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

在清醒和睡眠期间，利用脑电(EEG)技术在大脑中记录到了不同频段的节律性振荡，并与各种重要的认知和行为任务有关。这个项目的重点是其中的两个节律，theta(4-12赫兹)和伽马(30-80赫兹)，已经在海马体和内嗅皮层(EC)中观察到，并与学习、记忆、空间导航和路径整合(根据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、动力学系统技术和计算模拟，研究人员探索了这些节律是如何在单个细胞和网络水平上出现的，以及它们的动态特性是什么。目标是了解在从亚细胞到细胞再到网络水平的广泛相互作用的组织水平上控制这些节奏产生的基本动力学和生物物理原理，以及所有这些如何有助于这些节奏振荡的功能作用。在细胞水平上，焦点是来自内侧EC第二层的所谓星状细胞(SCs)，它们在theta频率区域显示混合模式振荡(亚阈值振荡和尖峰)。使用降维技术，我们发现了一个最小的生物物理上看似合理的模型，它再现了观察到的混合模式振荡模式。该模型具有非线性和多尺度的特点。研究其潜在的动态结构，即所谓的鸭子结构，使研究人员能够理解实验观察到的持续钠和超极化激活电流之间的相互作用是如何产生观察到的模式的。这些知识将被用来理解网络活动的两个重要方面：干细胞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theta频率区的SC活动；以及所有这些特性如何协作，在包括SC以及中间神经元、锥体细胞和其他细胞类型的网络中产生theta和Gamma频率的节律性活动。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和伽马节律活动的问题，以及这两种节律之间的突然转换是如何发生的。单个干细胞具有在伽马频率区域产生峰值的潜在能力，但相关的时间尺度隐藏在单个隔离细胞中，当抑制水平不足时，它在网络水平上被发现。这个项目解决了大脑如何能够在不同的频段产生节奏活动的一般性问题，这是作为这些节奏基础的网络的生物物理性质的结果。一组由实验结果激发的问题被考虑，这些问题是理解作为EC中观察到的节律振荡的衬底的神经电路的关键。这项研究的结果提供了关于这些节律产生的生物物理机制的有价值的信息，不仅在EC，而且在海马区也可以找到具有相似生物物理和动力学特性的细胞和网络，并且从EC直接输入。此外，这一结果将为诸如导航等行为问题提供重要的见解，在这些问题中，海马体和EC中的theta节奏都起着相关的作用。最后，这项研究将阐明从theta到超兴奋(伽马)频率的转变在癫痫发作发生中所起的作用。

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.