CRCNS: US-French Research Proposal: Synaptic plasticity rules under physiological conditions for hippocampus and cerebellum

神经科学的中心假设之一是，记忆是通过修改突触连接存储在大脑中的。这种突触的可塑性在体外得到了广泛的研究，这些实验导致了描述突触前和突触后活动的特定模式如何导致突触强度变化的数学规则的形式化。然而，这些实验研究中的绝大多数都是在远离生理学的条件下进行的。特别是，钙在许多制剂中被认为是诱导突触可塑性的关键，但大多数研究中使用的细胞外钙浓度明显高于活体内实验测量的浓度。本合作项目的目标是了解在生理条件下两个主要大脑结构--海马体和小脑--突触可塑性的规律。它将一个在突触可塑性模型方面有专长的理论团队(Brunel)和两个在海马区可塑性(Debanne)和小脑可塑性(Barbour)方面有专长的实验团队聚集在一起。该理论团队最近发现，在以钙为基础的突触可塑性模型中，降低细胞外钙浓度极大地改变了被广泛假设的标准可塑性规则。Debanne和Barbour团队进行的初步实验已经证实，在高钙水平诱导可塑性的方案中，可塑性降低，甚至完全消除。该项目将通过三个实验室的紧密合作，在比传统的体外研究更接近体内条件的条件下，进一步研究可塑性规律。特别是，合作者将研究神经调节和/或现实的活动模式是否可以挽救他们发现在生理钙水平上缺乏的可塑性。他们的目标是建立符合记录数据的突触可塑性的最小生物物理模型，并解释可塑性是如何由几个关键的生物物理变量决定的：细胞外钙浓度、一氧化氮和神经调节剂。这种对生理条件下的可塑性规律的数学描述，将通过使有效的模拟和分析计算成为可能，为理论界和实验研究提供服务，通过提供对可塑性的关键机制的洞察。该项目将有助于美国和法国之间的科学交流。将在两国举办联合研讨会，他们的参与者将为以辅导为基础的硕士课程做出贡献，该课程结合了神经科学研究问题的理论和实验研究。法国国家研究机构(ANR)正在资助一个配套项目。

One of the central hypotheses of neuroscience is that memories are stored in the brain through modifications of synaptic connectivity. This synaptic plasticity has been studied extensively in vitro, and these experiments have led to the formalization of mathematical rules that describe how specific patterns of pre- and post-synaptic activity lead to changes in synaptic strength. However, the vast majority of these experimental studies have been performed in conditions that are far from physiological. In particular, calcium is known to be critical for the induction of synaptic plasticity in many preparations, but the extracellular calcium concentration used in most studies is significantly higher than the experimentally measured concentration in vivo.The goal of the present collaborative project is to understand the rules of synaptic plasticity under physiological conditions in two major brain structures, the hippocampus and the cerebellum. It groups together a theoretical team (Brunel) with expertise in synaptic plasticity models, and two experimental teams with expertise in hippocampal plasticity (Debanne) and cerebellar plasticity (Barbour). The theoretical team has recently discovered that in a calcium-based model of synaptic plasticity, lowering the extracellular calcium concentration drastically changes the standard plasticity rules that have been widely assumed. Preliminary experiments performed by both the Debanne and Barbour teams have confirmed that plasticity is reduced, or even completely abolished, in protocols that induce plasticity at higher calcium levels. This project will investigate further plasticity rules under conditions that are far closer to in vivo conditions than traditional in vitro studies, through a tight collaboration among the three labs. In particular, the collaborators will investigate whether neuromodulation and/or realistic patterns of activity can rescue plasticity that they found to be absent at physiological calcium levels. They aim to produce minimal biophysical models of synaptic plasticity that will fit the recorded data, and explain how plasticity is determined by a few key biophysical variables: extracellular calcium concentration, nitric oxide, and neuromodulators. Such a mathematical description of plasticity rules under physiological conditions will serve both the theoretical community, by enabling efficient simulation and analytical calculation, and experimental research, by offering insight into key mechanisms of plasticity.This project will contribute to scientific exchanges between the US and France. Joint workshops will be held in both countries and their participants will contribute to a tutorial-based Masters course combining theoretical and experimental study of research problems in neuroscience. A companion project is being funded by the French National Research Agency (ANR).