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.

在过去的一年中，关于帕金森氏病（PD）的基底神经节功能变化的研究在神经生理药理科中一直集中在多巴胺丧失后运动电路中同步和振荡活性的性质和功能意义上。我们希望在PD的啮齿动物模型中进一步表征这种现象，将改善对PD患者的治疗方法，可深入了解多巴胺在运动系统功能中的作用，并促进我们对同步活性在脑电路中的重要性的理解。 如前所述，我们研究多巴胺细胞病变后基底神经节功能变化的第一个目标是制定策略，允许记录运动回路中正在进行的活动，而大鼠执行与帕金森氏运动不足有关的任务。我们通过使用圆形跑步机，在轨道上降低桨，以鼓励老鼠继续行走，从而实现了这一目标。只要他以与多巴胺细胞病变的方向定向，爪子在圆形轨道上的半球半球相对的爪子方向上，只要他在跑步机上定向，只要他在跑步机上定向，就可以有效地在该跑步机上行走。他在相反的对侧方向上行走的能力更加可变。跑步机设置使我们能够监视基底神经节电路尖峰和局部田间电势（LFP）在动物行走和休息时连续地从完整的和病变的半球中进行。重要的是，在跑步机行走期间，在跑步机期间，在Hemiparkinsonian大鼠的病变半球中，在这些记录中观察到高β（30 35Hz）范围的同步活性的显着增加。 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，在过去的一年中，调查人员在量化大鼠沿对侧方向行走时明显的踏脚缺陷的性质取得了进步。虽然有些大鼠根本不会朝这个方向行走，并尝试逆转方向或简单地冻结，但其他大鼠似乎具有较少的多巴胺细胞病变，在对侧行走时显示出阶梯模式的变化。我们新的步态功能障碍措施允许对踏入缺陷的神经生理机制进行更有意义的探索。一个新的目标是修改圆形跑步机以允许从下方记录大鼠步进模式，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表征在一系列行为状态下，马达电路成分最清楚地涉及到半骨骼大鼠夸张的振荡活动。该活动的鲁棒性质使我们能够在电机电路内的不同节点上跟踪它，并洞悉这些电路内不同组件内的峰频率，振荡能力和连贯性如何随行为状态而变化。 我们的累积数据集应洞悉异常振荡的来源，以及对啮齿动物和人的成像研究的观点。在多巴胺病变后的头几周，丘脑下核（STN）中的LFP光谱功率显着增加，在高β35Hz的高β35Hz频率范围内出现多巴胺半球的高β35Hz频率范围在Hemiparkinsinian老鼠时，在多巴胺的半球频率上是行动或groome groom necy n walling或Groom n. 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，注意力不集中的休息期间为12-25 Hz范围，在警报固定状态下接近28 Hz，在跑步机行走期间每周大约每周1 Hz的速度为30至35 Hz。最近，我们添加了内侧前额叶皮层和前扣带回皮层以及运动丘脑的区域的同时记录。有趣的是，新兴的观察结果是，跑步机行走过程中夸张的30 35 Hz振荡LFP活动显然是显而易见的，并且在基底神经节丘脑 - 皮质运动网络的某些区域内和之间相干。此外，在某些但不是所有LFP功率增加的区域中，尖峰活动与LFP振荡显着相位。增加30 35 Hz振荡活性仅在跑步机行走过程中多巴胺病变半球的纹状体中斑驳，并且在内侧的前额叶皮层中并不明显，并且在STN，SNPR和MIDEST-LESED SEPEST 5/6中观察到了强大的Spike-LFP相位锁定，而在STN，SNPR和MIDEST-LESEX上观察到了强大的相位锁定。这些观察结果与有关振荡活动来源的现有假设有关。我们正在进行的研究表明，缺乏纹状体和果皮球粒峰值活性的显着相锁定，这些峰值活性对皮质β范围的活性缺乏反对这些区域的同步输出的皮质β范围活性。 我们对高β节奏的可能性从动态状态出现，在运动网络中演变出来，多巴胺丢失后，大鼠的共振频率在高β范围内的谐振频率。 另一项持续的努力是确定神经生理功能的变化，这与病变后运动不足的最早迹象相关。 是否有证据表明运动缺陷与基底神经节电路中同步增加之间存在因果关系？ 在6-羟基胺介导的多巴胺细胞病变之后的一天内，运动缺陷是明显的，但是同步LFP功率的增加通常并不显着。但是，多巴胺细胞病变从40 Hz约40 Hz的峰值到较低的峰后，运动皮质的峰值频率发生了一种有趣的变化，因为峰值在30 Hz峰后的峰值频率在病变后的早期移动，并且在运动皮层和SNPR之间的30 Hz范围内相干性增加。 我们目前正在编写描述这种现象的手稿。 最后，我们已经开始研究，涉及将抑制性无知（由设计师药物专门激活的设计器受体）病毒，AAV2/8-HSYN-HM4D（GI）-MCJERRY，以评估SNPR，以评估这种方法在运动电路不同组件中操纵活性中这种方法的实用性。 在L-DOPA诱导的运动障碍期间，可以看到注射设计师药物，CNO（氯氮平-N-氧化物）的影响，以及在多巴胺诱导的Bradykineia期间运动皮层中LFPβ功率的降低。 为了准备获取具有Dreadd病毒的SNPR和Globus Pallidus神经元的靶向基因的大鼠的准备，我们还专注于对峰值活性的速率和模式进行更微妙的分析，以及如何在同步和振动性LFP活性中的峰值峰内与NEURON内部的不同Subsital Subsite neurons内部这些核心的峰值差异。特别是，数据来自于球pallidus的研究和SNPR，这表明存在多种亚型，这些亚型可能因蛋白质表达和解剖学连接的差异而有所区分。 最终，目的是利用基于遗传的（即Dreadd和Cre）技术来识别和靶向基底神经神经皮质皮层回路的特定遗传定义的亚组成部分，以补偿PD和其他神经疾病中多巴胺神经元的退化引起的问题。