摘要
生物神经网络是一个由大量神经元高度组织、相互作用的庞大而复杂的系统,其神经元电活动具有明显的时空特性。从细胞网络或组织的层面分析多个神经元的电生理特征,对神经元网络的信息处理、传导等研究具有重要的意义。随着微电子微机械加工技术的发展,用于多通道同步测量的微电极阵列(microelectrode array, MEA)和场效应晶体管(field effect transistor, FET)阵列得到快速发展,在神经元网络的研究中具有明显优势。其中,利用MEA与多种细胞或组织结合构建的细胞网络或组织传感器得到了广泛的应用,已成为神经元网络时空信号分析的重要手段。
在嗅觉的研究中,膜片钳记录技术和光学成像技术是目前主要的电生理检测手段。膜片钳技术不能实现多点同步测量,不利于神经元网络的时空特征分析。而光学成像技术对细胞具有毒性作用,不适合长时间的监测。因此,利用具有长时程、无损、多点同步采集特点的MEA芯片构建嗅觉细胞网络和组织传感器,对于嗅觉时空信息的获取与分析将具有重要的作用。本研究以离体的嗅觉细胞和组织为敏感元,通过MEA芯片构建细胞网络和组织传感器用于时空信号的分析,着重研究了嗅球切片各层的信号特征及功能。
本论文的主要内容和贡献如下：
1.深入研究了嗅觉细胞网络传感器,包括嗅上皮细胞网络传感器和嗅球细胞网络传感器。分析了乙酸、丁二酮和高K+作用下电生理响应的空间模式和时间特性,考察了嗅上皮细胞网络传感器的检测能力。结果表明,该细胞网络传感器能够有效区别不同条件下的刺激响应；嗅觉受体神经元对气味的响应具有一定的选择性。此研究为仿生电子鼻的开发和气味识别机制的探讨奠定了实验基础。利用嗅球神经元网络传感器对不同浓度谷氨酸(glumatic acid, Glu)作用下的电信号的特征进行了分析,发现Glu能够使嗅觉信号产生振荡和放大,这是气味识别、信息处理及时空编码的重要特征。
2.利用心肌细胞自主节律性搏动特点,设计了基于离体心肌组织及其切片的传感器,实验发现延迟时间是心肌传导分析的重要指标。利用MEA多点同步采集的特点,考察了心血管药物(盐酸肾上腺素和氯化乙酰胆碱)在不同位置的作用效果,对临床靶向给药的组织传感器研究具有重要的意义。该研究为嗅球组织切片传感器的设计奠定了基础并提供了有效的方法。
3.首次提出了基于嗅球组织切片的传感器的设计思想,分析了嗅球切片各层振荡信号特征和信息传导。根据嗅球形态和信号的空间分布特点,发现嗅觉信息在嗅球内由嗅神经层和突触小球层接收,经外丛层传递,由僧帽细胞层和颗粒细胞层输出。利用相关分析对Glu作用前后的响应进行时间和空间的特征分析,发现嗅球内各层之间存在一定的生物联系,存在Glu受体介导的突触连接。此外,分析结果还表明嗅球各层的信号具有不同的振荡频率。
Biological neural network is a huge and complicated system, which comprises abundant highly organized and interactional neurons. The neuronal electrical activities in the neural network take on distinctive spatio-temporal characteristics. Investigating the electrophysiological properties of multi-neurons in cell-networks or tissues is sig-nificant for the study of information processing and conduction in neural networks. With the development of micro-electro-mechanical systems (MEMS) technology, mi-croelectrode array (MEA) and field effect transistor (FET) array have developed rap-idly for their synchronously multi-channel measurement, presenting obvious advan-tages in the study of neural networks. Thereinto, the cell network- and tissue-based biosensors by combining multi-cells or tissues with MEA have gained extensive ap-plication, and become the important technique for spatio-temporal analysis of neuronal signals.
In usual olfaction study, patch clamp recoding technique and optic imaging tech-nique are the primary electrophysiological measurement methods. Patch clamp tech-nique is not convenient for spatio-temporal analysis of neural network for it can not realize synchronous multi-site measurement. While, optic imaging technique has tox-icity on cells, so it is not fit for long-term measurement. With the characteristics of long-term, scatheless and synchronous multi-site measurement, MEA is used to build up the olfactory cell network- or tissue-based biosensors, which are of great impor-tance for acquiring and analyzing the olfactory spatio-temporal information. In the present study, using in vitro olfactory neurons and tissues as the sensing elements, we developed the cell network-based and tissue-based biosensors with MEA to investigate the spatio-temperal characteristics of cell networks and tissues, principally analyze the signals detected from each layer of the olfactory bulb.
The major contents and contributions of this thesis are as follows:
1. We profoundly studied the olfactory epithelium cell network-based and olfac- tory bulb cell network-based biosensor. With the spatio-temporal characteristics of electrophysiological under acetic acid, butanedione and high K+ stimulation analyzed, the detecting capability of the olfactory epithelium cell network-based biosensor was investigated. Results indicate that this cell network-based biosensor can distinguish the responses under different conditions and olfactory receptor neurons selectively re-sponse to odors. This research provides the experimental basis for designing the elec-tronic nose and exploring the odor discrimination mechanism. Using the OB neu-ron-based biosensor, we investigated the neural signal characteristics in the presence of different dosages of glutamic acid (Glu). Results showed that Glu can make the olfac-tory signals oscillate and amplify, which are the important characteristics of odor dis-crimination and signal processing.
2. Due to self-beating of cardiomyocytes, we designed in vitro cardiac tis-sue-based biosensor. It was found that delay time is the important parameter of cardiac propagation analysis. Because MEA can realize multi-site synchronous measurement, we reviewed the action of cardiovascular drugs at different positions. This research is very significant to study novel tissue-based biosensor for target-administrating in clinic. This research provided the basis and effective method for designing the OB slice-based biosensor. In addition, the difference and characteristics of the cardiac tissue-based biosensor and the OB slice-based biosensors were also presented in the present thesis.
3. An OB slice-based biosensor was developed for the first time, which is used to analyze the oscillation signals and information conduction in the each layer of the OB slice. According to mordality of OB and spacial distribution of signals, we found that the olfactory information was received in olfactory nerve layer (ONL) and glomerulus layer (GL), and transferred to mitral cell layer (MCL) and granule cell layer (GCL) through external plexiform layer (EPL), and then output from MCL and GCL. With cross-correlation analysis, we investigated the spatio-temporal characteristics of the responses before and after using Glu, and found that some biological contacts and synapses mediated by Glu receptor maybe exist between layers of OB slice. Moreover, results showed that different frequency oscillation appeared in the different layers of OB slice, which contains signal temporal property.
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