。本研究将确定ERK招募的作用#946; 2AR在LTP，并证明如何不同的时间模式的刺激使用不同的信号通路下游的#946;2AR激活。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。 激酶活性的活细胞成像和模型开发之间的来回相互作用将产生实验约束和验证的信号通路模型。然后，模拟实验将被用来设计刺激协议，将与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/），以促进创建有助于解释活细胞成像结果的模型。

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).