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: 9358528
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 100.3万
• 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/9358528
• 关键词: Affect; Animals; Anterior; Area; Attention deficit hyperactivity disorder; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Beta Rhythm; Bradykinesia; Brain; Cell Nucleus; Cells; Clozapine; Contralateral; Corpus striatum structure; Data; Data Set; Deep Brain Stimulation; Designer Drugs; Disease; Dopa; Dopamine; Dopamine Receptor; Dyskinetic syndrome; Electrodes; Freezing; Frequencies; Functional disorder; Gait; Genetic; Gilles de la Tourette syndrome; Globus Pallidus; Goals; Grooming; Image; Implant; Infusion procedures; Injection of therapeutic agent; Ipsilateral; Lead; Lesion; Maintenance; Manuscripts; Measures; Medial; Mediating; Modeling; Monitor; Motor; Motor Cortex; Movement; Nature; Neurologist; Neurons; Neurotransmitters; Output; Oxides; Parkinson Disease; Parkinsonian Disorders; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Physiology; Prefrontal Cortex; Preparation; Rattus; Reporting; Research; Research Personnel; Rest; Rodent; Rodent Model; Role; Site; Source; Spike Potential; Structure of subthalamic nucleus; Substantia nigra structure; System; Technology; Thalamic structure; Therapeutic; Therapeutic Agents; Therapeutic procedure; Time; Treatment Efficacy; Virus; Walking; Writing; awake; base; chronic depression; chronic pain; cingulate cortex; designer receptors exclusively activated by designer drugs; dopaminergic neuron; improved; insight; interest; man; motor deficit; nervous system disorder; neurophysiology; protein expression; receptor; treadmill

Research conducted on changes in basal ganglia function in Parkinsons disease (PD) over the past year in the Neurophysiological Pharmacology Section has continued to focus on the nature and functional significance of synchronized and oscillatory activity emerging in motor circuits after loss of dopamine. We are hopeful that further characterization of this phenomena in a rodent model of PD will lead to improved treatments for the PD patient, provide insight into the role of dopamine in motor system function and facilitate our understanding of the significance of synchronized activity in brain circuits. As previously reported, our first goal in investigating the changes in basal ganglia function after dopamine cell lesion was to develop a strategy allowing recording of ongoing activity in motor circuits while the rat performs a task that is relevant to parkinsonian motor deficits. We accomplished this through the use of a circular treadmill with a paddle lowered over the track to encourage the rat to keep walking. A rat with a unilateral dopamine cell lesion - mimicking unilateral PD - is able to walk effectively on this treadmill as long as he is oriented in the direction ipsilateral to the dopamine cell lesion, with the paws opposite the lesioned hemisphere on the outside of the circular track. His ability to walk in the opposite contralateral direction is more variable. The treadmill setup allows us to monitor basal ganglia circuit spiking and local field potential (LFP) activity continuously from the intact and lesioned hemispheres as the animal walks and rests. Importantly, marked increases in synchronized activity in the high beta (30 35Hz) range are observed in these recordings in the lesioned hemisphere of the hemiparkinsonian rats during treadmill walking. These observations have provided multiple avenues for further research. With respect to the treadmill model, in the past year Section investigators have made advances in quantifying the nature of the stepping deficits evident when the rats are engaged in walking in the contralateral direction. While some rats will not walk in this direction at all, and try to reverse direction or simply freeze, other rats, which appear to have less complete dopamine cell lesions, show changes in stepping patterns when walking contralaterally. Our newly refined measures of gait dysfunction allow more meaningful exploration of neurophysiological mechanisms underlying the stepping deficits. A new goal is to modify the circular treadmill to allow recording of the rats stepping patterns from below, to better quantify changes in gait induced by loss of dopamine. A second goal relevant to ongoing studies has been to characterize, over a range of behavioral states, the motor circuit components most clearly entrained to the exaggerated oscillatory activity in the hemiparkinsonian rats. The robust nature of this activity allows us to track it across different nodes within the motor circuits and gather insight into how peak frequency, oscillatory power and coherence within different components of these circuits vary with behavioral state. Our accumulating data sets should provide insight into the source of the abnormal oscillations as well perspectives on imaging studies in rodents and man. Over the first weeks after dopamine lesion, significant increases in LFP spectral power in the subthalamic nucleus (STN), substantia nigra (SNpr) and motor cortex emerge in the high beta 30-35 Hz frequency range in the dopamine-lesioned hemisphere when the hemiparkinsonian rats are active, as in walking or grooming. LFP coherence in the 30 35 Hz range between these nuclei is also high during treadmill walking. Peak frequencies vary with behavioral state, being in 12-25 Hz range during inattentive rest, closer to 28 Hz during alert stationary states and ranging from 30 to 35 Hz, going up about 1 Hz per week post-lesion, during treadmill walking. Most recently we have added simultaneous recordings from the medial prefrontal cortex and anterior cingulate cortex, as well as areas in the motor thalamus. Of interest is the emerging observation that exaggerated 30 35 Hz oscillatory LFP activity during treadmill walking is clearly evident and coherent within and between some areas of the basal ganglia thalamo-cortical motor network and not others. Moreover, spiking activity is significantly phase locked to the LFP oscillations in some but not all of the areas where LFP power is increased. Increased 30 35 Hz oscillatory activity is only patchy in the striatum of the dopamine lesioned hemisphere during treadmill walking, and not evident in the medial prefrontal cortex, and neither area shows significant spike-LFP phase-locking, while robust phase locking is observed in the STN, SNpr and modest phase-locking is observed in layer 5/6 of the motor cortex. These observations are relevant to existing hypotheses regarding the source of the oscillatory activity. Our ongoing studies are indicating a lack of notable phase-locking of spiking activity in the striatum and globus pallidus to cortical beta range activity arguing against synchronized output from these areas driving the oscillatory activity. We are intrigued by the possibility that the high beta rhythms emerge from the dynamic state which evolves within the motor network, after loss of dopamine, with a resonance frequency in the rat in the high beta range. Another on-going effort has been to identify the changes in neurophysiological function which correlate with the earliest signs of motor deficit post lesion. Is there evidence for a causal relationship between motor deficits and increased synchronization in the basal ganglia circuits? Motor deficits are evident within a day after the 6-hydroxydoamine-mediated dopamine cell lesion, but increases in synchronized LFP power are not typically significant at that time point. However, there is an intriguing shift in peak frequency in the motor cortex early after dopamine cell lesion from a peak around 40 Hz to slightly lower, as the peak frequency moves over the early days post lesion toward the 30 Hz peak and coherence increases in the 30 hz range between motor cortex and SNpr. We are currently writing a manuscript describing this phenomenon. Finally, we have begun studies involving infusion of the inhibitory DREADD (Designer Receptors Exclusively Activated by Designer Drugs) virus, AAV2/8-hSyn-Hm4d(Gi)-mCjerry, into the SNpr to evaluate the utility of this approach in manipulating activity in different components of the motor circuit. Effects of injection of the designer drug, CNO (clozapine-N-oxide) can be seen with respect to the duration of cortical high gamma oscillations during l-dopa induced dyskinesia, and the reduction of LFP beta power in the motor cortex during dopamine-lesion-induced bradykinesia. In preparation for obtaining genetically modified rats with potential for targeting subsets of SNpr and globus pallidus neurons with DREADD viruses, we are additionally focused on obtaining a more fine-tuned analysis of how both rate and pattern of the spiking activity, as well as peak frequency of synchronized and oscillatory LFP activity varies with behavioral state within different subsets of neurons within these nuclei. In particular, data is emerging from studies in the globus pallidus and the SNpr suggesting the existence of multiple subtypes which may be differentiated by differences in protein expression and anatomical connections. Ultimately, the goal is to make use of genetic (i.e. DREADD and CRE) based technologies to identify and target specific genetically defined subcomponents of the basal ganglia thalamocortical circuitry to compensate for problems triggered by degeneration of dopamine neurons in PD and and other neurological disorders.

过去一年，神经生理药理学部分对帕金森病 (PD) 基底神经节功能变化进行的研究继续关注多巴胺丧失后运动回路中出现的同步和振荡活动的性质和功能意义。我们希望，在帕金森病啮齿动物模型中进一步表征这种现象将改善帕金森病患者的治疗方法，深入了解多巴胺在运动系统功能中的作用，并有助于我们理解脑回路中同步活动的重要性。 如前所述，我们研究多巴胺细胞损伤后基底神经节功能变化的第一个目标是开发一种策略，允许在大鼠执行与帕金森运动缺陷相关的任务时记录运动回路中的持续活动。我们通过使用圆形跑步机来实现这一目标，该跑步机上有一个低于轨道的桨，以鼓励老鼠继续行走。具有单侧多巴胺细胞病变的大鼠（模拟单侧 PD）只要其朝向与多巴胺细胞病变同侧的方向，并且爪子与圆形外侧的病变半球相对，就能够在该跑步机上有效行走追踪。他向相反的对侧方向行走的能力变化更大。跑步机设置使我们能够在动物行走和休息时从完整和受损的半球连续监测基底神经节电路尖峰和局部场电位 (LFP) 活动。重要的是，在跑步机行走期间，半帕金森病大鼠的病变半球的这些记录中观察到高β（30 35Hz）范围内的同步活动显着增加。 这些观察结果为进一步研究提供了多种途径。 关于跑步机模型，去年，该部门的研究人员在量化大鼠向对侧方向行走时明显的迈步缺陷的性质方面取得了进展。虽然有些大鼠根本不会朝这个方向行走，并试图反转方向或只是冻结，但其他多巴胺细胞损伤似乎不太完整的大鼠在对侧行走时表现出步进模式的变化。我们新近改进的步态功能障碍测量方法可以更有意义地探索步进缺陷背后的神经生理学机制。一个新的目标是修改圆形跑步机，以允许从下方记录大鼠的步进模式，以更好地量化多巴胺损失引起的步态变化。 与正在进行的研究相关的第二个目标是在一系列行为状态下表征偏侧帕金森病大鼠中最明显受到过度振荡活动影响的运动回路组件。这种活动的鲁棒性使我们能够在运动电路内的不同节点上跟踪它，并深入了解这些电路不同组件内的峰值频率、振荡功率和相干性如何随行为状态变化。 我们不断积累的数据集应该可以深入了解异常振荡的根源以及啮齿动物和人类成像研究的观点。在多巴胺损伤后的最初几周内，当偏帕金森病发作时，多巴胺损伤半球的高β 30-35 Hz频率范围内丘脑底核（STN）、黑质（SNpr）和运动皮层的LFP光谱功率显着增加。老鼠很活跃，比如散步或梳理毛发。 在跑步机行走期间，这些核之间 30-35 Hz 范围内的 LFP 相干性也很高。 峰值频率随行为状态而变化，在注意力不集中的休息期间在 12-25 Hz 范围内，在警觉静止状态下接近 28 Hz，在跑步机行走期间在 30 到 35 Hz 范围内，病变后每周上升约 1 Hz。最近，我们添加了来自内侧前额叶皮层和前扣带皮层以及运动丘脑区域的同步记录。令人感兴趣的是新出现的观察结果，即在跑步机行走期间夸大的 30 35 Hz 振荡 LFP 活动在基底节丘脑皮质运动网络的某些区域内和之间是明显明显且一致的，而在其他区域则不然。此外，在一些但不是所有 LFP 功率增加的区域中，尖峰活动与 LFP 振荡显着锁相。在跑步机行走期间，增加的 30 35 Hz 振荡活动仅在多巴胺损伤半球的纹状体中呈斑片状，而在内侧前额叶皮层中并不明显，并且两个区域都没有显示出显着的尖峰 LFP 锁相，而在在运动皮层的 5/6 层中观察到 STN、SNpr 和适度的锁相。这些观察结果与有关振荡活动来源的现有假设相关。我们正在进行的研究表明，纹状体和苍白球的尖峰活动与皮质β范围活动缺乏显着的锁相，反对这些区域驱动振荡活动的同步输出。 我们对高β节律从运动网络内演化的动态中出现的可能性感兴趣，在多巴胺损失后，大鼠体内的共振频率处于高β范围。 另一项正在进行的努力是确定与损伤后运动缺陷的最早迹象相关的神经生理功能的变化。 是否有证据表明运动缺陷与基底神经节回路同步性增强之间存在因果关系？ 6-羟基多胺介导的多巴胺细胞损伤后一天内运动缺陷很明显，但同步 LFP 功率的增加在该时间点通常并不显着。然而，在多巴胺细胞损伤后早期，运动皮层的峰值频率发生了有趣的变化，从 40 Hz 左右的峰值到略低，因为峰值频率在损伤后的早期向 30 Hz 峰值移动，并且多巴胺细胞损伤后的相干性增加。运动皮层和 SNpr 之间的 30 Hz 范围。 我们目前正在撰写描述这一现象的手稿。 最后，我们已经开始研究，将抑制性 DREADD（由设计药物独家激活的设计受体）病毒 AAV2/8-hSyn-Hm4d(Gi)-mCjerry 输注到 SNpr 中，以评估这种方法在操纵活性中的效用。电机电路的不同组成部分。 注射设计药物 CNO（氯氮平-N-氧化物）的效果可以在左旋多巴诱导的运动障碍期间皮层高伽马振荡的持续时间以及多巴胺-多巴胺期间运动皮层中 LFP β 功率的降低方面看到。病变引起的运动迟缓。 为了准备获得具有 DREADD 病毒靶向 SNpr 和苍白球神经元子集潜力的转基因大鼠，我们还致力于获得对尖峰活动的速率和模式以及峰值频率如何进行更精细的分析。同步和振荡 LFP 活性的变化随这些细胞核内不同神经元亚群内的行为状态而变化。特别是，来自苍白球和 SNpr 的研究数据表明存在多种亚型，这些亚型可能通过蛋白质表达和解剖连接的差异进行区分。 最终，我们的目标是利用基于遗传（即 DREADD 和 CRE）的技术来识别和靶向基底神经节丘脑皮质回路的特定遗传定义的子组件，以补偿 PD 和其他神经系统疾病中多巴胺神经元退化引发的问题。