Pharmacology And Physiology Of The Substantia Nigra And

黑质的药理学和生理学

• 批准号: 7143804
• 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/7143804
• 关键词: Huntington' s disease; Parkinson' s disease; anesthesia; attention deficit disorder; basal ganglia; brain electrical activity; corpus striatum; disease /disorder model; dopamine; dopamine agonists; dopamine antagonists; dopamine receptor; electrical potential; electroencephalography; electrophysiology; experimental brain lesion; hippocampus; laboratory rat; lenticular nucleus; motor cortex; neural information processing; neuropharmacology; neurophysiology; psychic activity level; receptor sensitivity; substantia nigra; subthalamus; transcranial magnetic stimulation

The dopamine system is critical to appropriate information processing in the basal ganglia. Dysfunction of this neuronal system has been implicated in the etiology of many neurological diseases, including Parkinson?s disease, tardive dyskinesia, Huntington?s chorea and attention deficit hyperactivity disorder. Current thinking about the dopamine?s impact on the basal ganglia has moved from a focus on rate based models to a focus on the effects of dopamine receptor stimulation on synchronous and oscillatory activity in basal ganglia networks. Our interest in the role of dopamine and oscillatory activity in the basal ganglia goes back many years and it is exciting that these issues are coming to the fore in current discussions in the literature regarding the functional role of dopamine and the mechanisms underlying dysfunction associated with dopamine cell death or over activity. Our older studies in locally anaesthetized, immobilized and artificially anesthetized rats indicated that dopamine agonists induced a dramatically enhanced oscillatory activity in ultraslow frequency ranges. Our more recent studies using the slow oscillation in cortical activity induced by some anesthetics as a tool have allowed us to develop a hypothesis regarding how dysfunctional increases and decreases in dopamine receptor stimulation may enhance passage of oscillatory activity through the basal ganglia networks. These extremes in dopamine receptor stimulation, we hypothesize, lead to disruption of the normal filtering effect of moderate levels of stimulation and promote coalescing of phase relationships and increased synchronization of oscillatory activity in basal ganglia output as a result of the imbalance in transmission of oscillatory activity through the indirect and direct pathways. We have been investigating this hypothesis in a variety of ways in the past year. 1) Section Researchers, in FY2005, have used a rodent model of Parkinson?s disease, rats with unilateral lesion of midbrain dopamine neurons, to study changes in neuronal function in the basal ganglia. One approach has taken advantage of the fact that systemic anesthesia induces slow synchronized oscillations in cortical activity. The effect of unilateral lesion of striatal dopaminergic innervation on the passage of these slow oscillations in neuronal activity through the basal ganglia nucleus has been examined in cojunction with the dramatically altered firing patterns observed in basal ganglia nuclei after -6-OHDA lesions. Examination of phase relationships has lead to the hypothesis that loss of dopamine at D2 receptors in the striatum brings about increased striatal sensitivity to slow cortical oscillatory firing patterns in the anesthetized rats and results in increased synchronization of striatal influence on globus pallidus and substantia nigra pars reticulata (SNpr). Synchronized pauses in pallidal activity may also contribute to synchronized bursts in the subthalamic nucleus (STN) and SNpr. These studies show that in a relatively simple system, the anesthetized rat, loss of dopamine brings about a consolidation of oscillatory activity via the striatal-pallidal and cortical-subthalamic pathways which coalesces at downstream sites and contributes to dysfunctional strong oscillatory activity in the basal ganglia output nuclei and highlights the dramatic difference the dopamine cell lesion makes on passage of this slow oscillation though the basal ganglia nuclei and focusing of the oscillatory activity on the output. 2) We have further used this model to determine whether the increased incidence of slow oscillations present in STN and SNpr spike trains after unilateral 6-OHDA-induced DA cell lesion are also present in the entopeduncular nucleus (EPN) spike trains, and whether slow oscillations from the SNpr and EPN influence neuronal activity in the ventrolateral (VL) thalamus and motor cortex. The data indicate that there was selective loss of slow oscillations in the VL thalamus, in the frequency range that dominates in the EPN and SNpr in anesthetized rats. The reduction in slow oscillations in the VL thalamus with DA loss may be related to coincident increased inhibitory oscillatory activity from SNpr and EPN dampening excitatory oscillatory activity from the motor cortex. These results suggest that increased synchronization of activity in basal ganglia output may interfere with activity in the same frequency range in thalamocortical loops. 3) To follow up on the observations above, Section researchers have gone on to take advantage of the changes in firing pattern induced in the basal ganglia by loss of dopamine neurons to investigate how changes in firing pattern and synchronization of activity relate to changes in local field potential (LFP). Clinical investigators have begun to record LFP from patients being treated for neurological disorders with implantation of deep brain stimulation electrodes. It is becoming an important issue how changes in LFP in basal ganglia nuclei reflect population activity. LFP and spike activity data were obtained from paired simultaneous recordings of SNpr neurons ipsi and contralateral to unilateral 6-OHDA lesions in anesthetized rats. Data were also obtained from paired recordings in the STN in intact rats and lesioned rats ipsilateral to the unilateral lesion. We found that STN spike train firing patterns ipsilateral to the dopamine cell lesion are highly correlated with LFPs on both lesioned and intact sides. Spectral power of LFP oscillations in slow and delta frequency ranges is significantly higher ipsilateral to the dopamine cell lesion in the STN but relative change in firing pattern as reflected in burstiness and spike train oscillations are much greater. This observation suggests LFP measurements can reflect differences in firing pattern and synchronization between paired neuronal populations in this frequency range - but do not adequately predict the extent of synchronization in neuronal populations. This agrees with last years?s observation that LFP differences were significant in only one of two sets of paired populations with notably different firing patterns - i.e. in the SNpr-SNpr paired recordings, but not in the GP-GP paired recordings. This study implies caution should be used in using LFP to assess changes in population activity in in vivo recordings from patients with neurological disorders performed for the purpose of placement of deep brain stimulation electrodes. 4)Section researchers have extensively documented the presence of ultraslow oscillation (2 - 60 sec periods) in the basal ganglia of immobilized, awake rats. Drugs which alter dopamine receptor stimulation have the ability to modulate the properties of these ultraslow oscillations in the activity of tonically active neurons throughout the basal ganglia. Questions have always come up, however, regarding the functional significance of these multisecond oscillations in normal preparations. In FY 2005 collaborations began with Dr. Braun to determine the presence of these oscillations in human EEG and with Dr. Wassermann and Dr. Guilbert to investigate whether they were evident in measures of the sensitivity of motor cortex to transcortical magnetic stimulation (TMS). We found multisecond oscillations in both EEG and TMS measures. Further supporting the idea that multisecond oscillations in cortical activity have functional significance, we found that self-paced movements are regularly initiated during the negative phase of ultraslow oscillation in cortical EEG, when the neurons are relatively more depolarized (excited) on this ultraslow time scales, as reflected by movement-triggered averages of the DC EEG. This has implications for the understanding of phenomena such as the Readiness Potential.

多巴胺系统对于基底神经节的适当信息处理至关重要。这种神经系统的功能障碍与许多神经系统疾病的病因有关，包括帕金森病、迟发性运动障碍、亨廷顿舞蹈病和注意力缺陷多动障碍。目前关于多巴胺对基底神经节影响的思考已经从关注基于速率的模型转向关注多巴胺受体刺激对基底神经节网络同步和振荡活动的影响。我们对多巴胺和基底神经节振荡活动的作用的兴趣可以追溯到很多年前，令人兴奋的是，这些问题在当前有关多巴胺的功能作用以及与多巴胺细胞死亡或过度活动相关的功能障碍的机制的文献讨论中脱颖而出。我们对局部麻醉、固定和人工麻醉大鼠的较早研究表明，多巴胺激动剂在超慢频率范围内诱导显着增强的振荡活动。我们最近的研究利用某些麻醉剂引起的皮质活动的缓慢振荡作为工具，使我们能够提出一个假设，即多巴胺受体刺激的功能失调的增加和减少如何可能增强振荡活动通过基底神经节网络的通道。我们假设，多巴胺受体刺激的这些极端情况会导致中等水平刺激的正常过滤效应被破坏，并促进相位关系的合并，并由于通过间接和直接途径传递振荡活动的不平衡而增加基底神经节输出中振荡活动的同步性。在过去的一年里，我们一直在以各种方式研究这一假设。 1) 2005财年，研究人员使用了帕金森病的啮齿动物模型，即中脑多巴胺神经元单侧损伤的大鼠，来研究基底神经节神经元功能的变化。一种方法利用了全身麻醉引起皮层活动缓慢同步振荡的事实。纹状体多巴胺能神经支配的单侧损伤对神经元活动中这些缓慢振荡通过基底神经节核的通道的影响已经与 -6-OHDA 损伤后在基底神经节核中观察到的显着改变的放电模式一起进行了检查。对相位关系的检查得出这样的假设：纹状体中 D2 受体的多巴胺缺失会导致麻醉大鼠纹状体对缓慢皮质振荡放电模式的敏感性增加，并导致纹状体对苍白球和黑质网状部 (SNpr) 影响的同步性增加。苍白球活动的同步暂停也可能导致丘脑底核 (STN) 和 SNpr 的同步爆发。这些研究表明，在一个相对简单的系统中，麻醉大鼠，多巴胺的丧失会通过纹状体-苍白球和皮质-底丘脑通路导致振荡活动的巩固，这些通路在下游位点合并，导致基底神经节输出核中功能失调的强振荡活动，并强调多巴胺细胞损伤在传代过程中产生的巨大差异 这种缓慢振荡通过基底神经节核，并将振荡活动集中在输出上。 2）我们进一步使用该模型来确定单侧6-OHDA诱导的DA细胞损伤后STN和SNpr尖峰序列中慢振荡发生率的增加是否也存在于内脚核（EPN）尖峰序列中，以及SNpr和EPN的慢振荡是否影响腹外侧（VL）丘脑和运动皮层的神经元活动。数据表明，在麻醉大鼠的 EPN 和 SNpr 中占主导地位的频率范围内，VL 丘脑中的慢振荡选择性丧失。 VL 丘脑缓慢振荡随着 DA 损失而减少，可能与 SNpr 和 EPN 抑制运动皮层兴奋性振荡活动同时增加的抑制性振荡活动有关。这些结果表明基底神经节输出活动同步性的增加可能会干扰丘脑皮质环中相同频率范围的活动。 3）为了跟进上述观察，该部门的研究人员继续利用多巴胺神经元损失引起的基底神经节放电模式的变化来研究放电模式的变化和活动同步性与局部场电位（LFP）的变化之间的关系。临床研究人员已经开始记录通过植入深部脑刺激电极接受神经系统疾病治疗的患者的 LFP。基底节核中LFP的变化如何反映群体活动正成为一个重要问题。 LFP 和尖峰活动数据是从麻醉大鼠的单侧 6-OHDA 损伤的同侧和对侧 SNpr 神经元的配对同步记录中获得的。数据还从完整大鼠和单侧病变同侧的病变大鼠的 STN 中的配对记录中获得。我们发现多巴胺细胞病变同侧的 STN 尖峰序列放电模式与病变侧和完整侧的 LFP 高度相关。 LFP 振荡在慢速和增量频率范围内的频谱功率明显高于 STN 中多巴胺细胞病变的同侧，但突发性和尖峰序列振荡所反映的放电模式的相对变化要大得多。这一观察结果表明，LFP 测量可以反映在此频率范围内成对神经元群体之间放电模式和同步的差异，但不能充分预测神经元群体同步的程度。这与去年的观察一致，即 LFP 差异仅在两组具有显着不同放电模式的配对群体中的一组中显着 - 即在 SNpr-SNpr 配对记录中，但在 GP-GP 配对记录中则不显着。这项研究表明，在使用 LFP 评估神经系统疾病患者体内记录中群体活动的变化时应谨慎，这些患者是为了放置深部脑刺激电极而进行的。 4)部门研究人员广泛记录了固定、清醒大鼠基底神经节中超慢振荡（2 - 60 秒周期）的存在。改变多巴胺受体刺激的药物能够调节整个基底神经节的紧张性活跃神经元活动中的这些超慢振荡的特性。然而，关于这些多秒振荡在正常准备过程中的功能意义的问题始终存在。 2005 财年，我们开始与 Braun 博士合作，以确定人类脑电图中是否存在这些振荡，并与 Wassermann 博士和 Guilbert 博士合作，研究这些振荡在运动皮层对经皮层磁刺激 (TMS) 敏感性的测量中是否明显。我们在脑电图和经颅磁刺激测量中发现了多秒振荡。进一步支持皮质活动中的多秒振荡具有功能意义的观点，我们发现，在皮质脑电图超慢振荡的负相期间，有规律地启动自定步调运动，此时神经元在超慢时间尺度上相对更加去极化（兴奋），正如运动触发的直流脑电图平均值所反映的那样。这对于理解准备潜力等现象具有重要意义。