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: 8149623
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 115.33万
• 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/8149623
• 关键词: Basal Ganglia; Pharmacology; Physiology; Substantia nigra structure

Current focus in the Neurophysiological Pharmacology Section is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. The Sections on-going neurophysiological studies in several different rat preparations - locally anaesthetized, immobilized and artificially respired rats, freely moving rats and systemically anesthetized rats - have provided evidence that normal levels of dopamine receptor stimulation act to prevent emergence of inappropriately synchronized and oscillatory neuronal firing activity in basal ganglia networks, while significant increases and decreases in dopamine receptor stimulation enhance the expression of these dysfunctional patterns. In the past year, we have been exploring the specifics of dysfunctional alterations in basal ganglia output in animal models of Parkinsons disease. In particular, we have focused on beta range (12 35 Hz) activity which appears enhanced in the subthalamic nucleus of parkinsonian patients and has been hypothesized to be antikinetic in nature. Studies in the current review period have also used the 1 Hz rhythm dominant in the cortex of the anesthetized rat to develop hypotheses about how loss of dopamine can lead to entrainment of basal ganglia output to cortical rhythms. The data from the anesthetized rat studies suggest that loss of dopamine affects the ability of the striatum to properly filter input from the cortex, and promotes entrainment of the basal ganglia to cortical rhythms. To further examine this hypothesis, we have developed an awake behaving rat model of Parkinsons disease which allows us to investigate changes in basal ganglia activity after loss of dopamine in conjunction with changes in gait. The goal was to determine whether increases in synchronized and oscillatory activity in the beta range would be evident in a rodent preparation and correlated with loss of dopamine and motor dysfunction. Such a model would allow us to explore a number of questions related to the source of the exaggerated beta activity expressed in the basal ganglia in Parkinsons disease, and the extent to which this activity is responsible for motor dysfunction in parkinsonian patients. Rats were trained to walk in a novel rotary treadmill while EMG activity in shoulder muscle and neuronal activity in basal ganglia output were recorded. After unilateral loss of dopamine, rats made progress walking counterclockwise on the rotary treadmill, but tended to freeze during clockwise walking as this required the affected side to make more demanding adjustments of gait and posture. Our first studies in the awake behaving rats focused on the effect of dopamine cell lesion on firing rate and pattern in the SNpr during epochs of treadmill walking and inattentive rest. We hypothesized that we would see elevations in beta range activity in the lesioned hemisphere, relative to the intact hemisphere, as predicted by observations of prominent beta activity in the subthalamic nucleus in Parkinson patients. Substantia nigra pars reticulata (SNpr) was chosen as our initial target for these studies because changes in basal ganglia output are critical to the ultimate impact of basal ganglia dysfunction on downstream sites, and data from the anesthetized preparation predicted that SNpr activity would be entrained by increased synchronization in basal ganglia circuits. Recordings began seven days after surgery for unilateral dopamine cell lesion and electrode bundle implantation, in order to allow the rat time to recover from those procedures. Epochs identified as inattentive rest showed that SNpr local field potential (LFP) power in the low beta range (relatively concentrated around the 1218 Hz) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned (opposite to the lesioned) or control (brains with no lesions) hemispheres. At the end of the rest epoch, a buzzer sounded, and the investigator adjusted the rat in the treadmill and turned it on. During this adjustment period, as rats became alert and began to move, low beta power was reduced in the SNpr in both intact and lesioned hemispheres and, strikingly, activity in the high beta range (25-40 Hz, technically high beta/low gamma) became quite prominent in the lesioned hemisphere only. During treadmill walking, this high beta band was consistently expressed in the lesioned hemisphere, centered around 33 Hz. Thus, in the hemiparkinson rat, dopamine loss is associated with increases in the synchronization of SNpr activity, with apparent differences in the peak frequency depending on the behavior expressed by the rat. To further examine factors modulating the expression of high beta oscillatory activity in the basal ganglia under conditions of dopamine cell loss, single neurons and LFPs in SNpr were simultaneously recorded from lesioned and non-lesioned hemispheres in the hemiparkinsonian rats during a range of behaviors including alert rest, grooming, REM sleep, and while under light anesthesia (urethane) with sensory stimulation, in addition to walking and inattentive rest. SNpr LFP high beta oscillations remained consistently elevated from 1 week to 8 weeks post lesion in the lesioned hemisphere during ipsiversive treadmill walking, with mean SNpr power in lesioned hemisphere 5 fold greater than in the non-lesioned SNpr. High beta power was greatest at walking onset and diminished during walking episodes to 2.5 fold increase by the fifth min. Results showed a subtle but significant decrease in the dominant frequency during the alert inactive state (29 Hz) relative to treadmill walking, and a further declined to approximately 21 Hz in the lightly anesthetized, lightly stimulated state. L-dopa treatment significantly reduced high beta power in the SNpr LFPs (by 80%) on the lesioned side and improved walking on the circular treadmill contraversive to the lesion. This treatment also reduced beta range activity in the lightly anesthetized state. The serotonin 1A agonist reversed L-dopas effects on SNpr high beta power during walking, consistent with evidence that serotoninergic terminals in the central nervous system are involved in conversion of L-dopa to dopamine and release of dopamine after dopamine cell death. The correlation between beta activity and motor deficits in this animal model of Parkinsons disease support the hypothesis that increased beta range synchronization of neuronal activity in basal ganglia output plays a role in the mediating deficits in gait expressed by these rats. The range of frequencies observed in the synchronized activity in the basal ganglia over a range of behaviors in the hemiparkinsonian rat suggests that the synchronized activity is generated by complex neuronal networks, like those in the cortex, as opposed to a more limited network like that defined by the reciprocal connections between the external globus pallidus and the subthalamic nucleus. Future studies will examine the effects of local manipulation of neuronal activity at different nodes in the basal ganglia circuit to better understand how alterations in basal ganglia activity lead to motor dysfunction in Parkinsons disease.

神经生理药理学部分当前的重点是含多巴胺神经元影响基底神经节和相关区域信息处理能力的机制。该部门正在进行的几种不同大鼠制剂（局部麻醉、固定和人工呼吸大鼠、自由活动大鼠和全身麻醉大鼠）的神经生理学研究提供了证据，表明正常水平的多巴胺受体刺激可防止出现不适当的同步和振荡神经元基底神经节网络的放电活动，而多巴胺受体刺激的显着增加和减少增强了这些功能障碍模式的表达。 在过去的一年中，我们一直在探索帕金森病动物模型中基底神经节输出功能障碍改变的细节。我们特别关注 β 范围（12 35 Hz）活动，该活动在帕金森病患者的丘脑底核中似乎增强，并被假设本质上具有抗动力作用。当前审查期间的研究还使用了麻醉大鼠皮质中占主导地位的 1 Hz 节律来提出关于多巴胺损失如何导致基底神经节输出夹带皮质节律的假设。 来自麻醉大鼠研究的数据表明，多巴胺的丧失会影响纹状体正确过滤来自皮质的输入的能力，并促进基底神经节对皮质节律的控制。 为了进一步检验这一假设，我们开发了帕金森病的清醒行为大鼠模型，该模型使我们能够研究多巴胺丧失后基底神经节活动的变化以及步态的变化。目的是确定在啮齿类动物制剂中，β 范围内的同步和振荡活动的增加是否明显，并与多巴胺的丧失和运动功能障碍相关。 这样的模型将使我们能够探索与帕金森病基底神经节中表达的过度β活性的来源相关的许多问题，以及这种活性在多大程度上导致帕金森病患者的运动功能障碍。 训练大鼠在新型旋转跑步机上行走，同时记录肩部肌肉的肌电图活动和基底神经节输出的神经元活动。单侧失去多巴胺后，大鼠在旋转跑步机上逆时针行走取得进展，但在顺时针行走时往往会僵住，因为这需要受影响的一侧对步态和姿势进行更严格的调整。 我们对清醒行为大鼠的第一项研究重点是在跑步机行走和不专心休息期间多巴胺细胞损伤对 SNpr 放电率和模式的影响。我们假设，与完整的半球相比，我们会看到病变半球的 β 范围活动升高，正如通过观察帕金森患者丘脑底核中显着的 β 活动所预测的那样。选择黑质网状部 (SNpr) 作为我们这些研究的初始目标，因为基底神经节输出的变化对于基底神经节功能障碍对下游位点的最终影响至关重要，来自麻醉制剂的数据预测 SNpr 活性将被夹带增加基底神经节回路的同步性。 在单侧多巴胺细胞损伤和电极束植入手术后 7 天开始记录，以便让大鼠有时间从这些手术中恢复。 被确定为注意力不集中的休息时期表明，在多巴胺耗尽的半球中，低 β 范围（相对集中在 1218 Hz 附近）的 SNpr 局部场电位 (LFP) 功率显着大于未损伤（与损伤相反）或对照的半球（没有病变的大脑）半球。在休息时间结束时，蜂鸣器响起，研究人员调整跑步机上的老鼠并将其打开。 在此调整期间，随着大鼠变得警觉并开始移动，完整半球和受损半球的 SNpr 中的低 β 功率均降低，并且引人注目的是，高 β 范围（25-40 Hz，技术上高 β/低 γ ）的活动）仅在病变半球中变得相当突出。 在跑步机上行走期间，这种高β带在病变半球中持续表达，以 33 Hz 为中心。因此，在偏侧帕金森病大鼠中，多巴胺损失与 SNpr 活性同步性的增加有关，峰值频率存在明显差异，具体取决于大鼠表达的行为。 为了进一步研究在多巴胺细胞丢失的情况下调节基底神经节高β振荡活性表达的因素，在包括警觉在内的一系列行为期间，同时记录了偏帕金森病大鼠的病变和非病变半球的SNpr中的单个神经元和LFP。休息、梳理毛发、快速眼动睡眠，以及在轻度麻醉（聚氨酯）下进行感官刺激，以及行走和注意力不集中的休息。 在自动跑步机行走过程中，从病变后 1 周到 8 周，SNpr LFP 高 β 振荡持续升高，病变半球的平均 SNpr 功率比未病变的 SNpr 大 5 倍。高β功率在步行开始时最大，并在步行过程中减弱，到第5分钟增加了2.5倍。结果显示，与跑步机行走相比，在警戒非活动状态下（29 Hz），主频率有微妙但显着的下降，并且在轻度麻醉、轻度刺激状态下进一步下降至约 21 Hz。左旋多巴治疗显着降低了病变侧 SNpr LFP 的高 β 功率（降低了 80%），并改善了在与病变相反的圆形跑步机上行走。这种治疗还降低了轻度麻醉状态下的β范围活性。血清素 1A 激动剂逆转了步行时左旋多巴对 SNpr 高β功率的影响，这与中枢神经系统中的血清素能末端参与左旋多巴转化为多巴胺以及多巴胺细胞死亡后释放多巴胺的证据一致。 在帕金森病动物模型中，β 活性与运动缺陷之间的相关性支持这样的假设：基底神经节输出中神经元活动的 β 范围同步性增加在介导这些大鼠表达的步态缺陷中发挥着作用。在偏侧帕金森病大鼠的一系列行为中观察到的基底神经节同步活动的频率范围表明，同步活动是由复杂的神经元网络（如皮层中的神经元网络）产生的，而不是像定义的更有限的网络那样。通过外部苍白球和丘脑底核之间的相互连接。未来的研究将检查基底神经节回路中不同节点神经元活动的局部操纵的影响，以更好地了解基底神经节活动的改变如何导致帕金森病的运动功能障碍。