Deducing the origin and effect of extracellular electric fields in hippocampus

描述(由申请人提供)： 项目摘要/摘要神经科学家监测细胞外的大脑信号，以推断计算和认知的潜在神经机制。虽然细胞内和跨膜过程垄断了研究人员的兴趣，但对细胞外过程的关注要少得多。然而，从细胞外记录过程中检索到的信息的质量和数量关键取决于我们对细胞内活动和细胞外空间之间的传递函数的理解。此外，已有研究表明，内源性胞外磁场确实通过触觉耦合影响单个神经元的状态和功能。这提供了一种持续的非突触反馈机制，在神经元和个体之间。在一项合作的EORT中，C.Koch和G.Buzsaki的实验室建议通过模拟/实验的方法来揭示海马CA1区在theta和锐波活动期间细胞外电场的起源和功能。在计算上，通过对组成大鼠CA1海马亚的大量生物物理上真实的锥体和抑制性中间神经元进行建模。这些细胞将与神经胶质细胞一起排列在一个三维电阻细胞质中，它们的细胞外贡献将被相加，以产生与单个神经元的电活动相关的NAL细胞外电势。来自单独的海马神经元的膜片钳实验将阐明CA1模式活动的细胞内和细胞外的关联。来自麻醉大鼠的录音将被用来约束这些模型并测试它们的准确性。将进行同时的光刺激(使用ChR2和相关的光遗传学技术在CA3中)和CA1的细胞外记录实验，以操纵细胞外的大脑活动，以回答一系列问题：(I)海马区细胞外ELD的详细组成是什么，(Ii)它的贡献者是什么(突触前和突触后的活性、峰电流、胶质细胞)，以及(Iii)即使在没有直接突触耦合的情况下，ELD如何起到同步CA1神经元阈值下和阈值上的活性的作用。这项研究还将与我们对一些病理学及其治疗的理解有关，特别是关于病理性超同步化的启动和传播，如在癫痫中，以及通过电流直接脑刺激的短程和长程效应，如脑深部刺激。在这里，治疗的成功关键依赖于对细胞外区域对神经元和神经回路的影响的坚实理解。

DESCRIPTION (provided by applicant): Project Summary/Abstract Neuroscientists monitor extracellular brain signals to infer the underlying neural mechanisms of computation and cognition. While intracellular and transmembrane processes have monopolized the interest of researchers, much less attention has been paid to extracellular eld eects. Yet, the quality and quantity of information retrieved from extracellular recording sessions critically depends on our understanding of the transfer function between intracellular activity and the ex- tracellular space. Moreover, it has been shown that endogenous extracellular elds do aect the state and function of individual neurons through ephaptic coupling. This provides a continuous non-synaptic feedback mechanism between the eld and individual neurons. In a collaborative eort, the laboratories of C. Koch and G. Buzsaki propose to unravel the origin and functionality of extracellular eld eects in the hippocampal CA1 region during theta and sharp waves activity by using a modeling/experimental approach. Computationally, by modeling a large number of biophysical realistic pyramidal and inhibitory interneurons making up the rat CA1 hippocampus subeld. These, in conjunction with glia cells, will be arranged in a 3-D resistive cytoplasm, and their extracellular contributions will be summed to yield the nal extracellular electrical potential associated with electrical activity in individual neurons. Patch-clamp experiments from individ- ual hippocampal neurons will shed light onto the intracellular and extracellular correlates of CA1 pattern activity. Recordings from anesthetized rats will be used to constrain these models and to test their accuracy. Simultaneous optical stimulation (in CA3 using ChR2 and related optogenetic techniques) and extracellular recording experiments in CA1 will be performed to manipulate ex- tracellular brain activity to answer a series of questions: (i) what is the detailed makeup of the extracellular eld in the hippocampus, (ii) what are its contributors (pre- versus post-synaptic ac- tivity, spiking currents, glia), and (iii) how does the eld serve to synchronize the underlying sub- and suprathreshold activity of CA1 neurons - even in the absence of direct synaptic coupling. This research will also bear on our understanding of a number of pathologies and their treatment, in particular on the initiation and spread of pathological hypersynchronziation, such as in epilepsy, and the short- and long-range eect of direct brain stimulation via electrical current, as in deep brain stimulation. Here, therapy ecacy crucially depends on a solid understanding of the eect of extracellular elds on neurons and neural circuits.