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

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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).