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

在清醒和睡眠期间，使用脑电图（EEG）技术在大脑中记录了各种识别频带的节律振荡，并将其与各种重要的认知和行为任务联系起来。本项目重点研究其中两种节律，theta （4 - 12hz）和gamma (30 - 80hz)，这两种节律在海马体和内嗅皮层（EC）中被观察到，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。利用生物物理（基于电导的）建模、动力系统技术和计算模拟，研究者探索了这些节律如何在单细胞和网络水平上出现，以及它们的动态特性是什么。我们的目标是了解在广泛的相互作用的组织水平上，从亚细胞到细胞再到网络水平，控制这些节律产生的基本动态和生物物理原理，以及所有这些如何促进这些节律振荡的功能作用。在细胞水平上，重点是来自内侧EC第二层的所谓的星状细胞（SCs），它们在θ频率范围内显示混合模式振荡（阈下振荡与尖峰穿插）。使用降维技术，我们发现了一个最小的生物物理似是而非的模型，再现了观察到的混合模式振荡模式。该模型是非线性和多尺度的。对其潜在动态结构的研究，即所谓的鸭状结构，使研究者能够理解所观察到的模式是如何从持久钠和超极化激活电流之间的相互作用中产生的，正如实验观察到的那样。这些知识将用于理解网络活动的两个重要方面：SCs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频率下的SC活动，以及所有这些特性如何在包括SCs以及中间神经元、锥体细胞和其他细胞类型的网络中产生θ和γ频率的节律性活动。更具体地说，将研究相同的网络如何以及在什么条件下能够产生θ和γ节律活动，以及两种节律之间的突变是如何发生的。单个SCs在伽马频率范围内具有潜在的峰值能力，但相关的时间尺度隐藏在单个分离细胞中，当抑制水平不足时，它在网络水平上被揭示。该项目解决了大脑如何能够在不同频段产生有节奏的活动的一般问题，这是作为这些节奏基础的网络的生物物理特性的结果。考虑了由实验结果引起的一系列问题，这些问题是理解神经回路的关键，神经回路是观察到的EC节律振荡的基础。这项研究的结果为这些节律的产生提供了有价值的生物物理机制信息，不仅在EC中，而且在海马中可以发现具有类似生物物理和动态特性的细胞和网络，并接受EC的直接输入。此外，这些结果将为导航等行为问题提供重要的见解，在这些问题上，海马体和EC中的θ节律都起着相关的作用。最后，这项研究将阐明从θ到超兴奋（伽马）频率的转变在癫痫发作的产生中所起的作用。

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.