An Integrated Approach to Synaptic Plasticity in the Hippocampus

突触可塑性被认为是促进学习、记忆和许多方面发展的重要机制。有重要的证据表明，皮层突触可塑性对感受野的发育起着重要的作用。例如，海马体中存在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，这是突触长时程可塑性的细胞表现。LTP和LTD可以由不同的诱导模式诱导，这些模式取决于突触前速率、突触前尖峰与突触后去极化的配对以及突触前和突触后尖峰的精确时间差。我们最近假设，一个单一的模型，这取决于钙流入通过NMDA受体可以解释这些不同的诱导范式。在这里，我们提出对分子动力学进行更详细的研究，包括改进但简单的CaMKII和钙调磷酸酶模型，这些模型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测试的统一塑性模型（UPM）的更新版本。我们假设分子动力学的波动可能在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验证UPM的一个关键假设的有效性，即反向传播的动作电位具有长尾，并测量海马细胞的关键生理参数。我们将使用海马体细胞中测量的生理参数来模拟UPM，以便创建适合海马体的定量理论。UPM将进一步发展，以解释突触可塑性的维持阶段。我们还将测试稳态元塑性对于获得稳定、选择性和鲁棒固定点至关重要的假设。

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.