大鼠黑质致密部多巴胺神经元的膜共振现象及其机制研究
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摘要
神经振荡性电活动是指在生理状态下核团内及神经网络中的神经元的电生理活动特点。振荡性电活动是电流/电压的周期性变化，分为同步振荡和异步振荡两种情况。其中，能够保持同步而稳定运行的振荡称为同步振荡。膜共振是用来描述神经元对输入信号的频率选择性能力的物理量，同时也是神经元振荡活动的内在机制之一。频率选择性是神经元膜共振活动所具有的一种内在特性。神经元的膜共振特性和频率选择性在调节脑内神经网络的节律性活动中发挥重要作用，其调控作用尤其体现在神经元相互之间进行信息传递的过程中。不同的神经元具有不同的膜共振特性是神经网络共振的基础。多巴胺能神经元是黑质致密部中的主要神经元。了解多巴胺能神经元的膜共振特性，将有助于增进我们对基底节区神经元细胞对信息处理过程的认识。黑质致密部的多巴胺神经元输出的信息涉及运动、学习和记忆等生理功能。这些信息的输出，对我们认知黑质致密部DA神经元及其损害后引起的神经系统疾病，特别是帕金森病，具有重要的意义。在前期研究中，已发现帕金森病患者基底节区存在病理性同步振荡现象，其主要表现是过度的同步振荡。一般认为，同步振荡与神经系统信息的检测、处理及整合密切相关，因此，过度的同步振荡也可能成为帕金森病感觉、运动信息紊乱并导致出现不同临床症状的内在机制之一。“振荡模型”是新近提出的一种帕金森病的发病机制，目前仍有很多机制尚不明确。此外，既往临床和基础研究已经表明，黑质致密部的多巴胺神经元的病理性的退行性改变是PD、抑郁症等多种疾病的发生和发展的重要特征。故研究探索PD的DA（dopamine）神经元的膜共振特性及机制将有助于我们从一个新的角度去认识PD的发病机制。
本课题分成二个部分，其一是在大鼠脑片水平上利用红外线可视全细胞膜片钳技术观察记录多巴胺神经元的电活动及其膜共振性质；其二是对膜共振特性潜在的离子机制进行更深入的探讨，以期在正常大鼠脑片水平上，了解多巴胺能神经元的膜共振特性，为进一步研究帕金森大鼠脑片水平的多巴胺神经元膜共振特性的改变，提供坚实的理论依据。一、黑质致密部多巴胺神经元的膜共振
神经元的振荡是神经系统电活动一个重要的生物节律，无论单个神经元的振荡，还是神经网络的振荡，对脑的功能都具有重要意义。神经元的膜共振是用来描述神经元对输入信号的频率选择性，是神经元网络振荡的内在机制之一。目前已在海马CA1区锥体神经元、海马下托锥体神经元及内嗅皮质Ⅱ层星形细胞等不同类型神经元中检测到θ膜共振。多巴胺神经元作为在黑质致密部结构中最主要的神经元，对神经网络的作用是通过直接、间接通路与其它核团神经元的相互作用而产生的结果，然而对于黑质致密部DA神经元是否也存在膜共振，尚未见报道。因此，本课题的第一部分实验内容就是给予黑质致密部DA神经元一个随时间增加频率连续变化的正弦电流（ZAP，0Hz～16Hz，20s）作为刺激电流，观察并检测出DA神经元的是否存在膜共振，及其膜共振的频率范围，并对其结果进行进一步的分析讨论。
主要结果如下：
1、使用红外线可视全细胞膜片钳技术在黑质致密部冠状脑片水平上记录到多巴胺神经元电生理活动，同时用TH染色证实DA神经元其形态为梭形神经元。
2、我们发现在给予SNc的DA神经元去极化电流刺激时，记录到的SNc的DA神经元放电模式为规则的低频的放电模式。实验还发现，我们利用电生理方法可以明确鉴定DA神经元，在给予ZAP电流刺激时，在-55mV到-85mV范围内DA神经元表现出膜共振反应。
3、DA神经元的膜共振频率具有温度依赖性，即膜共振频率随温度的升高而升高，在33℃～38℃为2Hz～4Hz左右，证实其频率值处在θ频率范围内。
4、DA神经元的膜共振频率具有电压依赖性，表现为当钳制在不同的超极化膜电位水平，其膜共振频率有所不同。
二、黑质致密部多巴胺神经元的膜共振特性的离子机制
DA神经元的离子通道主要有K~+、Na~+、Ca~(2+)离子通道。Ih电流是由HCN通道所介导一种混合性的阳离子流，由Na~+、K~+及其它阳离子共同组成，是一种缓慢激活的阳离子电流。目前已经证实这种电流对神经元细胞膜的兴奋性和节律性具有重要的调节作用，这在各个脑区的中枢神经元系统已经得到了充分验证。研究结果显示，Ih电流对神经元的调节，主要是通过对突触的传递的调节，而去调节神经元细胞膜的兴奋性及节律性，并且证实其参与了膜共振的形成。这在海马神经元、皮层等神经元业已被证实，其作为主动电流参与形成阈下膜共振。但其是否作为主动电流也参与形成DA神经元阈下膜共振，尚不明确。同时是否有其它离子通道也参与或调节了DA神经元的阈下膜共振，目前也不明确。另外，有文献报道，小电导钙依赖性钾通道（the small-conductance calcium-dependent potassiumchannel, SK）和Ca~(2+)通道参与了膜振荡的形成，其中SK通道的阻断和激活能够显著影响DA神经元的节律和兴奋性。但是能否证实其在膜共振方面的作用，还有待进一步研究。
主要结果如下:
1、超极化激活的阳离子流（Hyperpolarization-activated cation current，Ih）是DA神经元产生θ频率膜共振的主动电流成分，作用范围大概在-65mV～-85mV之间。
2、钙依赖性钾通道（SK）也是DA神经元产生θ频率膜共振的主动电流成分，其作用范围大概在-60mV～-70mV之间。
3、持续性钠电流（Persistent sodium currents，INap）可以水平放大膜共振。
主要结论
1、使用红外线可视全细胞膜片钳技术在大鼠黑质致密部冠状脑片水平上记录到梭形神经元，存在神经元膜共振。
2、大鼠黑质致密部DA神经元的膜共振具有温度依赖性和电压依赖性。
3、证实了大鼠黑质致密部多巴胺神经元在-65mV左右，产生膜共振的主动电流是SK通道电流。
4、证实了大鼠黑质致密部多巴胺神经元在-75mV左右，产生膜共振的主动电流是Ih电流。
5、证实了I_(Nap)可以增强膜共振峰，但对膜共振频率没有影响。
6、钙离子参与了膜共振的产生，具体机制尚需进一步研究。
我们的研究表明黑质致密部多巴胺神经元具有θ频率膜共振，其离子机制具有一定的特殊性，这种独特的离子机制，对于我们进一步了解黑质致密部DA神经元及其在脑内神经网络中的地位具有重要的作用，并且为进一步研究PD患者的DA电生理功能特性提供了基础。
Neural oscillation activity is the feature of neural network on physiological state.Different neuron resonance characteristics are the basic of neural networkresonance. Oscillatory electrical activity is the periodic changes of electricalcurrent, which can be divided into two types: synchronous oscillation andasynchronous oscillation. Synchronous oscillation is an operational oscillationwhich could keep stable synchronizing to the input stimulation. In contrast,asynchronous oscillation is characterized by the loss of synchronization and thuscannot oscillate to the input stimulation. Resonance is a phenomenon thatdescribes the frequency-selective ability of neurons to respond the input signal.Frequency selectivity represents an intrinsic property of neurons. Resonance andfrequency selectivity of neurons are very important because they serve as an important basis for coordinating network activity in the brain. Besides, they playa vital role in the information transmission among the neurons. Dopaminergicneuron is the main neuron of the substantia nigra compacta components. It hassignificant functions in processing the information of basal ganglia structuresand the output of dopaminergic neuron, referring to many physiologicalfunctions of the substantia nigra compacta, such as moving, learning andmemory. At present, Pathological synchronous oscillation has been observed inthe Parkinson's disease patients, and the main symptom is excessivesynchronization oscillation. Synchronous oscillation theory is thought to beclosely related to information detection, analysis and integration. And the theorymight be the internal mechanism of the sensational and movement informationdisorder and thus leading to different clinical symptoms of the Parkinson'sdisease.“Oscillation model” is one of newly raised pathogeneses of the PD.However, the pathogenesis of PD remains unclear. In addition, clinical and basicstudies show that the pathological changes of dopaminergic neuron in thesubstantia nigra compacta have involved in the emergence and development ofvariety diseases including Parkinson’s disease and depression. Therefore, thestudy on resonance property and neurons mechanism of DA resonance of PDwill discover the PD pathogenesis from a new perspective. This research includetwo parts: in the first part we recorded the electrical activity of dopaminergicneurons with infrared visual whole-cell patch clamp in rat horizontal brain slices;in the second part we studied its resonant characteristic and ionic mechanisms.
1.Membrane resonance of dopaminergic neurons in substantia nigracompacta.
Oscillation is an important biological rhythm in the brain. Whether a singleneurons or the whole neural network, the oscillation is of great significance for the functions of the brain. Resonance is used to describe the frequency-selectiveability of neurons to respond the input signal, and is one of the internalmechanisms of oscillation. As one of these intrinsic neuronal properties, θresonance has been found in hippocampal CA1pyramidal neurons, horizontalinterneurones in the stratum oriens, and stellate cells from layer II of the medialentorhinal cortex. As the one of the main type neurons in the brain, thedopaminergic neurons have unique physiological significance and functions insubstantia nigra compacta structure, as well as its direct and indirect pathways inbrain network. However, there is no data to show that membrane resonanceexists in DA neurons of substantia nigra compacta. Therefore, the first step ofthe research is to give the sine current (ZAP,0Hz~16Hz,20s) stimulation, whichwas continuously changed by the increasing frequency over time, to DA neuronsof substantia nigra compactan. Then we calculated the membrane resonantfrequency of neurons, and discuss the properties of DAergic neuronsmembrane resonance.
Main results:
1). The electrophysiological activities of dopaminergic neurons were recordedby whole-cell patch clamp in substantia nigra compacta in horizontal slices. Theresults with TH staining showed that these neurons were fusiform neurons.
2). According to the different firing patterns evoked by depolarizing currentstimulation, the DA neurons of SNc can be defined as regular spiking neurons.The experiment showed that all the DA neurons presentresonant response to theZAP stimulation in the range of-55mV and-85mV.
3). Membrane resonance frequency of the DA neurons were temperaturedependent. In other words, the frequency would increase with the rising of thetemperature. The frequency was increased from2Hz to4Hz with the temperature changed from33℃to38℃.And the frequency was in θ frequencyrange.
4). Membrane resonance of DA neurons was voltage dependent. In differentmembrane potential levels, it showed different frequency of resonance.
2. The Ionic mechanism of membrane resonance for dopaminergic neuronsin substantia nigra compacta
As reported, the main ionic channels related to DA neurons are K+, Na+and Ca2+ionic channels. Ih current is a mixture current which involves K+, Na+and otherpositive ionic components. Several studies have confirmed its modulation role inthe research of the neuron membrane excitability and its rhythms activities inseveral regions of neurons system. The research shows that Ih current havedifferent ways of modulation to synaptic transmission in presynaptic andpostsynaptic neurons. In addition, it has been confirmed in hippocampal neuronsand cortex. As an active current, it has participated in and thus formedsubthreshold membrane resonance. However, it is not clear that whether itparticipates in the formation of subthreshold membrane resonance of DAneurons as an active current. Besides, whether other ion channels have alsoinvolved in or mediated the properties of the subthreshold membrane resonanceof DA neurons was still unclear. At present, researches have shown that theblocking and activating of the small-conductance calcium-dependent potassiumchannel have some effect on the pacing and excitability of the DA neurons. Butits functions on the properties of membrane resonance still need furtherresearch.
Main results:
1). Hyperpolarization-activated cation current is the active current component toproduce theta frequency membrane resonance in DA neurons. The current component takes effect in the range of-65to-85mV.
2). The small-conductance calcium-dependent potassium channel is also theactive current component to produce theta frequency membrane resonance inDA neurons. It ranges from-60to70mV.
3). Persistent sodium currents, INap could magnify the amplitude of themembrane resonance at the level of depolarized transmembrane potential.
Main conclusions:
1). Dopaminergic neurons in substantia nigra compacta is about-65mV, theactive current which can produce membrane resonance is SK channel current.
2). Dopaminergic neurons in substantia nigra compacta is about-75mV, theactive current which can produce membrane resonance is h current.
3). INapcan diminish the membrane resonance amplitude in the hyperpolarizedlevel, but it has no effect on resonance frequency.
4).Calcium ions involved in membrane resonance, but the specificmechanisms need further study.
Our study showed that the membrane resonance of dopamine neurons insubstantia nigra pars compacta belonged to the θ frequency. Its ionic mechanismhad some particularity feature. This unique ionic mechanisms was better tounderstand the membrane resonance of DA neurons in substantia nigra parscompacta and important roles in the network. By the way, it provide a basicstudy for PD patients in electrophysiological features.
本课题分成二个部分，其一是在大鼠脑片水平上利用红外线可视全细胞膜片钳技术观察记录多巴胺神经元的电活动及其膜共振性质；其二是对膜共振特性潜在的离子机制进行更深入的探讨，以期在正常大鼠脑片水平上，了解多巴胺能神经元的膜共振特性，为进一步研究帕金森大鼠脑片水平的多巴胺神经元膜共振特性的改变，提供坚实的理论依据。一、黑质致密部多巴胺神经元的膜共振
神经元的振荡是神经系统电活动一个重要的生物节律，无论单个神经元的振荡，还是神经网络的振荡，对脑的功能都具有重要意义。神经元的膜共振是用来描述神经元对输入信号的频率选择性，是神经元网络振荡的内在机制之一。目前已在海马CA1区锥体神经元、海马下托锥体神经元及内嗅皮质Ⅱ层星形细胞等不同类型神经元中检测到θ膜共振。多巴胺神经元作为在黑质致密部结构中最主要的神经元，对神经网络的作用是通过直接、间接通路与其它核团神经元的相互作用而产生的结果，然而对于黑质致密部DA神经元是否也存在膜共振，尚未见报道。因此，本课题的第一部分实验内容就是给予黑质致密部DA神经元一个随时间增加频率连续变化的正弦电流（ZAP，0Hz～16Hz，20s）作为刺激电流，观察并检测出DA神经元的是否存在膜共振，及其膜共振的频率范围，并对其结果进行进一步的分析讨论。
主要结果如下：
1、使用红外线可视全细胞膜片钳技术在黑质致密部冠状脑片水平上记录到多巴胺神经元电生理活动，同时用TH染色证实DA神经元其形态为梭形神经元。
2、我们发现在给予SNc的DA神经元去极化电流刺激时，记录到的SNc的DA神经元放电模式为规则的低频的放电模式。实验还发现，我们利用电生理方法可以明确鉴定DA神经元，在给予ZAP电流刺激时，在-55mV到-85mV范围内DA神经元表现出膜共振反应。
3、DA神经元的膜共振频率具有温度依赖性，即膜共振频率随温度的升高而升高，在33℃～38℃为2Hz～4Hz左右，证实其频率值处在θ频率范围内。
4、DA神经元的膜共振频率具有电压依赖性，表现为当钳制在不同的超极化膜电位水平，其膜共振频率有所不同。
二、黑质致密部多巴胺神经元的膜共振特性的离子机制
DA神经元的离子通道主要有K~+、Na~+、Ca~(2+)离子通道。Ih电流是由HCN通道所介导一种混合性的阳离子流，由Na~+、K~+及其它阳离子共同组成，是一种缓慢激活的阳离子电流。目前已经证实这种电流对神经元细胞膜的兴奋性和节律性具有重要的调节作用，这在各个脑区的中枢神经元系统已经得到了充分验证。研究结果显示，Ih电流对神经元的调节，主要是通过对突触的传递的调节，而去调节神经元细胞膜的兴奋性及节律性，并且证实其参与了膜共振的形成。这在海马神经元、皮层等神经元业已被证实，其作为主动电流参与形成阈下膜共振。但其是否作为主动电流也参与形成DA神经元阈下膜共振，尚不明确。同时是否有其它离子通道也参与或调节了DA神经元的阈下膜共振，目前也不明确。另外，有文献报道，小电导钙依赖性钾通道（the small-conductance calcium-dependent potassiumchannel, SK）和Ca~(2+)通道参与了膜振荡的形成，其中SK通道的阻断和激活能够显著影响DA神经元的节律和兴奋性。但是能否证实其在膜共振方面的作用，还有待进一步研究。
主要结果如下:
1、超极化激活的阳离子流（Hyperpolarization-activated cation current，Ih）是DA神经元产生θ频率膜共振的主动电流成分，作用范围大概在-65mV～-85mV之间。
2、钙依赖性钾通道（SK）也是DA神经元产生θ频率膜共振的主动电流成分，其作用范围大概在-60mV～-70mV之间。
3、持续性钠电流（Persistent sodium currents，INap）可以水平放大膜共振。
主要结论
1、使用红外线可视全细胞膜片钳技术在大鼠黑质致密部冠状脑片水平上记录到梭形神经元，存在神经元膜共振。
2、大鼠黑质致密部DA神经元的膜共振具有温度依赖性和电压依赖性。
3、证实了大鼠黑质致密部多巴胺神经元在-65mV左右，产生膜共振的主动电流是SK通道电流。
4、证实了大鼠黑质致密部多巴胺神经元在-75mV左右，产生膜共振的主动电流是Ih电流。
5、证实了I_(Nap)可以增强膜共振峰，但对膜共振频率没有影响。
6、钙离子参与了膜共振的产生，具体机制尚需进一步研究。
我们的研究表明黑质致密部多巴胺神经元具有θ频率膜共振，其离子机制具有一定的特殊性，这种独特的离子机制，对于我们进一步了解黑质致密部DA神经元及其在脑内神经网络中的地位具有重要的作用，并且为进一步研究PD患者的DA电生理功能特性提供了基础。
Neural oscillation activity is the feature of neural network on physiological state.Different neuron resonance characteristics are the basic of neural networkresonance. Oscillatory electrical activity is the periodic changes of electricalcurrent, which can be divided into two types: synchronous oscillation andasynchronous oscillation. Synchronous oscillation is an operational oscillationwhich could keep stable synchronizing to the input stimulation. In contrast,asynchronous oscillation is characterized by the loss of synchronization and thuscannot oscillate to the input stimulation. Resonance is a phenomenon thatdescribes the frequency-selective ability of neurons to respond the input signal.Frequency selectivity represents an intrinsic property of neurons. Resonance andfrequency selectivity of neurons are very important because they serve as an important basis for coordinating network activity in the brain. Besides, they playa vital role in the information transmission among the neurons. Dopaminergicneuron is the main neuron of the substantia nigra compacta components. It hassignificant functions in processing the information of basal ganglia structuresand the output of dopaminergic neuron, referring to many physiologicalfunctions of the substantia nigra compacta, such as moving, learning andmemory. At present, Pathological synchronous oscillation has been observed inthe Parkinson's disease patients, and the main symptom is excessivesynchronization oscillation. Synchronous oscillation theory is thought to beclosely related to information detection, analysis and integration. And the theorymight be the internal mechanism of the sensational and movement informationdisorder and thus leading to different clinical symptoms of the Parkinson'sdisease.“Oscillation model” is one of newly raised pathogeneses of the PD.However, the pathogenesis of PD remains unclear. In addition, clinical and basicstudies show that the pathological changes of dopaminergic neuron in thesubstantia nigra compacta have involved in the emergence and development ofvariety diseases including Parkinson’s disease and depression. Therefore, thestudy on resonance property and neurons mechanism of DA resonance of PDwill discover the PD pathogenesis from a new perspective. This research includetwo parts: in the first part we recorded the electrical activity of dopaminergicneurons with infrared visual whole-cell patch clamp in rat horizontal brain slices;in the second part we studied its resonant characteristic and ionic mechanisms.
1.Membrane resonance of dopaminergic neurons in substantia nigracompacta.
Oscillation is an important biological rhythm in the brain. Whether a singleneurons or the whole neural network, the oscillation is of great significance for the functions of the brain. Resonance is used to describe the frequency-selectiveability of neurons to respond the input signal, and is one of the internalmechanisms of oscillation. As one of these intrinsic neuronal properties, θresonance has been found in hippocampal CA1pyramidal neurons, horizontalinterneurones in the stratum oriens, and stellate cells from layer II of the medialentorhinal cortex. As the one of the main type neurons in the brain, thedopaminergic neurons have unique physiological significance and functions insubstantia nigra compacta structure, as well as its direct and indirect pathways inbrain network. However, there is no data to show that membrane resonanceexists in DA neurons of substantia nigra compacta. Therefore, the first step ofthe research is to give the sine current (ZAP,0Hz~16Hz,20s) stimulation, whichwas continuously changed by the increasing frequency over time, to DA neuronsof substantia nigra compactan. Then we calculated the membrane resonantfrequency of neurons, and discuss the properties of DAergic neuronsmembrane resonance.
Main results:
1). The electrophysiological activities of dopaminergic neurons were recordedby whole-cell patch clamp in substantia nigra compacta in horizontal slices. Theresults with TH staining showed that these neurons were fusiform neurons.
2). According to the different firing patterns evoked by depolarizing currentstimulation, the DA neurons of SNc can be defined as regular spiking neurons.The experiment showed that all the DA neurons presentresonant response to theZAP stimulation in the range of-55mV and-85mV.
3). Membrane resonance frequency of the DA neurons were temperaturedependent. In other words, the frequency would increase with the rising of thetemperature. The frequency was increased from2Hz to4Hz with the temperature changed from33℃to38℃.And the frequency was in θ frequencyrange.
4). Membrane resonance of DA neurons was voltage dependent. In differentmembrane potential levels, it showed different frequency of resonance.
2. The Ionic mechanism of membrane resonance for dopaminergic neuronsin substantia nigra compacta
As reported, the main ionic channels related to DA neurons are K+, Na+and Ca2+ionic channels. Ih current is a mixture current which involves K+, Na+and otherpositive ionic components. Several studies have confirmed its modulation role inthe research of the neuron membrane excitability and its rhythms activities inseveral regions of neurons system. The research shows that Ih current havedifferent ways of modulation to synaptic transmission in presynaptic andpostsynaptic neurons. In addition, it has been confirmed in hippocampal neuronsand cortex. As an active current, it has participated in and thus formedsubthreshold membrane resonance. However, it is not clear that whether itparticipates in the formation of subthreshold membrane resonance of DAneurons as an active current. Besides, whether other ion channels have alsoinvolved in or mediated the properties of the subthreshold membrane resonanceof DA neurons was still unclear. At present, researches have shown that theblocking and activating of the small-conductance calcium-dependent potassiumchannel have some effect on the pacing and excitability of the DA neurons. Butits functions on the properties of membrane resonance still need furtherresearch.
Main results:
1). Hyperpolarization-activated cation current is the active current component toproduce theta frequency membrane resonance in DA neurons. The current component takes effect in the range of-65to-85mV.
2). The small-conductance calcium-dependent potassium channel is also theactive current component to produce theta frequency membrane resonance inDA neurons. It ranges from-60to70mV.
3). Persistent sodium currents, INap could magnify the amplitude of themembrane resonance at the level of depolarized transmembrane potential.
Main conclusions:
1). Dopaminergic neurons in substantia nigra compacta is about-65mV, theactive current which can produce membrane resonance is SK channel current.
2). Dopaminergic neurons in substantia nigra compacta is about-75mV, theactive current which can produce membrane resonance is h current.
3). INapcan diminish the membrane resonance amplitude in the hyperpolarizedlevel, but it has no effect on resonance frequency.
4).Calcium ions involved in membrane resonance, but the specificmechanisms need further study.
Our study showed that the membrane resonance of dopamine neurons insubstantia nigra pars compacta belonged to the θ frequency. Its ionic mechanismhad some particularity feature. This unique ionic mechanisms was better tounderstand the membrane resonance of DA neurons in substantia nigra parscompacta and important roles in the network. By the way, it provide a basicstudy for PD patients in electrophysiological features.
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