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)本实验室先前的研究已经证明了体内基底神经节放电率的周期性多秒（2-60 s）振荡，这是由许多直接作用的多巴胺受体激动剂调节的。在1999财政年度，我们发现兴奋剂d-安非他明、可卡因和哌醋甲酯也增加了清醒、固定大鼠苍白球单位活动的多秒振荡速度。兴奋剂和直接多巴胺受体激动剂（和氟哌啶醇的逆转）的相似性的影响表明，兴奋剂调制的多秒周期性苍白球介导的主要是通过多巴胺的释放。中枢活动的多秒模式变化可能与d-苯丙胺、可卡因和哌甲酯的运动和认知效应有关。2）基底神经节功能的当前模型预测DA如何影响基底神经节输出核、EPN和黑质网状核的活动。然而，很少有研究探讨DA受体激动剂对啮齿动物EPN放电活动的影响。我们发现了意想不到的影响，iv阿扑吗啡对EPN活动在完整的大鼠：阿扑吗啡增加大多数EPN神经元的放电率，并增加的强度和振荡频率的多秒周期，这是目前在大多数穗列车。D1和D2受体似乎都参与控制振荡强度。这些数据还表明，黑质纹状体损伤导致D1受体的超敏感性，影响放电率以及EPN的缓慢振荡。DA介导的行为激活不一定与EPN放电率的净减少相关，正如许多模型所预测的那样。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，因此进行了实验以评估基底神经节内神经元对中这些多秒振荡的一致性。结果表明，这种多秒振荡活动是同步的，在很大程度上，在这个意义上说，对神经元记录同时在不同地区的基底神经节和在相对的半球被发现振荡相同的频率。多巴胺受体激动剂可引起振荡周期的一致性增强、规律性增加和变化。在清醒的自由活动大鼠的苍白球中也观察到一致的观察结果。这些观察结果表明，基底神经节核连接的分布式网络，调节放电率在多秒的时间尺度。放电频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节帕金森病