Rhythmic oscillations in the entorhino-hippocampal system: biophysics and dynamics

在清醒和睡眠期间，已经使用EEG（脑电图）技术在大脑中记录了各种明确识别的频带的节律振荡，并且已经将其与各种重要的认知和行为任务相关联。 该项目重点关注其中两种节律，theta（4 - 12 Hz）和gamma（30 - 80 Hz），它们在海马和内嗅皮层（EC）中被观察到，并与学习，记忆，空间导航和路径整合（基于自我运动线索计算路径的能力）有关。 使用生物物理（基于电导）建模，动力系统技术和计算模拟，研究人员探索这些节奏如何出现在单细胞和网络水平，以及它们的动态特性是什么。 我们的目标是了解基本的动力学和生物物理学原则，这些节奏的产生在广泛的相互作用的组织水平，范围从亚细胞，通过细胞的网络水平，以及如何所有这一切有助于这些节奏振荡的功能作用。 在细胞水平上，重点是所谓的星状细胞（SC）从第二层的内侧EC显示混合模式振荡（阈下振荡穿插尖峰）在θ频率制度。使用降维技术，我们发现了一个最小的生物病理学合理的模型，再现所观察到的混合模式的振荡模式。该模型是一个非线性多尺度模型。 研究其潜在的动态结构，即所谓的鸭式结构，使研究人员能够理解所观察到的模式是如何从实验观察到的持续钠和超极化激活电流之间的相互作用中出现的。 这些知识将用于了解网络活动的两个重要方面：供应链如何处理结构化信息（正弦、噪声和突触输入），特别是内在电流和突触电流如何相互作用以维持θ频率范围内的SC活动，以及所有这些特性如何协作以在包括SC沿着的网络中产生θ和γ频率下的节律活动，锥体细胞和其他细胞类型。 更具体地说，将研究同一网络如何以及在什么条件下能够产生θ和伽马节律活动，以及两种节律之间的突然转换如何发生。 单个SC具有在伽马频率范围内尖峰的潜在能力，但是相关的时间尺度隐藏在单个孤立的细胞中，并且当抑制水平不足时，在网络水平上被揭示。该项目解决了大脑如何能够在各种频带上产生节律活动的一般问题，作为这些节律的基底的网络的生物物理特性的结果。 被认为是由实验结果的动机和关键的理解的神经回路的基板在EC中观察到的节奏振荡的一组问题。这项研究的结果提供了有价值的信息，这些节奏的产生的生物物理机制，不仅在EC中，而且在海马中，可以发现具有类似的生物物理和动态特性的细胞和网络，并从EC接收直接输入。 此外，这些结果将为行为问题提供重要的见解，例如海马体和EC中的θ节律发挥相关作用的导航。 最后，这项研究将揭示从θ波到超兴奋（伽马）频率的过渡在癫痫发作中的作用。

Rhythmic oscillations at various well identified frequency bands have been recorded in the brain using EEG (electroencephalogram) techniques during both wakefulness and sleep, and have been linked to various important cognitive and behavioral tasks. This project focuses on two of these rhythms, theta (4 - 12 Hz) and gamma (30 - 80 Hz), that have been observed in the hippocampus and the entorhinal cortex (EC), and have been implicated in learning, memory, spatial navigation and path integration (the ability to calculate a path on the basis of self motion cues). Using biophysical (conductance-based) modeling, dynamical systems techniques and computational simulations, the investigator explores how these rhythms emerge at the single cell and network leves, and what are their dynamic properties. The goal is to understand the basic dynamic and biophysical principles governing the generation of these rhythms over a wide spectrum of interacting levels of organization, ranging from the subcellular, through the cellular to the network leves, and how all this contributes to the functional role of these rhythmic oscillations. At the cellular level, the focus is on the so called stellate cells (SCs) from layer II of the medial EC that display mixed-mode oscillations (subthreshold oscillations interspersed with spikes) in the theta frequency regime. Using reduction of dimensions techniques we uncover a minimal biophysically plausible model that reproduces the observed mixed-mode oscillatory patterns. This model is both nonlinear and multi-scale. The study of its underlying dynamic structure, the so called canard structure, allows the investigator to understand how the observed patterns emerge from the interaction between a persistent sodium and a hyperpolarization-activated currents, as experimentally observed. This knowledge will be used to understand two important aspects of network activity: How SCs process structured information (sinusoidal, noisy and synaptic inputs), in particular how the intrinsic and synaptic currents interact to maintain the SC activity in the theta frequency regime, and how all these properties cooperate to generate rhythmic activity at theta and gamma frequencies in networks that include SCs along with interneurons, pyramidal cells and other cell types. More specifically, the questions of how and under what conditions the same network is able to generate theta and gamma rhythmic activity will be investigated, as well as how the abrupt transitions between both rhythms occur. Single SCs have the potential ability to spike in the gamma frequency regime, but the associated time scale is hidden in single isolated cells and it is uncover in the network level when the level of inhibition is deficient.This project addresses the general issue of how the brain is able to generate rhythmic activity at various frequency bands as the result of the biophysical properties of the networks that are substrate to these rhythms. A set of problems that are motivated by experimental results and are key to the understanding of the neural circuitries that are substrate to the observed rhythmic oscillations in the EC are considered. The results of this research provide valuable information about the biophysical mechanism of generation of these rhythms, not only in the EC, but also in the hippocampus where cells and networks with similar biophysical and dynamic properties can be found, and which receives direct inputs from the EC. In addition, the results will provide important insights into behavioral issues such as navigation where the theta rhythms in both the hippocampus and the EC plays a relevant role. Finally, this research will shed light into the role that the transition from theta to a hyper-excitable (gamma) frequency regime plays in the generation of epileptic seizures.