CRCNS: US-French Collaboration: Dopamine modulation of calcium in STDP

描述(申请人提供)：突触可塑性是允许存储记忆的主要机制，也是行为适应性变化的基础。与在海马区一样，纹状体的投射神经元中的中棘神经元(MSN)的LTP和LTD都需要升高细胞内钙，但在MSN中钙的作用更难以捉摸，主要是由于多巴胺在可塑性中的关键作用。要了解钙动力学和多巴胺(通过PKA)之间的相互作用如何控制突触可塑性，需要一种新的、数据驱动的建模方法来研究钙动力学。电生理学、钙成像、钙动力学建模之间的紧密合作可以首次提供对可塑性潜在机制的统一理解。这个项目的总体目标是根据控制神经元钙动力学的刺激参数来预测突触可塑性的发展方向和程度。这一目标是通过以下目标实现的：目的1：验证多巴胺通过PKA增加NMDA受体介导的钙内流和VDCC介导的钙内流的假设。目的：研究PKA通过NMDA受体和钙通道介导的钙内流变化对突触可塑性的影响。目的：证明突触可塑性规律可以解释体内突触可塑性，以及帕金森病多巴胺耗竭引起的可塑性改变。这些目标是通过模型开发和预测的循环实现的，然后是电生理学和钙成像实验。所提出的研究以及未来对其他类型细胞中钙动力学的研究，是通过开发和集成用于参数优化的软件与现实钙动力学的多隔室、多离子通道神经元模型来实现的。证明钙动力学和纹状体突触可塑性之间的关系具有远远超出纹状体可塑性的意义。建模 神经元中钙离子处理的复杂性将扩大与突触可塑性结果相关的细胞类型和刺激方案的范围。从卫生政策的角度来看，多巴胺在几种破坏性神经元疾病中的关键作用使其成为卫生政策的中心问题，研究多巴胺对可塑性诱导的控制可能有助于理解几种病理机制，并有助于确定最初的治疗靶点。帕金森病和成瘾引起的突触可塑性的改变部分是由于多巴胺介导的NMDA受体组成和钙内流的变化。接触和戒除滥用药物会导致NMDA受体和突触可塑性的改变。因此，了解钙和多巴胺在纹状体突触可塑性中的相互作用将有助于阐明正常记忆存储的机制，以及帕金森病和慢性药物和酒精滥用中观察到的异常可塑性。此外，多巴胺对行为的一般动机组织产生重大影响。因此，揭示多巴胺的作用不仅仅是理解大脑功能的各个方面，因为它可能涉及社会结构中个人的组织。更广泛的影响包括软件工具的开发以及跨学科的教育和培训。多尺度建模软件工具将(以开源形式)提供给社区。该软件不仅广泛适用于解决神经科学中的主要问题，而且还适用于其他生理系统，如信号通路与电特性相互作用的心脏病学。更重要的是，建模软件使用了一种声明性语言，参数名称取自生物化学，因此该软件对实验者来说是直观的。该项目将为培养学生和博士后研究员提供一个独特的跨学科环境。该项目的学员将在开发信号通路的数据驱动建模领域中发挥独特的作用。PI拥有广泛的国际跨学科教学记录，并公开提供关于信号通路建模的教程材料。

DESCRIPTION (provided by applicant): Synaptic plasticity is the main mechanism allowing storage of memories and underlies adaptive changes in behavior. As in the hippocampus, both LTP and LTD of the Medium Spiny Neurons (MSN), the projection neurons of the striatum, require elevation of intracellular calcium, but the role of calcium is more elusive in the MSN mostly due to the critical role of dopamine in plasticity. Understanding how the interactions between calcium dynamics and dopamine (via PKA) control synaptic plasticity requires a novel, data-driven modeling approach to study calcium dynamics. A tightly knit collaboration between electrophysiology, calcium imaging, calcium dynamics modeling can for the first time provide a unified understanding of mechanism underlying plasticity. The overall goal of this project is to predict the development of synaptic plasticity direction and magnitude from the stimulation parameters that control neuronal calcium dynamics. This goal is achieved through the following aims: Aim 1: Test the hypothesis that dopamine, via PKA, increases the difference between NMDA receptor mediated and VDCC mediated calcium influx. Aim 2: Investigate how the PKA mediated change in calcium influx through NMDA receptor and CaL channels alters synaptic plasticity. Aim 3: Demonstrate that synaptic plasticity rules can explain in vivo synaptic plasticiy, and the change in plasticity caused by the dopamine depletion of Parkinson's Disease. The aims are achieved through cycles of model development and prediction followed by electrophysiology and calcium imaging experiments. The proposed research, as well as future investigations of the calcium dynamics in other cell types, is enabled by development and integration of software for parameter optimization with multi-compartmental, multi-ion channel neuron models of realistic calcium dynamics. Demonstrating a relationship between calcium dynamics and striatal synaptic plasticity has implications far beyond striatal plasticity. Modeling the complexity of calcium handling in neurons will expand the range of cell types and stimulation protocols that can be correlated with synaptic plasticity outcomes. The key role of dopamine in several devastating neuronal disorders places dopamine as a central issue from the perspective of health policies, and it is likely that the study of the dopaminergic control of plasticity inducion will contribute to the understanding of several pathologies and to the identification of original therapeutic targets. Changes in synaptic plasticity due to Parkinson's and addiction are partly due to the dopamine mediated changes in NMDA receptor composition and calcium influx. Exposure to and withdrawal from drugs of abuse cause alteration in NMDA receptors and synaptic plasticity. Thus understanding the interaction between calcium and dopamine in striatal synaptic plasticity will illuminate mechanisms underlying normal memory storage, and also the abnormal plasticity observed in Parkinson's disease, and chronic drug and alcohol abuse. Moreover, dopamine exerts a major influence on the general motivational organization of behavior. Uncovering the action of dopamine thus reaches further than the understanding of aspects of brain functions, as it may touch on the organization of individuals within social structures. The broader impacts include development of software tools and cross-disciplinary education and training. The multi-scale modeling software tools will be made available (in open source form) to the community. This software is broadly applicable not only to address major questions in neuroscience, but also to other physiological systems, such as cardiology where signaling pathways interact with electrical properties. More importantly, the modeling software employs a declarative language with parameter names taken from biochemistry, such that the software is intuitive for experimentalists to learn. This project will provide a uniquely cross-disciplinary environment for training students and post-doctoral fellows. The trainees from this program will be uniquely positioned to develop the field of data driven modeling of signaling pathways. The PIs have extensive track records of international cross-disciplinary instruction, with tutorial material on modeling signaling pathways made publicly available.