THE PRIMATE SUBTHALAMIC NUCLEUS .2. NEURONAL-ACTIVITY IN THE MPTP MODEL OF PARKINSONISM
THE PRIMATE SUBTHALAMIC NUCLEUS .2. NEURONAL-ACTIVITY IN THE MPTP MODEL OF PARKINSONISM
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DOI：
10.1152/jn.1994.72.2.507
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发表时间：
1994-08-01
影响因子：
2.5
通讯作者：
DELONG, MR
中科院分区：
文献类型：
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作者：
BERGMAN, H;WICHMANN, T;DELONG, MR
1.在帕金森病猴的基底节对帕金森病主要运动体征的神经机制进行了研究。用1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)对三只非洲绿猴进行系统治疗，直到出现帕金森症状，包括动作迟缓、僵硬和显著的4至8赫兹震颤。记录MPTP处理前(STN，n=220个细胞；GPI，n=175个细胞)和MPTP处理后(STN，n=326个细胞；GPI，n=154个细胞)丘脑底核(STN)和苍白球内段(GPI)神经元的活动。STN的自发放电频率由治疗前的19+/-10个(SD)/S增加到治疗后的26+/-15个/S。将MPTP处理后记录到的STN神经元划分为节律性放电发生在4-8赫兹(自相关分析的定义)的神经元和没有4-8赫兹周期活动的神经元，发现4-8赫兹振荡神经元的放电率更显着增加。在GPI中，细胞平均放电率的总体变化在不同动物和行为状态之间是不一致的。然而，MPTP处理后具有4-8 Hz周期振荡活动的神经元亚群的平均放电频率显著高于处理前的所有神经元(从53个峰/S增加到76个峰/S，平均在猴子中)。在正常状态下，STN和GPI中爆发放电神经元的百分比(自相关分析)分别为69%和78%。经MPTP处理后，突发性放电的细胞比例分别增加到79%和%。同时，平均猝发持续时间缩短(STN由121+/-98缩短至81+/-99ms，GPI由213+/-120缩短至146+/-134ms)，而平均每个猝发的棘波数目无明显变化。MPTP处理(平均振荡频率分别为6.0和5.1 Hz)后，在STN和GPI的大量细胞内检测到与震颤高度相关的低频周期性振荡神经元活动。这些神经元的棘波序列的自相关图证实，周期振荡活动非常稳定。经MPTP处理后，STN中具有4~8赫兹周期活动的细胞比例从2%增加到16%，GPI中从0.6%增加到25%。MPTP后，以8~20赫兹(平均14.4赫兹，GPI 10.5赫兹)频率的周期性爆发放电的神经元也较多。这些神经元的自相关图显示出高度的抑制。MPTP处理后，STN中8-20赫兹振荡神经元的比例从0.7%增加到10%，GPI从0.6%增加到12%。在STN和GPI.8中，对肘部施加屈曲和伸展扭矩脉冲的阶段反应的平均幅度和持续时间在MPTP治疗后都有增加的趋势。细胞外记录的动作电位时程随着MPTP处理的增加而显著延长(STN从0.67±-0.1增加到0.81+/-0.2ms，GPI从0.73+/-0.1增加到0.8+/-0.1ms)。酪氨酸羟化酶免疫组织化学显示，MPTP处理的猕猴纹状体以及STN和GPI几乎没有多巴胺能终末。这些结果支持一种模型，在该模型中，多巴胺能去神经支配基底节(可能包括纹状体外部位)导致STN和GPI的紧张和时相活动增加。GPI输出对丘脑皮质神经元的抑制作用增强可能最终导致动作迟钝和强直，而皮质-STN-GPI-丘脑回路的周期性振荡活动可能参与帕金森震颤的发生。
1. The neuronal mechanisms underlying the major motor signs of Parkinson's disease were studied in the basal ganglia of parkinsonian monkeys. Three African green monkeys were systemically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until parkinsonian signs, including akinesia, rigidity, and a prominent 4- to 8-Hz tremor, appeared. The activity of neurons in the subthalamic nucleus (STN) and in the internal segment of the globus pallidus (GPi) was recorded before (STN, n = 220 cells; GPi, n = 175 cells) and after MPTP treatment (STN, n = 326 cells; GPi, n = 154 cells).2. In STN the spontaneous firing rate was significantly increased from 19 +/- 10 (SD) spikes/s before to 26 +/- 15 spikes/s after MPTP treatment. Division of STN neurons recorded after MPTP treatment into cells with rhythmic bursts of discharge occurring at 4-8 Hz (as defined by autocorrelation analysis) and neurons without 4- to 8-Hz periodic activity revealed an even more prominent increase in the firing rate of the 4- to 8-Hz oscillatory neurons.3. In GPi overall changes in the average firing rate of cells were inconsistent between different animals and behavioral states. However, the average firing rate of the subpopulation of neurons with 4- to 8-Hz periodic oscillatory activity after treatment with MPTP was significantly increased over that of all neurons before MPTP treatment (from 53 to 76 spikes/s, averaged across monkeys).4. In the normal state the percentage of neurons with burst discharges (as defined by autocorrelation analysis) was 69% and 78% in STN and GPi, respectively. After MPTP treatment the percentage of cells that discharged in bursts was increased to 79% and 89%, respectively. At the same time the average burst duration decreased (from 121 +/- 98 to 81 +/- 99 ms in STN and from 213 +/- 120 to 146 +/- 134 ms in GPi) with no significant change in the average number of spikes per burst.5. Periodic oscillatory neuronal activity at low frequency, highly correlated with tremor, was detected in a large number of cells in STN and GPi after MPTP treatment (average oscillation frequency 6.0 and 5.1 Hz, respectively). The autocorrelograms of spike trains of these neurons confirm that the periodic oscillatory activity was very stable. The percentage of cells with 4- to 8-Hz periodic activity significantly increased from 2% to 16% in STN and from 0.6% to 25% in GPi with the MPTP treatment.6. Neurons discharging with periodic bursts at frequencies between 8 and 20 Hz (average 14.4 Hz in STN and 10.5 Hz in GPi) were also detected more often after MPTP. The autocorrelograms of these neurons showed a high degree of dampening. The percentage of neurons with 8- to 20-Hz oscillations significantly increased from 0.7% to 10% in STN and from 0.6% to 12% in GPi after MPTP treatment.7. The average magnitude and duration of phasic responses (increases and decrease in firing rate) to the application of flexion and extension torque pulses to the elbow tended to be increased after MPTP treatment in both STN and GPi.8. The duration of extracellularly recorded action potentials significantly increased with the MPTP treatment (from 0.67 +/- 0.1 to 0.81 +/- 0.2 ms in STN and from 0.73 +/- 0.1 to 0.8 +/- 0.1 ms in GPi).9. Tyrosine hydroxylase immunohistochemistry revealed that the striatum as well as STN and GPi of the MPTP-treated monkeys were virtually devoid of dopaminergic terminals.10. These results support a model in which dopaminergic denervation of the basal ganglia (possibly including extrastriatal sites) leads to increased tonic and phasic activity in STN and GPi. Increased inhibition of thalamocortical neurons by GPi output may eventually result in akinesia and rigidity, whereas periodic oscillatory activity in the cortico-STN-GPi-thalamic circuitry is possibly involved in the development of parkinsonian tremor.