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

CRCNS：美法合作：STDP 中钙的多巴胺调节

• 批准号: 8837243
• 负责人: Kim L Blackwell
• 金额: $ 16.98万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837243
• 关键词: Address; Agonist; Alcohol abuse; Algorithms; Behavior; Biochemistry; Brain; Calcium; Calcium Channel; Cardiology; Chemosensitization; Chronic; Collaborations; Communities; Computer Simulation; Computer software; Corpus striatum structure; Cyclic AMP-Dependent Protein Kinases; Data; Dendrites; Development; Disease; Dopamine; Drug abuse; Electrophysiology (science); Endocannabinoids; Environment; Exposure to; Frequencies; Future; Glutamates; Goals; Health Policy; Hippocampus (Brain); Image; In Vitro; Individual; Instruction; International; Investigation; Ion Channel; Language; Lasers; Learning; Measures; Mediating; Memory; Mental Depression; Microscope; Modeling; N-Methyl-D-Aspartate Receptors; Names; Neurons; Neurosciences; Outcome; Parkinson Disease; Pathology; Pattern; Physiological; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Protocols documentation; Records; Research; Resolution; Role; Scanning; Signal Pathway; Software Tools; Source; Structure; Students; Synapses; Synaptic plasticity; System; Testing; Time; Touch sensation; Training; Training and Education; Validation; Withdrawal; addiction; base; calcium indicator; cell type; drug of abuse; electrical property; in vivo; model development; models and simulation; multi-scale modeling; neuronal cell body; novel; open source; postsynaptic; presynaptic; programs; research study; response; simulation; social; therapeutic target; two-photon; voltage clamp

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.

描述（由申请人提供）：突触可塑性是允许存储记忆的主要机制，是行为适应性变化的基础。在海马体中，中棘神经元（MSN）（纹状体的投射神经元）的LTP和LTD都需要细胞内钙的升高，但钙在MSN中的作用更难以捉摸，主要是由于多巴胺在可塑性中的关键作用。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、钙动力学模型之间的紧密合作可以首次提供对可塑性机制的统一理解。本项目的总体目标是从控制神经元钙动力学的刺激参数预测突触可塑性发展的方向和幅度。目的1：验证多巴胺通过PKA增加NMDA受体介导的和VDCC介导的钙内流之间的差异的假设。目的2：研究PKA介导的NMDA受体和CaL通道钙内流的变化对突触可塑性的影响。目标三：证明突触可塑性规则可以解释体内突触可塑性，以及帕金森氏病多巴胺耗竭引起的可塑性变化。这些目标是通过模型开发和预测的循环，然后是电生理学和钙成像实验来实现的。所提出的研究，以及其他细胞类型的钙动力学的未来调查，是通过开发和集成的软件参数优化与多房室，多离子通道神经元模型的现实钙动力学。证明钙动力学和纹状体突触可塑性之间的关系的影响远远超出了纹状体可塑性。建模 神经元中钙处理的复杂性将扩大可与突触可塑性结果相关的细胞类型和刺激方案的范围。多巴胺在几种破坏性神经元疾病中的关键作用使多巴胺成为卫生政策的核心问题，并且很可能多巴胺能控制可塑性诱导的研究将有助于理解几种病理学和识别原始治疗靶点。帕金森病和成瘾引起的突触可塑性变化部分是由于多巴胺介导的NMDA受体组成和钙内流的变化。暴露于滥用药物和从滥用药物中戒断引起NMDA受体和突触可塑性的改变。因此，了解纹状体突触可塑性中钙和多巴胺之间的相互作用将阐明正常记忆储存的机制，以及在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，揭示多巴胺的作用比理解大脑功能的各个方面更深入，因为它可能触及社会结构中的个体组织。更广泛的影响包括开发软件工具和跨学科教育和培训。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，例如信号通路与电特性相互作用的心脏病学。更重要的是，建模软件采用了一种声明性语言，其参数名称取自生物化学，因此该软件对于实验人员来说是直观的。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。来自该计划的学员将处于独特的地位，以发展信号通路的数据驱动建模领域。PI在国际跨学科教学方面有着广泛的记录，并公开了关于建模信号通路的教程材料。