Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia

在帕金森病（PD）停药患者中，在β频率范围内发现了非典型振荡活动，而高伽马频率活动同步增加与左旋多巴诱导的运动障碍（LID）有关。据推测，基底神经节-丘脑皮质回路的过度同步活动是导致这些患者运动障碍的原因，而基底神经节目标的深部脑刺激（DBS）通过破坏这种活动是有益的。在过去的几年里，我们在大鼠PD模型中同时记录了运动皮质（mCx）和黑质网状部（SNpr）（基底节区输出核），以探索该模型的潜力，以深入了解这种活动如何在基底节区出现，以及它是否在功能上与帕金森病相关的运动障碍和运动障碍的运动症状相关。单侧多巴胺细胞损伤后，大鼠在环形跑步机上行走时表现出明显的运动障碍。我们的记录研究表明，多巴胺损伤后第7天，这些大鼠的局部场电位（LFP）频谱功率和高β /低γ 25-40 Hz频率范围内的SNpr-mCx相干性显著增加，这在许多方面与PD患者的振荡活动增加相似，表明这是研究这些大脑活动变化的功能意义的良好模型。今年我们使用这个模型来探索1)的表达β丘脑核的活动范围,DBS在人类的目标,和非机动车的贡献对STN变化区域的皮质活动,2)的时间课程的出现高伽马运动皮层的活动与运动障碍的症状和作用的血清素激活的系统以及D1和D2多巴胺受体在调节高伽马的表达活动,3)纹状体在基底神经节输出区多巴胺丢失相关的异常皮质节律的产生和传递中的争议性作用。

In Parkinsons disease (PD) patients off medication, atypical oscillatory activity has been found in the beta frequency range, while increases in the synchronization of high gamma frequency activity have been associated with L-dopa-induced dyskinesia (LID). It has been hypothesized that this excessively synchronized activity in basal ganglia-thalamocortical circuits is responsible for the motor impairments seen in these patients and that deep brain stimulation (DBS) of basal ganglia targets is beneficial by disrupting this activity. In previous years we have performed simultaneous recordings from the motor cortex (mCx) and the substantia nigra pars reticulata (SNpr), a basal ganglia output nucleus, in a rat model of PD to explore the potential for this model to provide insight into how this activity emerges in the basal ganglia and whether it is functionally related to the motor symptoms of akinesia and dyskinesia associated with Parkinsons disease. After unilateral dopamine cell lesion, rats show notable motor deficits during treadmill walking in a circular treadmill. Our recording studies have shown that significant increases in local field potential (LFP) spectral power and in SNpr-mCx coherence in the high beta/low gamma 25-40 Hz frequency range emerge in the dopamine-lesioned hemisphere of these rats by day 7 after dopamine lesion which parallel in many ways the increases in oscillatory activity noted in PD patients, indicating that this is a good model for investigating the functional significance of these changes in brain activity. This year we have used this model to explore 1) the expression of beta range activity in the subthalamic nucleus, the target of DBS in humans, and the contribution of non-motor areas of the cortex to changes in STN activity, 2) the time course of the emergence of the high gamma activity in the motor cortex in conjunction with symptoms of dyskinesia and role of the serotonergic system as well as the D1 and D2 dopamine receptors in regulating the expression of the high gamma activity, and 3) the controversial role of the striatum in generating and transmitting abnormal cortical rhythms associated with loss of dopamine to output zones of the basal ganglia. 1) Simultaneous recordings from the STN and motor cortex showed significant increases in high beta/low gamma LFP spectral power in both areas and increases in STN-motor cortex coherence, as we have seen previously in the motor cortex and SNpr recordings during treadmill walking. Importantly, the amplitude of this exaggerated rhythm during treadmill walking in the STN was modulated by movement, varying with the rhythm of the stepping of the affected paw. In contrast to recordings from the motor cortex, recordings from the medial prefrontal cortex after DA cell lesion failed to show peaks in 25-40 Hz LFP power during treadmill walking. However, simultaneous recordings from the medial prefrontal cortex and STN showed significant peaks in the 46-55 Hz frequency range in LFP power and in medial prefrontal cortex coherence during treadmill walking before DA cell lesion. This activity was not evident in motor cortex. Interestingly, after DA cell lesion, both medial prefrontal cortex and STN power and coherence in the 46-55 Hz frequency range was reduced for about two weeks, but by 3 weeks, this activity had partially to fully recovered. The results indicate that STN LFP activity can become synchronized with, and presumably modulated by, activity in both medial prefrontal cortex and motor cortex in a manner that varies with frequency range, behavioral state and the integrity of the dopamine system. These results are likely to be relevant to both the positive and negative effects of DBS in the STN. 2) Although the underlying mechanisms of LID are not fully understood, previous studies have focused on the neuronal activity of the basal ganglia. Indeed, high gamma oscillatory LFP activity within the basal ganglia has been reported in PD patients who were treated with L-dopa. More recently, similar activity in the primary motor cortex has been linked to dyskinetic symptoms in a rodent model of PD and attributed to stimulation of cortical dopamine D1 receptors. To characterize the relationship between high gamma cortical activity and the development of LID, chronic recordings were performed in the motor cortex of the hemiparkinsonian rats in animals with dopamine cell lesions subsequently treated with L-dopa for 7 days. Findings demonstrate that the power and peak frequency of high gamma cortical LFP activity increases between days 1 and 7 of L-dopa priming, along with an increase in abnormal involuntary movements and rotations suggesting that this oscillatory activity correlates with the severity of LID. However, abnormal involuntary movements and rotations were consistently observed prior to the emergence of the distinct band of high gamma oscillatory activity, raising questions about the causative nature of this phenomenon. Further results demonstrate that the high gamma cortical activity is neither D1 nor D2 receptor specific; however, the two receptors had different effects on peak frequency and rotational behavior. While our findings show that high gamma cortical LFP activity is strongly associated with LID, further questions remain regarding the role of this activity in generating dyskinesia and the neural substrates responsible for its generation. 3) Although exaggerated oscillatory activity has been observed in the majority of basal ganglia nuclei in PD, it is still unclear how it emerges and whether it engages the major basal ganglia input nucleus most directly affected by dopamine loss, the striatum. To get a better perspective on this, we analyzed the time course of emergence of the high beta/low gamma and high gamma range pathologic activities in the striatum and motor cortex, to determine how these rhythms propagate through the striatum after loss of dopamine and after 7 days of chronic l-dopa treatment resulting in dyskinesia. Results show increases in striatal oscillatory LFP activity after dopamine depletion during treadmill walking in the high beta/low gamma frequency range, and during LID in the high gamma range. However, unlike in our previous studies comparing activity in the motor cortex and SNpr, the oscillatory activity in the striatum was significantly increased only in recordings from subsets of electrodes. This synchronized striatal LFP activity showed very strong coherence between dorsal medial and dorsal lateral striatum, suggesting that both regions also receive common cortical input. Substantial coherence with motor cortex and SNpr LFPs was seen in conjunction with increased power in both frequency ranges. These results indicate that, in the hemipakinsonian rat, the excessive synchronized activity observed in the MCx during walking epochs and during LID propagates to a set of cortico-striatal pathways that target both dorsal medial and dorsal lateral subpopulations the striatum, although its expression is irregularly distributed. However, whether the activity at these different resonance frequencies observed during these behaviors plays a causative role in inducing the opposing kinetic motor impairments is still to be determined.