基于多电极阵列的培养神经元网络动态特征分析
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摘要
了解大脑中一个基本的微网络是如何组织,它的功能及其行为是如何实现的,即表现出怎样的动力学特性,是神经科学中的一个重要问题。为了解答这一问题,有必要同时记录和分析神经元网络的活动。
多电极阵列(Multi-electrode arrays,MEA)系统有高的时间分辨( MEA上每一个电极检测的信号可能是邻近多个细胞的动作电位和各种噪声的整合,因此,对这些信号的分离和分析成为一项重要工作。同时,培养神经元网络缺乏与外部环境的交流,目前,对采集信号代表涵义的解释还有许多困难。
本文以多电极阵列记录的离体培养大鼠海马或皮层神经元网络的自发和电脉冲刺激诱导的信号为研究对象,利用信号提取、锋电位分离以及神经元网络活动动态分析的数学方法,探讨了网络结构与功能之间的关系,并对记录过程中一些重要现象进行了神经生物学和生理学的初步解释。
在锋电位分离过程中,存在一个不容忽视的问题,即MEA上集成的多个电极之间距离通常比较小,当一个细胞处于两个电极之间时,它的活动是否能够同时为不同电极所检测(crosstalk)?对这一问题的回答是正确检测生物信号的关键之一。文中讨论了MEA上单个电极的检测域,并利用记录的不同神经元放电模式验证了讨论结果。
在离体培养神经元网络连续记录的锋电位序列中,观察到几种不同的活动模式:单个锋电位发放和短时间内一群在幅度上逐渐衰减的锋电位集中发放。不同放电模式可能与神经元网络的组织结构有关。其中一种连续发放的同步单个峰电位模式可能有着重要的生理意义。在不同芯片上观察到由单个锋电位发放向爆发(burst)模式的转变。爆发开始之前,网络都有一个快速发放过程,表明爆发的产生需要网络有足够的兴奋性。爆发后比转变前单个锋电位发放速率相对降低,但前后峰间距改变不大;爆发的产生同时使相邻电极上的活动高度同步化,暗示网络受到共同的抑制作用。
分析了网络对不同刺激的响应。在具有相似自发神经元活动模式网络区域中,邻近刺激位点的电极上检测到诱导响应信号,表明神经元网络的形成并与电极之间建立了良好的电接触。比较两次脉冲的试验,第二次响应持续时间比第一次的要长。随间隔时间减小,响应持续时间增加。第二次响应持续时间有很大增加,并且出现快响应(10ms内)和慢响应(接近或超过100ms)两个阶段。比较自发与响应信号的发放速率,不同刺激模式分别使网络响应明显增强或受到抑制。实验结果提示神经元网络的响应建立了与外界刺激之间的联系和修饰。
It is one of important issues in neuronal science to be made it clear how a basic micro network in brain is organized, how its function and behavior are realized and what dynamic characteristic it presents. To answer these questions it is necessary to record and analyze the activities of a population of neurons simultaneously.
Multi-electrode array(MEA) system provides a convenient and practical platform for precise and detailed analysis of the dynamics of the network because of its high resolution in spatial(~μm) and temporal( Because the signal detected by each electrode on MEA may be from all cells adjacent the electrode and integrated with several noises, it becomes an important task to separate and analyze the signal. Furthermore,the cultured network has a poor communication with outside environment and there are many difficulties to explain the neuronal signification of the signal now.
In the dissertation I will use several common mathematical methods of biological signal detection and analysis to probe the dynamic characteristic and the relation between organization and function of network, to explain several remarkable phenomena observed in experiments in neurobiology and neurophysiology based on the spontaneous and evoked with electric pulse signals of separated hippocampal and cortical neuron chltures detected with MEA.
In the process of spike sorting there is a problem which not be neglected. Many electrodes are integraded in a small chip. So the electrodes are close each other. If a neuron is just in the middle of two electrodes, will it be detected by two electrodes at the same time—or crosstalk? The answer is one of the keys to detect the action of neuronal network well and truly. The single electrod recording-horizon in MEA is dicussed and the result is confirmed with the spike train recorded in the experiments.
Several spike firing patterns have been observed in spontaneous neuronal network electrophysiological activities recorded with MEA constantly. The patterns fall into two main types: single spikes firing and burst firing which is a series of spikes of decreasing amplitude rhythmic firing at short≤6ms inter spike intervals(ISIs) followed by a period of quiescence or single spikes. The pattern may depend on the organization and different developing stages of network because“function follows form”. A synchronous single spikes firing pattern is remarkable which may imply a certain important physiological mechanism.
A transition from single spikes firing to burst firing and the variation of firing rate at burst beginning are observed on several substrates. The firing rate during burst is lower than that during single spikes firing before burst but the difference between inter spike intervals of two firing patterns is little. Moreover, the electric activities on neighboring electrodes show strongly synchronous during burst. It can be concluded from the facts that burst generation requires network a sufficient level of excitation as well as the balance by synaptic inhibition.
Cultured network is stimulated extracellularly with bipolar electric pulses through the electrode on MEA and the responded spike trains are analyzed. The responded signals can be detected only on neighboring electrodes near the stimulating site in partial area of substrate having the same spontaneous activity patterns, which indicates the establishment of a good electrical contact between the neuronal network and the recording electrodes. The response duration to second pulse is longer than that to first pulse and will increase with the interval of two pulses decreased in two pulses stimulating text. The second response duration to 10ms interval two pulses increases greatly which exhibits two stages of quick response(within 10ms) and slow response(approaching to even excess 100ms). Whereas there is a lack of clear relation and no duration difference between two responses to 100ms interval two pulses. Both durations are short and within the duration few spikes fire and their amplitudes are small, which is similar to the responses to absolute single pulses. It can be seen that neuronal network firing can either be potentiated or be depressed with different stimulation schemes by comparison of responded signal with spontaneous activity. The experimental results suggest that sets of associations between outside stimuli and responses have been formed and modulated.
多电极阵列(Multi-electrode arrays,MEA)系统有高的时间分辨(
本文以多电极阵列记录的离体培养大鼠海马或皮层神经元网络的自发和电脉冲刺激诱导的信号为研究对象,利用信号提取、锋电位分离以及神经元网络活动动态分析的数学方法,探讨了网络结构与功能之间的关系,并对记录过程中一些重要现象进行了神经生物学和生理学的初步解释。
在锋电位分离过程中,存在一个不容忽视的问题,即MEA上集成的多个电极之间距离通常比较小,当一个细胞处于两个电极之间时,它的活动是否能够同时为不同电极所检测(crosstalk)?对这一问题的回答是正确检测生物信号的关键之一。文中讨论了MEA上单个电极的检测域,并利用记录的不同神经元放电模式验证了讨论结果。
在离体培养神经元网络连续记录的锋电位序列中,观察到几种不同的活动模式:单个锋电位发放和短时间内一群在幅度上逐渐衰减的锋电位集中发放。不同放电模式可能与神经元网络的组织结构有关。其中一种连续发放的同步单个峰电位模式可能有着重要的生理意义。在不同芯片上观察到由单个锋电位发放向爆发(burst)模式的转变。爆发开始之前,网络都有一个快速发放过程,表明爆发的产生需要网络有足够的兴奋性。爆发后比转变前单个锋电位发放速率相对降低,但前后峰间距改变不大;爆发的产生同时使相邻电极上的活动高度同步化,暗示网络受到共同的抑制作用。
分析了网络对不同刺激的响应。在具有相似自发神经元活动模式网络区域中,邻近刺激位点的电极上检测到诱导响应信号,表明神经元网络的形成并与电极之间建立了良好的电接触。比较两次脉冲的试验,第二次响应持续时间比第一次的要长。随间隔时间减小,响应持续时间增加。第二次响应持续时间有很大增加,并且出现快响应(10ms内)和慢响应(接近或超过100ms)两个阶段。比较自发与响应信号的发放速率,不同刺激模式分别使网络响应明显增强或受到抑制。实验结果提示神经元网络的响应建立了与外界刺激之间的联系和修饰。
It is one of important issues in neuronal science to be made it clear how a basic micro network in brain is organized, how its function and behavior are realized and what dynamic characteristic it presents. To answer these questions it is necessary to record and analyze the activities of a population of neurons simultaneously.
Multi-electrode array(MEA) system provides a convenient and practical platform for precise and detailed analysis of the dynamics of the network because of its high resolution in spatial(~μm) and temporal(
In the dissertation I will use several common mathematical methods of biological signal detection and analysis to probe the dynamic characteristic and the relation between organization and function of network, to explain several remarkable phenomena observed in experiments in neurobiology and neurophysiology based on the spontaneous and evoked with electric pulse signals of separated hippocampal and cortical neuron chltures detected with MEA.
In the process of spike sorting there is a problem which not be neglected. Many electrodes are integraded in a small chip. So the electrodes are close each other. If a neuron is just in the middle of two electrodes, will it be detected by two electrodes at the same time—or crosstalk? The answer is one of the keys to detect the action of neuronal network well and truly. The single electrod recording-horizon in MEA is dicussed and the result is confirmed with the spike train recorded in the experiments.
Several spike firing patterns have been observed in spontaneous neuronal network electrophysiological activities recorded with MEA constantly. The patterns fall into two main types: single spikes firing and burst firing which is a series of spikes of decreasing amplitude rhythmic firing at short≤6ms inter spike intervals(ISIs) followed by a period of quiescence or single spikes. The pattern may depend on the organization and different developing stages of network because“function follows form”. A synchronous single spikes firing pattern is remarkable which may imply a certain important physiological mechanism.
A transition from single spikes firing to burst firing and the variation of firing rate at burst beginning are observed on several substrates. The firing rate during burst is lower than that during single spikes firing before burst but the difference between inter spike intervals of two firing patterns is little. Moreover, the electric activities on neighboring electrodes show strongly synchronous during burst. It can be concluded from the facts that burst generation requires network a sufficient level of excitation as well as the balance by synaptic inhibition.
Cultured network is stimulated extracellularly with bipolar electric pulses through the electrode on MEA and the responded spike trains are analyzed. The responded signals can be detected only on neighboring electrodes near the stimulating site in partial area of substrate having the same spontaneous activity patterns, which indicates the establishment of a good electrical contact between the neuronal network and the recording electrodes. The response duration to second pulse is longer than that to first pulse and will increase with the interval of two pulses decreased in two pulses stimulating text. The second response duration to 10ms interval two pulses increases greatly which exhibits two stages of quick response(within 10ms) and slow response(approaching to even excess 100ms). Whereas there is a lack of clear relation and no duration difference between two responses to 100ms interval two pulses. Both durations are short and within the duration few spikes fire and their amplitudes are small, which is similar to the responses to absolute single pulses. It can be seen that neuronal network firing can either be potentiated or be depressed with different stimulation schemes by comparison of responded signal with spontaneous activity. The experimental results suggest that sets of associations between outside stimuli and responses have been formed and modulated.
引文
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