An Integrated Approach to Synaptic Plasticity in the Hippocampus

海马突触可塑性的综合方法

• 批准号: 7463735
• 负责人: HAREL Zeev SHOUVAL
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7463735
• 关键词: Accounting; Action Potentials; Back; Calcium; Cells; Development; Hippocampus (Brain); Learning; Long-Term Depression; Long-Term Potentiation; Maintenance; Measures; Memory; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; Phase; Physiological; Play; Rate; Role; Simulate; Synaptic plasticity; Tail; Testing; Time; Update; base; calmodulin-dependent protein kinase II; improved; molecular dynamics; postsynaptic; presynaptic; receptive field; theories

Synaptic plasticity is believed to be an important mechanism contributing to of learning, memory, and many aspects of development. There is significant evidence that in cortex synaptic plasticity contributes significantly to receptive field development. For example, in the hippocampus there is abundant cellular and molecular information about long term potentiation (LTP) and long term depression (LTD), the cellular manifestation of long lasting synaptic plasticity. LTP and LTD can be induced by different induction paradigms that depend on presynaptic rate, on pairing presynaptic spikes with postsynaptic depolarization, and on the precise time difference between pre and postsynaptic spikes. We have recently hypothesized that a single model, which depends on calcium influx through NMDA receptors can account for these different induction paradigms. Here we propose a more detailed study of the molecular dynamics, including improved but simple models of CaMKII and Calcinurin that underlie synaptic plasticity. Based on this detailed study as well as new experimental results and measured parameters, we will develop an updated version of the unified plasticity model (UPM) that can be quantitatively tested. We hypothesize that fluctuations in molecular dynamics can play a significant role in the resulting synaptic plasticity. We propose to analyze these fluctuations and calculate their effect on the different induction paradigms of synaptic plasticity. We also propose to test experimentally the validity of a key assumption of the UPM, that the back propagating action potential has a long tail, and to measure key physiological parameters in hippocampal cells. We will use measured physiological parameters in hippocampal cells in simulating the UPM in order to create a quantitative theory appropriate for the hippocampus. The UPM will be further developed to account for the maintenance phase of synaptic plasticity. We will also test the hypothesis that homeostatic metaplasticity is crucial in attaining stable, selective and robust fixed points.

突触可塑性被认为是促进学习、记忆和许多方面发育的重要机制。有重要证据表明，在大脑皮层，突触的可塑性对感受野的发育有重要贡献。例如，在海马体中有丰富的关于长时程增强(LTP)和长时程抑制(LTD)的细胞和分子信息，长时程增强(LTP)和长时程抑制(LTD)是长时间突触可塑性的细胞表现。LTP和LTD可以由不同的诱导模式引起，这些模式取决于突触前的速率、突触前和突触后去极化的配对以及突触前和突触后的精确时差。我们最近假设，依赖于通过NMDA受体的钙内流的单一模型可以解释这些不同的诱导范式。在这里，我们建议对分子动力学进行更详细的研究，包括改进但简单的CaMKII和Calcinurin模型，它们是突触可塑性的基础。基于这项详细的研究以及新的实验结果和测量参数，我们将开发一个可以定量检验的统一塑性模型(UPM)的更新版。我们假设，分子动力学的波动可以在由此产生的突触可塑性中发挥重要作用。我们建议分析这些波动，并计算它们对突触可塑性的不同诱导范式的影响。我们还建议从实验上检验UPM的一个关键假设的有效性，即反向传播动作电位有一个长尾，并测量海马细胞的关键生理参数。我们将使用测量的海马细胞生理参数来模拟UPM，以创建适合于海马区的定量理论。UPM将进一步发展，以适应突触可塑性的维持阶段。我们还将测试这一假设，即稳态超塑性对于获得稳定、选择性和健壮的固定点至关重要。