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)本实验室以前的研究表明，活体基底神经节的放电频率存在周期性的多秒(2-60 S)振荡，这种振荡受许多直接作用的多巴胺受体激动剂的调节。在1999财年，我们发现兴奋剂d-苯丙胺、可卡因和哌醋甲酯也提高了清醒的、被束缚的大鼠苍白球单位活动的多秒振荡速度。刺激剂和直接多巴胺激动剂(以及氟哌啶醇逆转)作用的相似性表明，刺激对苍白球多秒周期的调制主要是通过多巴胺释放来实现的。中枢活动多秒模式的改变可能与D-苯丙胺、可卡因和甲基苯丙胺的运动和认知效应有关。2)现有的基底节功能模型预测DA如何影响基底节输出核团、EPN和黑质网状核的活动。然而，很少有研究考察DA激动剂对啮齿动物EPN放电活动的影响。我们发现，静脉注射阿朴吗啡对正常大鼠的EPN活动有意想不到的影响：阿朴吗啡增加了大多数EPN神经元的放电频率，并增加了大多数棘波序列中存在的多秒周期的强度和振荡频率。D1和D2受体似乎都参与了振荡强度的控制。数据还表明，黑质纹状体损毁导致D1受体的超敏，从而影响EPN的放电率和缓慢的振荡。DA介导的行为激活并不一定像许多模型预测的那样与EPN放电率的净减少有关。3)由于神经元活动的协调被认为与运动回路中的功能有关，因此我们进行了实验，以评估基底节内神经元对中这些多秒振荡的一致性。结果表明，这种多秒振荡活动在很大程度上是同步的，即同时记录在基底节不同区域和相对半球的成对神经元以相同的频率振荡。多巴胺激动剂可引起符合增强、规律性增加和振荡周期的改变。在清醒自由活动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，基底节核由分布式网络连接，这些网络在多秒的时间尺度上调节放电率。放电频率的同步周期性振荡可能有助于协调基底节和皮质结构之间的活动。多巴胺激动剂的作用可能反映了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、基底节、帕金森氏病