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弱激光对神经元离子通道的影响及其电流检测方法
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摘要
弱激光生物刺激效应研究目前仍处于初级阶段,其作用机理机制尚不清楚,有待进一步探索。论文利用膜片钳技术,从神经元兴奋性方面探讨弱激光生物刺激效应。围绕弱激光对大鼠海马神经元电压门控钠、钾离子通道电流的时间依赖性、电压依赖性、刺激频率依赖性、可逆性、作用的剂量效应关系、稳态激活和失活动力学特征的影响、弱激光诱导神经元动作电位及其发放特征以及离子单通道电流检测方法等几个大的方面展开理论和实验研究。
     利用全细胞膜片钳实验方法研究弱激光诱导下,神经元电压门控Na~+、K~+通道特性。结果显示:弱激光作用可显著影响神经元离子通道激活电位和通道电流,对I_(Na)、I_A、I_K的作用具有时间依赖性、电压依赖性和可逆性。弱激光效应与激光能量密度相关,与刺激频率无关。激光作用可改变通道稳态激活和失活动力学特征,使激活和失活曲线显著移动。结果表明,弱激光可诱导神经元电压门控离子通道特性改变,提示弱激光生物刺激作用与细胞膜离子通道构象及功能有关。
     利用电流钳实验方法研究弱激光诱导下,神经元动作电位及其发放特征。结果显示:正常海马神经元给予大于阈强度的连续斜坡电流刺激和脉冲电流刺激,均可诱发神经元动作电位连续发放,产生动作电位的数目在一定范围内随着刺激强度的增大而增加。弱激光作用使神经元静息膜电位和阈电位降低,动作电位幅度增大,90%复极化动作电位时程APD_(90)增加,动作电位连续发放频率减慢,且这种作用在停止激光作用后可基本恢复。结果表明,弱激光作用可改变神经元动作电位及发放特征,有助于提高神经元兴奋性和改善传导功能。
     膜片钳技术中,由于离子单通道电流的微弱性,信号往往淹没在背景噪声中。基于HMM的离子单通道信号恢复是一种有效去噪方法。针对HMM模式分类能力差以及训练易陷入局部最优的缺陷,论文采用基于HMM和RBF网络的混合模型,从强噪声污染的膜片钳采样数据中恢复离子单通道电流信号,并把随机松弛算法引入HMM参数估计,确保模型训练中参数收敛到最大似然估计值。仿真实验和实际膜片钳采样数据的应用显示了该方法的可行性和有效性。
     膜片钳技术为从细胞分子水平探讨弱激光生物刺激效应提供了一个全新的方法,本文的研究成果为探索弱激光生物刺激效应机理机制以及发展离子通道微观信息检测方法奠定了理论和实验基础。
The research for bio-stimulation effect of low-level laser irradiation is in a relatively fundamental stage. And its mechanism is not still clarified. In this dissertation, a series of researches were taken from the viewpoint of excitability of cell membrane using the patch clamp technique, which focused on the bio-stimulation effect of low-level laser irradiation. The theory and experiments included the time dependency, frequency dependency, voltage dependency, reversibility, does-effect correlation, steady-state activation and inactivation kinetics of ion channel currents, action potential of neuron and its firings induced by low-level laser as well as the method to detection of ionic single-channel currents.
     The properties of voltage-gated Na+ and K+ channel of neuron induced by low-level laser irradiation were studied using the whole-cell patch clamp technique. The experimental results showed that low-level laser irradiation significantly affected the activation potentials and current amplitudes of ion channel. The amplitudes of INa, IA and IK reversibly changed in a time-dependent and voltage-dependent, but not frequency-dependent manner. In addition, the action of low-level laser showed itself irradiating-does dependency and correlation to energy density of laser. The kinetic characteristics of steady-state activation and inactivation altered and the curves of activation and inactivation were shifted by low-level laser irradiation. Therefore, low-level laser irradiation induced the changes of voltage-gated ionic channel property of neurons. It is suggested that the bio-stimulation effect of low-level laser was potentially correlative to the configuration and function of ion channel.
     The characteristics of action potential and its firings of neuron induced by low-level laser irradiation were investigated using the whole-cell current clamp technique. The experiments revealed that the repetitive firings of the normal neuron were elicited by continuous ramp currents and pulse currents respectively more than threshold intensity and increased with input excitatory current intensity. Under low-level laser irradiation, the resting potential and threshold potential of neurons lowered, action potential amplitude increased, action potential duration of 90% repolarization (APD_(90)) widened, firing frequency of action potential slowed. And the effects were mostly recovered after the end of laser irradiating. The results suggest that low-level laser irradiation could change the properties of action potential, which facilitated excitability of neurons and improved its conductive function.
     Because of the weakness of the single ionic channel current of cell membrane, the background noise always dominates in the patch-clamp recordings. The restoration of ionic single-channel signal based on HMM was an effective means of idealizing patch-clamp recordings. For the defects of weak classifying ability and the parameters falling into local maximum in HMM training, in this dissertation, a hybrid model of HMM and RBF network was applied to restore ionic single-channel currents under the white background noise. To ensure parameters’convergence to the maximal likelihood value, we used a global optimization algorithm of HMM parameters based on the stochastic relaxation. The experimental results of simulating and practical sampling data from patch-clamp system have shown the effectiveness and feasibility of the methods.
     The patch-clamp technique provided a new method to exploring bio-stimulation effect of low-level laser in cell and molecule level. Theory and experimental results disclosed by this dissertation establish a solid basis of the researches for the bio-stimulation mechanism of low-level laser and the microinformation detection to ionic single-channel currents.
引文
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