Deducing the origin and effect of extracellular electric fields in hippocampus

描述（由申请人提供）： 神经科学家监测细胞外脑信号，以推断计算和认知的潜在神经机制。 细胞内和跨膜过程一直是研究者关注的焦点，而细胞外过程的研究则相对较少。 然而，从细胞外记录会话检索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，已经表明内源性胞外酶确实通过突触偶联影响单个神经元的状态和功能。 这就提供了一个连续的非突触反馈机制之间的领域和个别神经元。 在一项合作研究中，C. Koch和G. Buzsaki提出通过使用建模/实验方法来解开海马CA 1区在θ波和尖波活动期间的细胞外场效应的起源和功能。 在计算上，通过模拟大量的生物物理现实的锥体和抑制性中间神经元，使大鼠CA 1海马subeld。 这些，与神经胶质细胞，将安排在一个3-D电阻细胞质，和他们的细胞外的贡献将被相加，以产生最终的细胞外电位与电活动在个别神经元。 来自单个海马神经元的膜片钳实验将揭示CA 1模式活动的细胞内和细胞外相关性。 来自麻醉大鼠的记录将用于约束这些模型并测试其准确性。 同时光刺激将在CA 1中进行细胞外记录实验（在CA 3中使用ChR 2和相关光遗传学技术）和细胞外记录实验以操纵细胞外脑活动来回答一系列问题：（i）海马中细胞外ELD的详细组成是什么，（ii）它的贡献者是什么（前与突触后活性，尖峰电流，神经胶质），以及（iii）ELD如何用于同步CA 1神经元的潜在阈下和阈上活性-即使在没有直接突触耦合的情况下。 这项研究也将影响我们对一些病理及其治疗的理解，特别是对病理性超同步的启动和传播，如癫痫，以及通过电流直接脑刺激的短期和长期效应，如深部脑刺激。 在这里，治疗的准确性关键取决于对细胞外ELD对神经元和神经回路的影响的深刻理解。 公共卫生相关性： 项目叙述本项目的目的是分析大脑内测量的电场的起源以及该电场如何影响大脑过程。 这个电场很可能在癫痫发作期间传播超同步放电中很重要。 脑深部电刺激，经常用于治疗帕金森病和某些形式的抑郁症，也将直接影响这一电场，其后果尚不清楚。 因此，有必要研究内源性或施加的电致发光的直接和间接生物物理效应。

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. PUBLIC HEALTH RELEVANCE: Project Narrative The aim of this project is to analyze the origin of the electric eld measured inside the brain and how changes in this eld aect brain processes. This electrical eld is most likely important in propagating hyper-synchronous electrical discharges during epileptic seizures. Deep brain stimula- tion, as frequently used to treat Parkinsons disease and some forms of depression, will also directly aect this electrical eld with ill-understood consequences. It is thus essential to study the direct and indirect biophysical eects of electrical elds, either endogenous or imposed.