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）本实验室之前的研究表明，体内基底神经节的放电频率存在周期性的多秒（2-60秒）振荡，这是由许多直接作用的多巴胺受体激动剂调节的。在 99 财年，我们发现兴奋剂 d-苯丙胺、可卡因和哌醋甲酯也会增加清醒、固定大鼠的苍白球单位活动的多秒振荡速度。兴奋剂和直接多巴胺激动剂作用的相似性（以及氟哌啶醇的逆转）表明，兴奋剂对苍白球多秒周期性的调节主要是通过多巴胺释放介导的。中枢活动的多秒模式变化可能与 d-苯丙胺、可卡因和哌醋甲酯的运动和认知作用有关。2) 当前的基底神经节功能模型可以预测 DA 如何影响基底神经节输出核、EPN 和黑质网状结构。然而，很少有研究探讨 DA 激动剂对啮齿动物 EPN 放电活动的影响。我们发现静脉注射阿扑吗啡对完整大鼠的 EPN 活性有意想不到的影响：阿扑吗啡增加了大多数 EPN 神经元的放电率，并增加了大多数尖峰序列中存在的多秒周期性的强度和振荡频率。 D1 和 D2 受体似乎都参与振荡强度的控制。数据还表明，黑质纹状体损伤会导致 D1 受体超敏，从而影响放电率以及 EPN 的缓慢振荡。正如许多模型预测的那样，DA 介导的行为激活不一定与 EPN 放电率的净降低相关。3) 由于神经元活动的协调被认为与运动回路的功能相关，因此进行了实验来评估这些多秒的一致性基底神经节内神经元对的振荡。结果表明，这种多秒振荡活动在很大程度上是同步的，即在基底神经节的不同区域和相对半球同时记录的成对神经元被发现以相同的频率振荡。多巴胺激动剂诱导了重合性的增强、规律性的增加和振荡周期的变化。在清醒、自由活动的大鼠的苍白球中也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通过分布式网络连接，该网络在多秒时间尺度上调节放电率。放电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动。多巴胺激动剂的作用可以反映多巴胺介导的相关回路功能连接的变化。 - 黑质 丘脑底核 神经生理学 D1 D2 纹状体 苍白球 多巴胺 基底神经节 帕金森病