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.

人们认为突触可塑性是有助于学习，记忆和发展许多方面的重要机制。有大量证据表明，在皮质中，突触可塑性对接受场的发展有显着贡献。例如，在海马中，有有关长期增强（LTP）和长期抑郁症（LTD）的大量细胞和分子信息，这是持久的突触可塑性的细胞表现。 LTP和LTD可以通过取决于突触前速率的不同感应范例，与突触后去极化以及突触前和突触后尖刺之间的精确时间差的不同感应范式。我们最近假设，一个依赖于NMDA受体钙涌入的单个模型可以解释这些不同的诱导范例。在这里，我们提出了对分子动力学的更详细的研究，包括基于突触可塑性的改进但简单的CAMKII和Colcinurin模型。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测试的统一可塑性模型（UPM）的更新版本。我们假设分子动力学的波动可以在产生的突触可塑性中起重要作用。我们建议分析这些波动，并计算它们对突触可塑性不同诱导范式的影响。我们还建议通过实验测试UPM的关键假设的有效性，即向后传播动作电位具有很长的尾巴，并测量海马细胞中的关键生理参数。我们将使用海马细胞中测量的生理参数模拟UPM，以创建适合海马的定量理论。将进一步开发UPM以说明突触可塑性的维护阶段。我们还将检验以下假设：体内稳态性对于达到稳定，选择性和健壮的固定点至关重要。