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: 8940031
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 109.99万
• 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/8940031
• 关键词: Acute; Affect; Affective Symptoms; Area; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Behavior Therapy; Behavioral; Bradykinesia; Brain; Catalepsy; Cell Nucleus; Cells; Chronic; Code; Cognitive; Contralateral; Corpus striatum structure; Coupling; Data; Data Analyses; Data Set; Deep Brain Stimulation; Disease; Dopamine; Dopamine Receptor; Dyskinetic syndrome; Electrodes; Entropy; Exhibits; Frequencies; Gilles de la Tourette syndrome; Goals; Investigation; Lead; Lesion; Levodopa; Link; Maintenance; Manuscripts; Medial; Modeling; Motor; Motor Cortex; Movement; Neurons; Neurotransmitters; Output; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiology; Prefrontal Cortex; Preparation; Process; Rattus; Reporting; Rodent Model; Role; Site; Source; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Therapeutic Agents; Therapeutic procedure; Time; Walking; Writing; awake; dopamine system; insight; interest; motor deficit; motor impairment; receptor; tool

In Parkinsons disease (PD) patients off medication, atypical oscillatory activity has been found in the beta frequency range. It has been hypothesized that this excessively synchronized activity in the basal ganglia 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 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 continued to use this model better understand relationship between changes in high beta/low gamma power and the emergence of bradykinesia after dopamine cell lesion and chronic dopamine receptor blockade. 1) Anatomical studies indicate that the subthalamic nucleus (STN) is an important point of integration of both motor and associative/limbic input into the basal ganglia circuit This observation appears particularly relevant to understanding the impact of STN deep brain stimulation on both motor and affective symptoms of Parkinsons disease. Excessive beta range (12-30 Hz) as well as low (30-70Hz) and high gamma range oscillations have been reported in the STN of PD patients depending on the patients drug treatment and behavioral state. These observations raise questions about the sources and functional significance of the different types of oscillatory and synchronized activity observed in the STN in the PD patients, and whether specific frequency ranges can be linked to activity in limbic vs motor networks. In the past year we have used the hemiparkinsonian rat to compare the relationships between synchronized oscillatory activity in the STN with synchronized activity in the motor cortex (mCx) vs the medial prefrontal cortex (mPFC), an area connected to the STN and known to be involved in cognitive processes, across different behavioral states. Our results show that STN LFP activity in the rat can exhibit significant coherence with activity in both mPFC and mCx, highlighting the potential for STN integration of both limbic and motor networks. This was demonstrated by examining relationships between mPFC and mCx activity and activity in the STN during behavioral states which were found to differentially affect oscillatory activity in the two cortical areas. The circular treadmill proved to be a useful tool in this regard, as the presence of a stationary paddle encouraged the rats to attend to their walking to avoid being pushed, providing a cognitive component to the motor task. Recordings showed that both cortical areas showed changes in LFP in conjunction with treadmill walking. In mPFC, treadmill walking was associated with a selective increase LFP power in a low gamma range in both control rats and in dopamine cell lesioned rats. In contrast, only a slight increase low gamma activity was observed in mCx of control rats LFP treadmill walking induced, but in lesioned rats, a dramatic increase in high beta 29-36 Hz range emerged in mCx LFP power after dopamine cell lesion. Strikingly, STN LFP showed marked increases in LFP power and coherence in conjunction with both the 51 Hz peak in the mCx and the 29-36 Hz activity in the motor cortex. Interestingly, the amplitude of oscillations of the STN LFP in the high beta frequency range was significantly linked to the contralateral paw movement whereas the elevation of STN LFP in the low gamma frequency range appeared more linked to engagement with the walking task than with the rhythm of the stepping. These results show that STN LFP activity can become synchronized with, and presumably modulated by, activity in both limbic and motor cortex networks in a manner that varies with frequency range, behavioral state and the integrity of the dopamine system. The manuscript is in preparation. 2) In a second set of studies, we have completed collecting data for our investigation into changes in spiking and LFP in two areas in the striatum in conjunction with recordings in motor cortex and SNpr in the hemilesioned Parkinsonian rat. 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. Our results show increases in striatal oscillatory LFP activity after dopamine depletion during treadmill walking in the high beta/low gamma frequency range, and during L-dopa-induced dyskinesia in the high gamma range. However, unlike in our previous studies comparing activity in the motor cortex, STN and SNpr, the oscillatory activity in the striatum was patchy, significantly increased only in recordings from subsets of electrodes. In addition, striatal projection neurons showed very little phase coupling to the increased oscillatory activity in the 28-36 Hz range in motor cortex and striatum, suggesting a minimum role of the striatum in transmitting this hyper-synchronized activity downstream to the basal ganglia output, the SNpr. Together with higher phase coupling of cortical, STN and SNpr neurons to the motor cortex LFP activity in the beta frequency range, these data suggests that this activity propagates via the hyper-direct pathway, that is, from motor cortex to STN, and then to SNpr. The next phase of this data analysis will involve use of a stochastic entropy model to study how dopamine depletion alters coding capacity and information flow in the basal ganglia of hemiparkinsonian rats. 3) Finally, we have also finished adding rats to another set of data examining the time course of changes in coherence and power in the low beta/high gamma range in motor cortex and SNpr in association with the time course of emergence of motor symptoms after a) unilateral dopamine cell lesion and b) twice daily chronic dopamine D1 and D2 antagonist treatment. Both treatments lead to emergence of motor symptoms on day 1 after lesion or drug. However, the time course of the increase in LFP oscillations is slower. Increased coherence between cortex and SNpr is the change most evident after acute los of dopamine or blockade of dopamine receptors. These results argue the dramatic changes observed in high beta/low gamma activity in motor circuits after dopamine cell lesion or dopamine receptor blockade are not critical to the expression of bradykinesia and catalepsy. While it is quite possible that than the more subtle early changes in synchronization of activity in these circuits disrupts information transfer, inducing akinesia, it is also possible the robust changes in oscillatory activity which evolve over the first week post lesion is at least in part compensatory. Writing has begun for this manuscript.

在帕金森病（PD）患者停药后，在β频率范围内发现了不典型的振荡活动。据推测，基底节区过度同步的活动是导致这些患者出现运动障碍的原因，而基底节区目标的深部脑刺激（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层和黑质网状部（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，我们继续使用这个模型来更好地理解多巴胺细胞损伤和慢性多巴胺受体阻断后高β /低γ功率的变化与运动迟缓的出现之间的关系。