丘脑底核神经元的共振及其和多巴胺受体的关系
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摘要
研究背景
大脑是一个高度分布式系统，不同感知信息在大脑的不同脑区得到处理和并行执行，但并没有一个统一的协调中心负责管理不同脑区功能的协调。大脑的同步振荡活动被认为是捆绑一些空间上分隔，但又彼此相关的神经信息的机制之一，可协助大脑实现多脑区的协同工作。目前普遍认为神经元共振是神经网络振荡活动的重要基础。现已发现皮层和海马等部位神经元均存在共振现象，并证实这些细胞的共振参与了振荡节律的形成，具有重要生理功能。但对基底节（BG）各核团神经元共振特性的研究还处于空白状态，研究BG各核团神经元的共振及其机制，有可能帮助我们深入认识BG系统调节运动功能的电生理机制。
帕金森病（PD）等病理条件下，BG的异常同步振荡可通过神经投射通路影响大脑皮层，导致皮层感觉运动区活动异常，从而错误地捆绑了多脑区的运动信息，造成本该协同工作的肌肉群发生紊乱，导致相应的临床症状。目前，BG-皮层环路的异常同步振荡已成为PD的新病理机制，但发生异常振荡的机理仍不清。神经元共振是神经网络振荡活动的重要基础，故研究BG各核团神经元的共振现象及其和PD的关系意义重大，有可能在PD发生的电生理机制方面有所突破。
丘脑底核（STN）在PD的形成发展过程中起了重要作用，是临床DBS治疗PD的主要靶核之一。目前已证实黑质致密部和STN间存在直接的多巴胺能纤维联系，多巴胺可通过STN神经元表面的多巴胺受体直接作用于其神经元。故本课题首先选取STN作为研究对象，研究其共振现象及机制，并深入研究该神经元共振和多巴胺受体的关系。实验目的
（1）研究STN神经元是否有共振现象并研究其常规特性；
（2）探索STN神经元共振的离子机制；
（3）分别研究多巴胺D1、D2受体阻断剂对STN神经元共振特性的影响及其和超极化激活的阳离子流（Ih）的关系；
（4）初步探索多巴胺受体阻断剂影响STN神经元共振的信号转导途径。
实验方法
（1）脑片准备及钳制细胞
异氟烷吸入麻醉后断头处死大鼠（13-18天，雄性），迅速取脑，置于予充混合氧（95%O_2，5%CO_2）的冰浴人工脑脊液（ACSF）中，振动切片机切取含STN的脑片（350-400μm），在ACSF中孵育（34℃）1小时，以恢复脑片状态，将脑片移至记录浴槽，用氧饱和的ACSF持续灌流(2ml/min)。开启浴槽加热系统，使脑片温度维持在34℃。镜下定位核团并选取活性较好的细胞，常规钳制细胞形成全细胞模式，所用玻璃微电极电阻3-7MΩ。让细胞恢复约5分钟后，利用细胞的电生理特征鉴定细胞并测试细胞膜电位、动作电位等常规参数，选择串联电阻在10-20MΩ，静息电位负于-55mV，同时动作电位超射较好的神经元进行实验。
（2）神经元共振特性测试
在全细胞电流钳模式下，先用直流电将细胞钳制于目标电压（-50mV，-60mV，-70mV，-80mV及-90mV），通过记录电极给予细胞一个振幅固定、频率随时间线性增大的正弦电流（ZAP）刺激，记录神经元的电压反应。共振表现为神经元膜电压在某个特定的频段出现一个可重复的凸起共振峰，共振峰所对应的频率即为细胞的共振频率(f_(res))。为了量化共振的强度，将共振峰的阻抗值与0.5Hz对应的阻抗值的比值作为衡量共振强度的指标，称为Q值。调整ZAP电流强度使其引起的电压反应峰峰值控制在±10mV以内，以免诱发动作电位，必要时可适当使用河豚毒素（TTX）。为了方便测量f_(res)及Q值，将记录到的电压反应和输入的ZAP电流进行快速傅立叶变换(FFT)，计算阻抗值(Z)，公式为： Z=FFT(V)/FFT(I)，绘制阻抗曲线，在阻抗曲线上很容易读出f_(res)并计算出Q值。为了排除刺激的时间依赖性对细胞共振峰的影响，给予反向ZAP电流（时程20s，频率18-0Hz）刺激，观察细胞的电压反应与正常ZAP刺激结果是否一致。
（3）神经元放电的频率选择性测试
在全细胞电流钳模式下，先用直流电将细胞钳制于目标电压（-70mV），通过调节增益水平逐渐加大ZAP电流的幅度，直至刚刚出现动作电位，观察细胞放电所对应的频段。为了排除放电的时间及波形依赖性，换一种刺激方式，给予不同频率的等幅恒频的正弦电流刺激，同法观察细胞的优先放电频率。
（4）神经元I_h的记录
钳制细胞形成全细胞模式并待细胞状态稳定后，在全细胞电压钳模式下，给予一串超极化step电压刺激，记录膜电流，I_h表现为一缓慢激活的内向电流。
（5）Ih在STN神经元阈下共振及放电频率选择性中的作用
在外液中给予I_h特异性阻断剂ZD7288(20μM)，观察给药前后STN神经元阈下共振及放电频率选择性的变化。
（6）不同多巴胺受体阻断剂对STN神经元共振的影响
①分别给予氯氮平（Clozapine，50μM）、氟哌啶醇（Haloperidol，30μM）、SCH-23390(1μM)、舒必利（Sulpiride，1μM）等不同亚型多巴胺受体的阻断剂，观察给药前后STN神经元共振特性的变化，研究其对STN神经元共振特性的影响。
②前面实验证实D2受体特异性阻断剂Sulpiride可阻断STN神经元的共振现象，但D1受体特异性阻断剂SCH-23390对共振无显著影响。故我们进一步研究Sulpiride对Ih的影响，探索其影响共振的离子机制，并研究其对STN神经元放电频率选择性的影响。
（7）Sulpiride影响STN神经元的信号转导途径初探
①按下表分组、加药（n=10）
②主要观察指标有：神经元阈下共振特性、神经元放电的频率选择性。钳制细胞形成全细胞模式后等20min左右，待GDP-β-S、GTP-γ-S、GTP等药物扩散至细胞内、有效作用于细胞后再开始实验，方法同前。
（8）所记录神经元的定位及形态学观察
随机抽取部分神经元(15个)行荧光黄标记染色，用含荧光黄的电极内液(1.5‰)在避光条件下钳制细胞，常规行电生理记录，留置电极30min以上，荧光光源下观察神经元形态，确认染色充分后，缓慢退出电极。将脑片切掉一角并记录，以标记正反面，在4%多聚甲醛中避光固定。将甲醛固定过的脑片铺于载玻片上，有标记细胞的一面朝上，荧光封片液、指甲油封片，激光共聚焦显微镜下观察并拍照。
（9）统计学处理
采用SPSS13.0进行分析，实验结果用均值±标准差（x±SD）表示。各组间的数据用One-way ANOVA或Two-way ANOVA进行比较，两两之间用LSD方法进行比较，两组间均数的比较采用t检验，如P <0.05则认为有统计学差异。
实验结果
（1）STN神经元的形态学定位及电生理鉴定
激光共聚焦显微镜下观察荧光黄标记的STN神经元，低倍镜下证实实验所选细胞均位于STN，高倍镜下可见神经元胞体、轴突清晰可见，形态符合STN神经元特征。电压钳下给予一串超极化Step电压刺激，可见明显Ih及尾电流。电流钳下给予一串外向电流刺激，使细胞超极化，记录细胞的电压反应，其主要特征有刺激起始段的Sag、刺激末伴随动作电位的反跳去极化及动作电位后的平台电位，符合STN神经元的电生理特性。
（2）STN神经元的阈下膜共振
在34℃条件下，将细胞钳制于-70mV水平，给予ZAP电流刺激，记录到的电压反应呈梭形，在2.5-3Hz频段，电压反应显著增强，证实细胞存在共振现象。将数据做快速傅立叶变换，绘制阻抗曲线，可见该细胞fres亦在2.5-3Hz频段。统计分析示神经元共振的fres和Q值分别为2.67±0.29Hz和1.093±0.0202(n=8)。反向ZAP电流刺激产生的电压反应较上述结果无明显差异(P>0.05, n=6)。
（3）STN神经元共振的温度依赖性
将细胞钳制于-70mV水平，在30℃、34℃、38℃三个不同温度水平观察STN神经元的共振特性。神经元fres随温度升高而升高，统计数据示：神经元fres在30℃、34℃、38℃条件下分别为1.99±0.36Hz、2.67±0.29Hz、4.07±0.40Hz，经单因素方差分析统计三组间统计学差异显著(P <0.05，n=8)。
（4）STN神经元共振的电压依赖性
在-60mV到-90mV水平神经元对ZAP电流的电压反应呈梭形，共振明显。fres随电压的超极化而升高，可从-60mV时的2.01±0.25Hz升高到-90mV时的3.09±0.32Hz，经方差分析统计各组间统计学差异显著(P <0.05，n=10)。Q值亦有显著电压依赖性，-60mV、-90mV时其水平较低，-70mV条件下Q值最大，达1.092±0.021。-50mV条件下神经元对ZAP电流的电压反应呈喇叭口状，无明显共振现象。
（5）STN神经元放电的频率选择性
给予ZAP电流证实STN神经元存在阈下共振后，逐渐加大ZAP电流的幅度，直至刚刚出现动作电位，发现细胞最先出现放电的频段和其fres一致。换一种刺激方式，给予不同频率的等幅恒频的正弦电流刺激，结果亦证实细胞最先出现放电的频段与fres一致。
（6）抑制Ih可阻断STN神经元的阈下共振及其放电频率选择性
在全细胞电压钳模式下， Ih表现为一缓慢激活的内向电流，在各电位水平均可被ZD7288显著抑制（P <0.05，n=12）。生理条件下神经元存在共振现象，放电的频率选择性明显，给予ZD7288阻断Ih后，记录的电压反应变为喇叭口状，共振消失、神经元放电的频率选择性也同时消失。统计分析显示ZD7288消除共振及放电频率选择性的有效率均可达100%(n=10)。
（7）多巴胺受体阻断剂对STN神经元阈下共振的影响
外液中加入Clozapine (50μM)或Haloperidol (30μM)同时阻断D1、D2受体后，神经元对ZAP的电压反应呈喇叭口状，共振现象被消除。外液中加入Sulpiride单纯阻断D2受体效果类似。统计分析显示Clozapine、Haloperidol及Sulpiride消除共振的有效率均可达100%(n=10)。外液中加入SCH-23390单纯阻断D1受体，STN神经元阈下共振未见明显改变（P>0.05，n=10）。
（8）Sulpiride对STN神经元放电频率选择性的影响
在34℃、-70mV条件下，给药前，细胞最先出现放电的频段与细胞的fres一致。外液中加入Sulpiride (1μM)阻断D2受体后，细胞在最低频率处首先出现放电，与ZD7288的效果类似。更换刺激方式为不同频率的等幅恒频的正弦电流刺激，结果类似。上述两种方法均证实Sulpiride阻断STN神经元放电频率选择性的有效率达100%(n=10)。
（9）Sulpiride对STN神经元Ih的影响
给予Sulpiride (1μM)阻断D2受体，各电位水平的Ih均被显著抑制(P<0.05,n=10)，与ZD7288效果类似。
（10）Sulpiride通过G蛋白偶联受体影响STN神经元共振及其放电频率选择性
正常对照组神经元对ZAP电流的电压反应呈梭形，共振现象明显，在其fres附近频段最易出现放电，内液中加入GDP-β-S阻断G蛋白偶联受体（GPCRs）可模拟Sulpiride的作用，神经元共振、放电频率选择性均被抑制。内液中加入GTP-γ-S激动GPCRs后，可阻断Sulpiride的作用。统计分析显示：Sulpiride、GDP-β-S完全消除共振的有效率均达100%(n=10)，GTP-γ-S阻断Sulpiride作用的有效率亦达100%(n=10)。该结果提示，Sulpiride通过阻断多巴胺对GPCRs的作用实现其对STN神经元共振的影响。结论
（1）STN神经元存在共振现象，该现象具有温度依赖性及电压依赖性；
（2）Ih介导了STN神经元的共振；
（3）D2受体特异性阻断剂（Sulpiride）可阻断STN神经元的共振现象，但D1受体特异性阻断剂(SCH-23390)对上述共振现象无显著影响；
（4）Sulpiride通过抑制Ih阻断STN神经元的共振现象；
（5）Sulpiride通过阻断多巴胺对GPCRs的作用实现其对STN神经元共振的影响。
The realization that different behavioral and perceptual states of the brainare associated with different brain rhythms has sparked growing interest in theoscillatory behavior of neurons. With the emergence of new techniques, studieshave shown that temporally and spatially organized activity among distributedneuronal populations often takes the form of synchronous oscillations. Thesesynchronous oscillations may evolve to dynamically control the grouping ofneurons into organized assemblies. Recent research has revealed a closeassociation between electrical oscillations and resonance in neurons. It has beensuggested that resonance underlies oscillatory behavior in neural networks.Resonance is the ability of neurons to respond selectively to inputs at preferredfrequencies, which can serve as a substrate for coordinating network activityaround a particular frequency. Resonance dramatically affects the ability ofnetworks to produce oscillatory patterns of activity. Gimbarzevsky has studiedthe property of resonance since the1980s. There is accumulating evidence thatneurons in different brain areas have prominent resonant properties, such as inthe neocortical cortex, entorhinal cortex, prefrontal cortex, hippocampus and thalamus.
Studies in recent years have shown that there are several types ofoscillatory phenomena in the basal ganglia. Investigations in humans andanimals have demonstrated the existence of a range of oscillatory activity in thevarious nuclei of the basal ganglia, and the oscillatory activity is believed toplay an important role in both the physiology and pathophysiology of thissystem. Studies using electroencephalography and magnetoencephalographyalso support the theory that basal ganglia engage in synchronous oscillatoryactivity. However, little is known about the actual mechanisms underlying thegeneration of neuronal oscillatory activity in basal ganglia. Now, it is possible toimage the resonance underlying oscillatory behavior in basal ganglia.
A critical role of the subthalamic nucleus (STN) in the control ofmovement has been proposed based in part on the observation that its lesion orhigh-frequency electrical stimulation is highly effective in alleviating theakinesia, rigidity and tremor of Parkinson’s disease (PD). PD, which is causedby the progressive loss of dopaminergic neurons in the substantia nigra, isassociated with hyperactivity of neurons in the STN as detected by metabolicand electrophysiological studies in parkinsonian patients and in parkinsonianrats and monkeys. In this paper, we studied the resonance characteristics of STNneurons and its correlation with the dopamine receptor using whole-cellpatch-clamp recordings in rat brain slices.
Methods
Tissue preparation
Coronal slices containing STN (350-400μm thick) were prepared frommale young (13-18days of age) Sprague-Dawley rats as described previously.Rats were euthanized with isoflurane anesthesia in accordance with the Principles of Medical Laboratory Animal Care issued by the NationalMinistry of Health. The brain was removed rapidly and slices were cut with avibratome in ice-cold artificial cerebrospinal fluid (ACSF) solution of thefollowing composition (in mM): NaCl (126), KCl (2.5), CaCl2(2.4), MgCl2(1.2), NaH2PO4(1.2), NaHCO3(19), and glucose (11), gassed with95%O2and5%CO2(pH7.35-7.45). The slices were incubated in95%O2/5%CO2-equilibrated ACSF and kept at34°C for at least one hour. A slice was thenplaced on the recording chamber and submerged in a continuously flowingACSF (2ml/min) gassed with95%O2and5%CO2and heated to34°C, exceptin a few experiments performed to test the temperature dependence of resonance,when the medium was heated from30°C to34°C and38°C. Using a10×objective for visual guidance, STN was readily identified as ovoid gray matterimmediately medial to the cerebral peduncle.
Electrophysiological recording
In some experiments, tetrodotoxin (TTX,1μM) was applied to blockaction potentials. Individual neurons were visualized (40×water immersionobjective) using differential interference contrast infra-red microscopy. STNneurons were not consciously selected on the basis of somatic size or shape.Whole-cell recordings were made with borosilicate glass pipettes of3-7MΩresistance containing (in mM): potassium gluconate (125), NaCl (10), MgCl2(2.0) CaCl2(1.0), EGTA (10), HEPES (10), ATP (2.0), GTP (0.3)(pH7.3,osmolarity285-295). Recorded electrical signals were amplified with anAxopatch-700B amplifier. Data were acquired using a computer with thedigidata1440A acquisition system. All potentials were corrected online for thejunction potential using the multiclamp700B commander software. Onlyneurons with a stable resting membrane potential more negative than-55mV and stable action potential amplitudes were used for recording.
Recording and analysis of electrical resonance
The impedance amplitude profile (ZAP) method was used to characterizethe electrical resonance behavior of the neurons as previously described. TheZAP current waveform was a swept-sine-wave current with constant amplitudeand linearly increasing frequency (0-18Hz for20s) generated by computer. Adirect current was firstly used to hold neurons near a desired membranepotential, then the ZAP current was injected, and the resulting voltage responsewas recorded. The amplitude of the ZAP current was adjusted to keep theperturbation of the membrane potential close to±10mV (peak to peak) to avoidfiring of action potentials. Resonance was manifest as a distinct andreproducible peak in the voltage response at a certain frequency. The Q value,the ratio of the impedance at the resonance peak to the impedance at0.5Hz, wasused to quantify the strength of the resonance. To plot the magnitude of the cellimpedance as a function of frequency, data were transformed into the frequencydomain through fast Fourier transformation (FFT). Impedance (Z) is a complexnumber defined as Z=FFT (V)/FFT (I). The magnitude of impedance wasplotted against frequency to give an impedance curve. The resonance frequency(fres) could be read at the peak of the impedance profile.
Morphology of electrophysiologically characterized neurons
Some STN neurons were labeled by adding Lucifer Yellow (0.15%) in thepipette solutions. During the course of recording, Lucifer Yellow diffused fromthe pipette into the cell. A period of30min of simple diffusion was sufficient toobtain complete labeling. Stained neurons were visualized with a laser scanningconfocal microscope.
Drug application
All drugs were dissolved in aqueous stock solutions with the exceptions ofclozapine and haloperidol, which were dissolved in dimethyl sulfoxide, andsulpiride which was dissolved in dehydrated alcohol. Each stock solution wasdiluted at least1:1000in perfusate immediately prior to its use. Dimethylsulfoxide and dehydrated alcohol, diluted1:1000in ACSF, had no side effect.Most drugs were applied by superfusion. Approximately30s were required forthe drug solution to enter the recording chamber; this delay was due to passageof the perfusate through a heat exchanger. Complete exchange of the bathsolution occurred within3min. In some experiments, drugs (Lucifer Yellow,GDP-β-S and GTP-γ-S) were added directly to the pipette internal solution fromwhich they diffused spontaneously into the cell.
Results
Membrane resonance of STN neurons
STN neurons were characterized by obvious voltage sags in response to aseries of hyperpolarizing current injections and anodal break rebounddepolarization. Most of the STN neurons tested exhibited membrane resonance,which manifested as a distinct and reproducible hump in the voltage response toZAP current injection. This resonant hump occurred at2.67±0.29Hz at34°Cwhen the holding potential was at-70mV, and the Q value was1.093±0.0202at the same condition.To test whether the resonant humps reflectedfrequency-dependent as opposed to time-dependent membrane properties, aninverted ZAP current with the same amplitude and linearly decreasing frequency(from18to0Hz for20s) was injected. The fresand Q values yielded from theinverted protocol were2.64±0.31and1.090±0.0213, respectively (n=6). Thevalues were similar to those generated from the standard ZAP protocol in the same neurons (P>0.05and0.05, paired t-test), suggesting that the resonancedid not depend on the input waveform.
Temperature dependence of resonance in STN neurons
To test the temperature dependence of the resonance, the temperature ofperfusion solutions in the recording chamber was raised from30°C to34°C and38°C at a holding potential of-70mV. The resonant hump shifting as thetemperature rises. The fresshifted from1.99±0.36Hz at30°C, to2.67±0.29Hz, and4.07±0.40Hz at34and38°C, respectively. Higher temperaturessignificantly shifted the resonant hump to a higher frequency (n=8; P <0.05,one-way ANOVA).
Voltage dependence of resonance in STN neurons
To determine the voltage dependence of the electrical resonance, cells wereheld at different membrane potentials from-50to-90mV (10mV increment).TTX was added to perfusion solutions to avoid depolarization-evokedspikes.The voltage responses to the ZAP current injections exhibited distinctmembrane resonance at holding potentials from-60to-90mV. At-50mV, nosignificant resonance was observed. Both the fresand Q values werevoltage-dependent. The freswas2.01±0.25Hz at-60mV, and increased to3.09±0.32Hz at-90mV (n=10). The Q value was1.009±0.015at-50mV,suggesting a very weak resonance occurs at this potential in a handful ofneurons. The Q value reached its peak of1.092±0.021at-70mV (n=10).These results indicate voltage-dependent membrane resonance of STN neurons.
Hyperpolarization-activated cation current (Ih) in STN neurons and itsrole in resonance
STN neurons exhibited significant Ihin voltage-clamp mode or distinctvoltage sags in response to hyperpolarizing current injections in current-clamp mode. Ihand voltage sags could be completely blocked by ZD7288(20μM)(n=12; P <0.05, two-way ANOVA). Therefore, ZD7288was used to test the roleof Ihin the resonance of STN neurons. The ZAP currents were injected beforeand after application of20μM ZD7288at-70mV. The resonant hump wasdistinct in the absence of ZD7288and completely abolished in the presence ofZD7288. The results suggest that Ihis essential for the resonance in STNneurons.
Resonance-mediated frequency-selective coupling of inputs and firing
Large-amplitude ZAP current was injected to evoke action potentials atholding potentials of-70mV. Action potentials fired most readily as the ZAPinput swept through frequencies near fres. We also used single-frequency sinewave current to evoke firing at the same potentials. Neurons preferred to firewhen the input frequency was near fres. After application of ZD7288(20μM),the spikes evoked by both ZAP current and single-frequency sine waves currentarose readily at the lowest frequencies. In summary, the frequency preference ofneurons resulted in a preferential coupling at frequencies near fresbetween inputsand firing, which could be blocked by ZD7288.
Dopamine receptor pharmacology
The ZAP currents were injected before and after application of clozapine(50μM) or haloperidol (30μM), the effective antagonist of D1and D2. Theresonant hump was distinct in the absence of clozapine or haloperidol andcompletely abolished in the presence of clozapine or haloperidol. The effect ofclozapine was found to be mimicked by sulpiride, a D2antagonist, but not bythe D1antagonist SCH-23390. So we can conclude that the D2antagonistsulpiride, but not the D1antagonist SCH-23390, blocked resonance of STNneurons.
Effect of sulpiride on the frequency preference and Ihof STN neurons
Large-amplitude ZAP current was injected to evoke action potentials atholding potentials of-70mV. Action potentials fired most readily as the ZAPinput swept through frequencies near fres. We also used single-frequency sinewave current to evoke firing at the same potentials. Neurons preferred to firewhen the input frequency was near fres. After application of sulpiride (1μM), thespikes evoked by both ZAP current and single-frequency sine waves currentarose readily at the lowest frequencies. Ihof STN neurons could be significantlyinhibited by sulpiride (1μM)(n=10; P <0.05, two-way ANOVA)
G-protein is involved in the effect of sulpiride on STN neurons.
In order to test for involvement of G proteins in effect of sulpiride onmembrane resonance of STN neurons. we compared the voltage response toZAP current injection with patch pipettes that contained either0.5mM GDP-β-Sor GTP-γ-S in the absence or presence of sulpiride. When the pipette solutioncontained the non-hydrolyzable G-protein inhibitor GDP-β-S and the ACSF donot contained the sulpiride, the resonant hump was completely abolished. Incontrast, when the pipette solution contained the GTP analogue GTP-γ-S and theACSF contained the sulpiride, the resonant hump was distinct. On the otherhand, similar to that on resonance, the effect of sulpiride on frequencypreference of STN neurons firing was mimicked in the presence of GDP-β-S inthe pipette solution, and was completely abolished in the presence of GTP-γ-S inthe pipette solution. These data suggest that G-protein is involved in effect ofsulpiride on membrane resonance and frequency preference of STN neurons.
Conclusion
There is a θ-frequency resonance in STN neurons. It is mediated by Ih.The resonance characteristics are temperature-and voltage-dependent. Theresonance mediates a frequency-selective coupling between inputs and firing.The D2antagonist sulpiride, but not the D1antagonist SCH-23390, blockedresonance and Ihof STN neurons. G-protein-coupled D2-like receptor isinvolved in the effect of sulpiride on STN neurons.
大脑是一个高度分布式系统，不同感知信息在大脑的不同脑区得到处理和并行执行，但并没有一个统一的协调中心负责管理不同脑区功能的协调。大脑的同步振荡活动被认为是捆绑一些空间上分隔，但又彼此相关的神经信息的机制之一，可协助大脑实现多脑区的协同工作。目前普遍认为神经元共振是神经网络振荡活动的重要基础。现已发现皮层和海马等部位神经元均存在共振现象，并证实这些细胞的共振参与了振荡节律的形成，具有重要生理功能。但对基底节（BG）各核团神经元共振特性的研究还处于空白状态，研究BG各核团神经元的共振及其机制，有可能帮助我们深入认识BG系统调节运动功能的电生理机制。
帕金森病（PD）等病理条件下，BG的异常同步振荡可通过神经投射通路影响大脑皮层，导致皮层感觉运动区活动异常，从而错误地捆绑了多脑区的运动信息，造成本该协同工作的肌肉群发生紊乱，导致相应的临床症状。目前，BG-皮层环路的异常同步振荡已成为PD的新病理机制，但发生异常振荡的机理仍不清。神经元共振是神经网络振荡活动的重要基础，故研究BG各核团神经元的共振现象及其和PD的关系意义重大，有可能在PD发生的电生理机制方面有所突破。
丘脑底核（STN）在PD的形成发展过程中起了重要作用，是临床DBS治疗PD的主要靶核之一。目前已证实黑质致密部和STN间存在直接的多巴胺能纤维联系，多巴胺可通过STN神经元表面的多巴胺受体直接作用于其神经元。故本课题首先选取STN作为研究对象，研究其共振现象及机制，并深入研究该神经元共振和多巴胺受体的关系。实验目的
（1）研究STN神经元是否有共振现象并研究其常规特性；
（2）探索STN神经元共振的离子机制；
（3）分别研究多巴胺D1、D2受体阻断剂对STN神经元共振特性的影响及其和超极化激活的阳离子流（Ih）的关系；
（4）初步探索多巴胺受体阻断剂影响STN神经元共振的信号转导途径。
实验方法
（1）脑片准备及钳制细胞
异氟烷吸入麻醉后断头处死大鼠（13-18天，雄性），迅速取脑，置于予充混合氧（95%O_2，5%CO_2）的冰浴人工脑脊液（ACSF）中，振动切片机切取含STN的脑片（350-400μm），在ACSF中孵育（34℃）1小时，以恢复脑片状态，将脑片移至记录浴槽，用氧饱和的ACSF持续灌流(2ml/min)。开启浴槽加热系统，使脑片温度维持在34℃。镜下定位核团并选取活性较好的细胞，常规钳制细胞形成全细胞模式，所用玻璃微电极电阻3-7MΩ。让细胞恢复约5分钟后，利用细胞的电生理特征鉴定细胞并测试细胞膜电位、动作电位等常规参数，选择串联电阻在10-20MΩ，静息电位负于-55mV，同时动作电位超射较好的神经元进行实验。
（2）神经元共振特性测试
在全细胞电流钳模式下，先用直流电将细胞钳制于目标电压（-50mV，-60mV，-70mV，-80mV及-90mV），通过记录电极给予细胞一个振幅固定、频率随时间线性增大的正弦电流（ZAP）刺激，记录神经元的电压反应。共振表现为神经元膜电压在某个特定的频段出现一个可重复的凸起共振峰，共振峰所对应的频率即为细胞的共振频率(f_(res))。为了量化共振的强度，将共振峰的阻抗值与0.5Hz对应的阻抗值的比值作为衡量共振强度的指标，称为Q值。调整ZAP电流强度使其引起的电压反应峰峰值控制在±10mV以内，以免诱发动作电位，必要时可适当使用河豚毒素（TTX）。为了方便测量f_(res)及Q值，将记录到的电压反应和输入的ZAP电流进行快速傅立叶变换(FFT)，计算阻抗值(Z)，公式为： Z=FFT(V)/FFT(I)，绘制阻抗曲线，在阻抗曲线上很容易读出f_(res)并计算出Q值。为了排除刺激的时间依赖性对细胞共振峰的影响，给予反向ZAP电流（时程20s，频率18-0Hz）刺激，观察细胞的电压反应与正常ZAP刺激结果是否一致。
（3）神经元放电的频率选择性测试
在全细胞电流钳模式下，先用直流电将细胞钳制于目标电压（-70mV），通过调节增益水平逐渐加大ZAP电流的幅度，直至刚刚出现动作电位，观察细胞放电所对应的频段。为了排除放电的时间及波形依赖性，换一种刺激方式，给予不同频率的等幅恒频的正弦电流刺激，同法观察细胞的优先放电频率。
（4）神经元I_h的记录
钳制细胞形成全细胞模式并待细胞状态稳定后，在全细胞电压钳模式下，给予一串超极化step电压刺激，记录膜电流，I_h表现为一缓慢激活的内向电流。
（5）Ih在STN神经元阈下共振及放电频率选择性中的作用
在外液中给予I_h特异性阻断剂ZD7288(20μM)，观察给药前后STN神经元阈下共振及放电频率选择性的变化。
（6）不同多巴胺受体阻断剂对STN神经元共振的影响
①分别给予氯氮平（Clozapine，50μM）、氟哌啶醇（Haloperidol，30μM）、SCH-23390(1μM)、舒必利（Sulpiride，1μM）等不同亚型多巴胺受体的阻断剂，观察给药前后STN神经元共振特性的变化，研究其对STN神经元共振特性的影响。
②前面实验证实D2受体特异性阻断剂Sulpiride可阻断STN神经元的共振现象，但D1受体特异性阻断剂SCH-23390对共振无显著影响。故我们进一步研究Sulpiride对Ih的影响，探索其影响共振的离子机制，并研究其对STN神经元放电频率选择性的影响。
（7）Sulpiride影响STN神经元的信号转导途径初探
①按下表分组、加药（n=10）
②主要观察指标有：神经元阈下共振特性、神经元放电的频率选择性。钳制细胞形成全细胞模式后等20min左右，待GDP-β-S、GTP-γ-S、GTP等药物扩散至细胞内、有效作用于细胞后再开始实验，方法同前。
（8）所记录神经元的定位及形态学观察
随机抽取部分神经元(15个)行荧光黄标记染色，用含荧光黄的电极内液(1.5‰)在避光条件下钳制细胞，常规行电生理记录，留置电极30min以上，荧光光源下观察神经元形态，确认染色充分后，缓慢退出电极。将脑片切掉一角并记录，以标记正反面，在4%多聚甲醛中避光固定。将甲醛固定过的脑片铺于载玻片上，有标记细胞的一面朝上，荧光封片液、指甲油封片，激光共聚焦显微镜下观察并拍照。
（9）统计学处理
采用SPSS13.0进行分析，实验结果用均值±标准差（x±SD）表示。各组间的数据用One-way ANOVA或Two-way ANOVA进行比较，两两之间用LSD方法进行比较，两组间均数的比较采用t检验，如P <0.05则认为有统计学差异。
实验结果
（1）STN神经元的形态学定位及电生理鉴定
激光共聚焦显微镜下观察荧光黄标记的STN神经元，低倍镜下证实实验所选细胞均位于STN，高倍镜下可见神经元胞体、轴突清晰可见，形态符合STN神经元特征。电压钳下给予一串超极化Step电压刺激，可见明显Ih及尾电流。电流钳下给予一串外向电流刺激，使细胞超极化，记录细胞的电压反应，其主要特征有刺激起始段的Sag、刺激末伴随动作电位的反跳去极化及动作电位后的平台电位，符合STN神经元的电生理特性。
（2）STN神经元的阈下膜共振
在34℃条件下，将细胞钳制于-70mV水平，给予ZAP电流刺激，记录到的电压反应呈梭形，在2.5-3Hz频段，电压反应显著增强，证实细胞存在共振现象。将数据做快速傅立叶变换，绘制阻抗曲线，可见该细胞fres亦在2.5-3Hz频段。统计分析示神经元共振的fres和Q值分别为2.67±0.29Hz和1.093±0.0202(n=8)。反向ZAP电流刺激产生的电压反应较上述结果无明显差异(P>0.05, n=6)。
（3）STN神经元共振的温度依赖性
将细胞钳制于-70mV水平，在30℃、34℃、38℃三个不同温度水平观察STN神经元的共振特性。神经元fres随温度升高而升高，统计数据示：神经元fres在30℃、34℃、38℃条件下分别为1.99±0.36Hz、2.67±0.29Hz、4.07±0.40Hz，经单因素方差分析统计三组间统计学差异显著(P <0.05，n=8)。
（4）STN神经元共振的电压依赖性
在-60mV到-90mV水平神经元对ZAP电流的电压反应呈梭形，共振明显。fres随电压的超极化而升高，可从-60mV时的2.01±0.25Hz升高到-90mV时的3.09±0.32Hz，经方差分析统计各组间统计学差异显著(P <0.05，n=10)。Q值亦有显著电压依赖性，-60mV、-90mV时其水平较低，-70mV条件下Q值最大，达1.092±0.021。-50mV条件下神经元对ZAP电流的电压反应呈喇叭口状，无明显共振现象。
（5）STN神经元放电的频率选择性
给予ZAP电流证实STN神经元存在阈下共振后，逐渐加大ZAP电流的幅度，直至刚刚出现动作电位，发现细胞最先出现放电的频段和其fres一致。换一种刺激方式，给予不同频率的等幅恒频的正弦电流刺激，结果亦证实细胞最先出现放电的频段与fres一致。
（6）抑制Ih可阻断STN神经元的阈下共振及其放电频率选择性
在全细胞电压钳模式下， Ih表现为一缓慢激活的内向电流，在各电位水平均可被ZD7288显著抑制（P <0.05，n=12）。生理条件下神经元存在共振现象，放电的频率选择性明显，给予ZD7288阻断Ih后，记录的电压反应变为喇叭口状，共振消失、神经元放电的频率选择性也同时消失。统计分析显示ZD7288消除共振及放电频率选择性的有效率均可达100%(n=10)。
（7）多巴胺受体阻断剂对STN神经元阈下共振的影响
外液中加入Clozapine (50μM)或Haloperidol (30μM)同时阻断D1、D2受体后，神经元对ZAP的电压反应呈喇叭口状，共振现象被消除。外液中加入Sulpiride单纯阻断D2受体效果类似。统计分析显示Clozapine、Haloperidol及Sulpiride消除共振的有效率均可达100%(n=10)。外液中加入SCH-23390单纯阻断D1受体，STN神经元阈下共振未见明显改变（P>0.05，n=10）。
（8）Sulpiride对STN神经元放电频率选择性的影响
在34℃、-70mV条件下，给药前，细胞最先出现放电的频段与细胞的fres一致。外液中加入Sulpiride (1μM)阻断D2受体后，细胞在最低频率处首先出现放电，与ZD7288的效果类似。更换刺激方式为不同频率的等幅恒频的正弦电流刺激，结果类似。上述两种方法均证实Sulpiride阻断STN神经元放电频率选择性的有效率达100%(n=10)。
（9）Sulpiride对STN神经元Ih的影响
给予Sulpiride (1μM)阻断D2受体，各电位水平的Ih均被显著抑制(P<0.05,n=10)，与ZD7288效果类似。
（10）Sulpiride通过G蛋白偶联受体影响STN神经元共振及其放电频率选择性
正常对照组神经元对ZAP电流的电压反应呈梭形，共振现象明显，在其fres附近频段最易出现放电，内液中加入GDP-β-S阻断G蛋白偶联受体（GPCRs）可模拟Sulpiride的作用，神经元共振、放电频率选择性均被抑制。内液中加入GTP-γ-S激动GPCRs后，可阻断Sulpiride的作用。统计分析显示：Sulpiride、GDP-β-S完全消除共振的有效率均达100%(n=10)，GTP-γ-S阻断Sulpiride作用的有效率亦达100%(n=10)。该结果提示，Sulpiride通过阻断多巴胺对GPCRs的作用实现其对STN神经元共振的影响。结论
（1）STN神经元存在共振现象，该现象具有温度依赖性及电压依赖性；
（2）Ih介导了STN神经元的共振；
（3）D2受体特异性阻断剂（Sulpiride）可阻断STN神经元的共振现象，但D1受体特异性阻断剂(SCH-23390)对上述共振现象无显著影响；
（4）Sulpiride通过抑制Ih阻断STN神经元的共振现象；
（5）Sulpiride通过阻断多巴胺对GPCRs的作用实现其对STN神经元共振的影响。
The realization that different behavioral and perceptual states of the brainare associated with different brain rhythms has sparked growing interest in theoscillatory behavior of neurons. With the emergence of new techniques, studieshave shown that temporally and spatially organized activity among distributedneuronal populations often takes the form of synchronous oscillations. Thesesynchronous oscillations may evolve to dynamically control the grouping ofneurons into organized assemblies. Recent research has revealed a closeassociation between electrical oscillations and resonance in neurons. It has beensuggested that resonance underlies oscillatory behavior in neural networks.Resonance is the ability of neurons to respond selectively to inputs at preferredfrequencies, which can serve as a substrate for coordinating network activityaround a particular frequency. Resonance dramatically affects the ability ofnetworks to produce oscillatory patterns of activity. Gimbarzevsky has studiedthe property of resonance since the1980s. There is accumulating evidence thatneurons in different brain areas have prominent resonant properties, such as inthe neocortical cortex, entorhinal cortex, prefrontal cortex, hippocampus and thalamus.
Studies in recent years have shown that there are several types ofoscillatory phenomena in the basal ganglia. Investigations in humans andanimals have demonstrated the existence of a range of oscillatory activity in thevarious nuclei of the basal ganglia, and the oscillatory activity is believed toplay an important role in both the physiology and pathophysiology of thissystem. Studies using electroencephalography and magnetoencephalographyalso support the theory that basal ganglia engage in synchronous oscillatoryactivity. However, little is known about the actual mechanisms underlying thegeneration of neuronal oscillatory activity in basal ganglia. Now, it is possible toimage the resonance underlying oscillatory behavior in basal ganglia.
A critical role of the subthalamic nucleus (STN) in the control ofmovement has been proposed based in part on the observation that its lesion orhigh-frequency electrical stimulation is highly effective in alleviating theakinesia, rigidity and tremor of Parkinson’s disease (PD). PD, which is causedby the progressive loss of dopaminergic neurons in the substantia nigra, isassociated with hyperactivity of neurons in the STN as detected by metabolicand electrophysiological studies in parkinsonian patients and in parkinsonianrats and monkeys. In this paper, we studied the resonance characteristics of STNneurons and its correlation with the dopamine receptor using whole-cellpatch-clamp recordings in rat brain slices.
Methods
Tissue preparation
Coronal slices containing STN (350-400μm thick) were prepared frommale young (13-18days of age) Sprague-Dawley rats as described previously.Rats were euthanized with isoflurane anesthesia in accordance with the Principles of Medical Laboratory Animal Care issued by the NationalMinistry of Health. The brain was removed rapidly and slices were cut with avibratome in ice-cold artificial cerebrospinal fluid (ACSF) solution of thefollowing composition (in mM): NaCl (126), KCl (2.5), CaCl2(2.4), MgCl2(1.2), NaH2PO4(1.2), NaHCO3(19), and glucose (11), gassed with95%O2and5%CO2(pH7.35-7.45). The slices were incubated in95%O2/5%CO2-equilibrated ACSF and kept at34°C for at least one hour. A slice was thenplaced on the recording chamber and submerged in a continuously flowingACSF (2ml/min) gassed with95%O2and5%CO2and heated to34°C, exceptin a few experiments performed to test the temperature dependence of resonance,when the medium was heated from30°C to34°C and38°C. Using a10×objective for visual guidance, STN was readily identified as ovoid gray matterimmediately medial to the cerebral peduncle.
Electrophysiological recording
In some experiments, tetrodotoxin (TTX,1μM) was applied to blockaction potentials. Individual neurons were visualized (40×water immersionobjective) using differential interference contrast infra-red microscopy. STNneurons were not consciously selected on the basis of somatic size or shape.Whole-cell recordings were made with borosilicate glass pipettes of3-7MΩresistance containing (in mM): potassium gluconate (125), NaCl (10), MgCl2(2.0) CaCl2(1.0), EGTA (10), HEPES (10), ATP (2.0), GTP (0.3)(pH7.3,osmolarity285-295). Recorded electrical signals were amplified with anAxopatch-700B amplifier. Data were acquired using a computer with thedigidata1440A acquisition system. All potentials were corrected online for thejunction potential using the multiclamp700B commander software. Onlyneurons with a stable resting membrane potential more negative than-55mV and stable action potential amplitudes were used for recording.
Recording and analysis of electrical resonance
The impedance amplitude profile (ZAP) method was used to characterizethe electrical resonance behavior of the neurons as previously described. TheZAP current waveform was a swept-sine-wave current with constant amplitudeand linearly increasing frequency (0-18Hz for20s) generated by computer. Adirect current was firstly used to hold neurons near a desired membranepotential, then the ZAP current was injected, and the resulting voltage responsewas recorded. The amplitude of the ZAP current was adjusted to keep theperturbation of the membrane potential close to±10mV (peak to peak) to avoidfiring of action potentials. Resonance was manifest as a distinct andreproducible peak in the voltage response at a certain frequency. The Q value,the ratio of the impedance at the resonance peak to the impedance at0.5Hz, wasused to quantify the strength of the resonance. To plot the magnitude of the cellimpedance as a function of frequency, data were transformed into the frequencydomain through fast Fourier transformation (FFT). Impedance (Z) is a complexnumber defined as Z=FFT (V)/FFT (I). The magnitude of impedance wasplotted against frequency to give an impedance curve. The resonance frequency(fres) could be read at the peak of the impedance profile.
Morphology of electrophysiologically characterized neurons
Some STN neurons were labeled by adding Lucifer Yellow (0.15%) in thepipette solutions. During the course of recording, Lucifer Yellow diffused fromthe pipette into the cell. A period of30min of simple diffusion was sufficient toobtain complete labeling. Stained neurons were visualized with a laser scanningconfocal microscope.
Drug application
All drugs were dissolved in aqueous stock solutions with the exceptions ofclozapine and haloperidol, which were dissolved in dimethyl sulfoxide, andsulpiride which was dissolved in dehydrated alcohol. Each stock solution wasdiluted at least1:1000in perfusate immediately prior to its use. Dimethylsulfoxide and dehydrated alcohol, diluted1:1000in ACSF, had no side effect.Most drugs were applied by superfusion. Approximately30s were required forthe drug solution to enter the recording chamber; this delay was due to passageof the perfusate through a heat exchanger. Complete exchange of the bathsolution occurred within3min. In some experiments, drugs (Lucifer Yellow,GDP-β-S and GTP-γ-S) were added directly to the pipette internal solution fromwhich they diffused spontaneously into the cell.
Results
Membrane resonance of STN neurons
STN neurons were characterized by obvious voltage sags in response to aseries of hyperpolarizing current injections and anodal break rebounddepolarization. Most of the STN neurons tested exhibited membrane resonance,which manifested as a distinct and reproducible hump in the voltage response toZAP current injection. This resonant hump occurred at2.67±0.29Hz at34°Cwhen the holding potential was at-70mV, and the Q value was1.093±0.0202at the same condition.To test whether the resonant humps reflectedfrequency-dependent as opposed to time-dependent membrane properties, aninverted ZAP current with the same amplitude and linearly decreasing frequency(from18to0Hz for20s) was injected. The fresand Q values yielded from theinverted protocol were2.64±0.31and1.090±0.0213, respectively (n=6). Thevalues were similar to those generated from the standard ZAP protocol in the same neurons (P>0.05and0.05, paired t-test), suggesting that the resonancedid not depend on the input waveform.
Temperature dependence of resonance in STN neurons
To test the temperature dependence of the resonance, the temperature ofperfusion solutions in the recording chamber was raised from30°C to34°C and38°C at a holding potential of-70mV. The resonant hump shifting as thetemperature rises. The fresshifted from1.99±0.36Hz at30°C, to2.67±0.29Hz, and4.07±0.40Hz at34and38°C, respectively. Higher temperaturessignificantly shifted the resonant hump to a higher frequency (n=8; P <0.05,one-way ANOVA).
Voltage dependence of resonance in STN neurons
To determine the voltage dependence of the electrical resonance, cells wereheld at different membrane potentials from-50to-90mV (10mV increment).TTX was added to perfusion solutions to avoid depolarization-evokedspikes.The voltage responses to the ZAP current injections exhibited distinctmembrane resonance at holding potentials from-60to-90mV. At-50mV, nosignificant resonance was observed. Both the fresand Q values werevoltage-dependent. The freswas2.01±0.25Hz at-60mV, and increased to3.09±0.32Hz at-90mV (n=10). The Q value was1.009±0.015at-50mV,suggesting a very weak resonance occurs at this potential in a handful ofneurons. The Q value reached its peak of1.092±0.021at-70mV (n=10).These results indicate voltage-dependent membrane resonance of STN neurons.
Hyperpolarization-activated cation current (Ih) in STN neurons and itsrole in resonance
STN neurons exhibited significant Ihin voltage-clamp mode or distinctvoltage sags in response to hyperpolarizing current injections in current-clamp mode. Ihand voltage sags could be completely blocked by ZD7288(20μM)(n=12; P <0.05, two-way ANOVA). Therefore, ZD7288was used to test the roleof Ihin the resonance of STN neurons. The ZAP currents were injected beforeand after application of20μM ZD7288at-70mV. The resonant hump wasdistinct in the absence of ZD7288and completely abolished in the presence ofZD7288. The results suggest that Ihis essential for the resonance in STNneurons.
Resonance-mediated frequency-selective coupling of inputs and firing
Large-amplitude ZAP current was injected to evoke action potentials atholding potentials of-70mV. Action potentials fired most readily as the ZAPinput swept through frequencies near fres. We also used single-frequency sinewave current to evoke firing at the same potentials. Neurons preferred to firewhen the input frequency was near fres. After application of ZD7288(20μM),the spikes evoked by both ZAP current and single-frequency sine waves currentarose readily at the lowest frequencies. In summary, the frequency preference ofneurons resulted in a preferential coupling at frequencies near fresbetween inputsand firing, which could be blocked by ZD7288.
Dopamine receptor pharmacology
The ZAP currents were injected before and after application of clozapine(50μM) or haloperidol (30μM), the effective antagonist of D1and D2. Theresonant hump was distinct in the absence of clozapine or haloperidol andcompletely abolished in the presence of clozapine or haloperidol. The effect ofclozapine was found to be mimicked by sulpiride, a D2antagonist, but not bythe D1antagonist SCH-23390. So we can conclude that the D2antagonistsulpiride, but not the D1antagonist SCH-23390, blocked resonance of STNneurons.
Effect of sulpiride on the frequency preference and Ihof STN neurons
Large-amplitude ZAP current was injected to evoke action potentials atholding potentials of-70mV. Action potentials fired most readily as the ZAPinput swept through frequencies near fres. We also used single-frequency sinewave current to evoke firing at the same potentials. Neurons preferred to firewhen the input frequency was near fres. After application of sulpiride (1μM), thespikes evoked by both ZAP current and single-frequency sine waves currentarose readily at the lowest frequencies. Ihof STN neurons could be significantlyinhibited by sulpiride (1μM)(n=10; P <0.05, two-way ANOVA)
G-protein is involved in the effect of sulpiride on STN neurons.
In order to test for involvement of G proteins in effect of sulpiride onmembrane resonance of STN neurons. we compared the voltage response toZAP current injection with patch pipettes that contained either0.5mM GDP-β-Sor GTP-γ-S in the absence or presence of sulpiride. When the pipette solutioncontained the non-hydrolyzable G-protein inhibitor GDP-β-S and the ACSF donot contained the sulpiride, the resonant hump was completely abolished. Incontrast, when the pipette solution contained the GTP analogue GTP-γ-S and theACSF contained the sulpiride, the resonant hump was distinct. On the otherhand, similar to that on resonance, the effect of sulpiride on frequencypreference of STN neurons firing was mimicked in the presence of GDP-β-S inthe pipette solution, and was completely abolished in the presence of GTP-γ-S inthe pipette solution. These data suggest that G-protein is involved in effect ofsulpiride on membrane resonance and frequency preference of STN neurons.
Conclusion
There is a θ-frequency resonance in STN neurons. It is mediated by Ih.The resonance characteristics are temperature-and voltage-dependent. Theresonance mediates a frequency-selective coupling between inputs and firing.The D2antagonist sulpiride, but not the D1antagonist SCH-23390, blockedresonance and Ihof STN neurons. G-protein-coupled D2-like receptor isinvolved in the effect of sulpiride on STN neurons.
引文
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