PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

黑质和基底神经节的药理学和生理学

• 批准号: 6290613
• 负责人: JUDITH RICHMOND WALTERS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290613
• 关键词: 6 hydroxydopamine; Parkinson's disease; basal ganglia; brain electrical activity; brain mapping; corpus striatum; disease /disorder model; dopamine agonists; dopamine antagonists; dopamine receptor; electrophysiology; experimental brain lesion; laboratory rat; neural information processing; neuropharmacology; neurophysiology; receptor sensitivity; single cell analysis; substantia nigra; transcription factor

1)Previous studies from this laboratory have demonstrated periodic multisecond (2-60 s) oscillations in firing rate in the basal ganglia in vivo, which are modulated by a number of directly-acting dopamine receptor agonists. In FY 99 we have found that the stimulants d- amphetamine, cocaine and methylphenidate also increase the speed of multisecond oscillations in globus pallidus unit activity in awake, immobilized rats. The similarity of effects of stimulants and direct dopamine agonists (and the reversals by haloperidol) suggests that stimulant modulation of multisecond periodicities in the globus pallidus is mediated mainly via dopamine release. Changes in multisecond patterning of central activity may relate to the motor and cognitive effects of d-amphetamine, cocaine and methylphenidate.2)Current models of basal ganglia function make predictions about how DA affects the activity of the basal ganglia output nuclei, the EPN and the substantia nigra reticulata. However, few studies have examined the effects of DA agonists on EPN firing activity in rodents. We found unexpected effects of iv apomorphine on EPN activity in intact rats: apomorphine increased firing rates of most EPN neurons, and increased the strength and oscillatory frequency of multisecond periodicities which were present in most spike trains. Both D1 and D2 receptors appear to be involved in control of oscillatory strength. The data also show that nigrostriatal lesion causes supersensitivity of the D1 receptors that influence firing rate as well as slow oscillations in the EPN. DA-mediated behavioral activation is not necessarily related to net reductions in EPN firing rate, as predicted by many models.3)As coordination of neuronal activity is thought to relate to function in motor circuitry, experiments were performed to assess the coincidence of these multisecond oscillations in neuronal pairs within the basal ganglia. Results show that this multisecond oscillatory activity is synchronized to a substantial extent, in the sense that pairs of neurons recorded simultaneously in different areas of the basal ganglia and in opposite hemispheres were found to be oscillating with identical frequencies. enhanced coincidence, increased regularity and change in oscillatory period were induced by dopamine agonists. Coincident observations were also observed in the globus pallidus of awake freely moving rats. These observations suggest that the basal ganglia nuclei are connected by distributed networks which regulate firing rate on multisecond time scales. Synchronized periodic oscillations in firing rate may serve to coordinate activity between the basal ganglia and cortical structures. Effects of dopamine agonists could reflect dopamine-mediated changes in the functional connectivity of related circuits. - substantia nigra subthalamic nucleus neurophysiology D1 D2 striatum globus pallidus dopamine basal ganglia Parkinson's disease

1）该实验室的先前研究表明，体内基底神经节的发射速率周期性的多秒（2-60 s）振荡，这受到许多直接作用的多巴胺受体激动剂的调节。在99财年中，我们发现刺激剂D-苯丙胺，可卡因和甲化酯也会增加在醒着，固定的大鼠中的球pallidus单位活性中多秒振荡的速度。刺激剂和直接多巴胺激动剂（以及氟哌啶醇的逆转）的作用相似性表明，pallidus多秒周期性的刺激性调节主要是通过多巴胺释放介导的。中央活动多秒模式的变化可能与D-苯丙胺，可卡因和甲基苯甲酸酯的运动和认知作用有关。2）基底神经节功能的当前模型可以预测DA如何影响基底神经节输出核的活性，EPN和EPNIA NIGRA NIGRA RETICICULATA。但是，很少有研究检查了DA激动剂对啮齿动物中EPN发射活性的影响。我们发现静脉反寄养对完整大鼠EPN活性的意外作用：丙氨酸增加了大多数EPN神经元的发射速率，并提高了大多数尖峰列车中存在的多秒周期性的强度和振荡频率。 D1和D2受体似乎都与控制振荡强度有关。数据还表明，骨纹状体病变会导致D1受体的超敏反应，从而影响发射速率以及EPN中缓慢的振荡。 DA介导的行为激活不一定与许多模型所预测的EPN发射速率的净降低有关。3）由于神经元活动的协调与运动电路中的功能有关，因此进行了实验以评估基底神经节内神经元对的这些多相位振荡的一致性。结果表明，这种多秒振荡活性在很大程度上被同步，因为发现在基底神经节的不同区域同时记录的神经元和相对半球的神经元对具有相同的频率振荡。多巴胺激动剂诱导了增强的巧合，规律性的提高和振荡期的变化。在醒着的自由移动大鼠的球形帕利德斯中，还观察到了一致的观察结果。这些观察结果表明，基底神经节核是通过分布式网络连接的，分布式网络在多秒时间尺度上调节发射速率。发射速率的同步周期性振荡可能有助于协调基底神经节和皮质结构之间的活性。多巴胺激动剂的作用可能反映了相关电路功能连通性的多巴胺介导的变化。 - 黑质Nigra丘脑核神经生理学D1 D2纹状体Globus pallidus pallidus pallidus dopamine basal神经节帕金森氏病