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: 7969508
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 154.61万
• 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/7969508
• 关键词: Acute; Address; Affect; Animal Model; Animals; Area; Attention; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Cell Death; Cell Nucleus; Cells; Chronic; Clinical; Collaborations; Corpus striatum structure; Correlative Study; Data; Deafferentation procedure; Deep Brain Stimulation; Denervation; Disease; Dopa; Dopamine; Dopamine Receptor; Dyskinetic syndrome; Electrodes; Environment; Exhibits; Freezing; Frequencies; Functional Magnetic Resonance Imaging; Gait; Gilles de la Tourette syndrome; Goals; Image; Interneurons; Investigation; Label; Lesion; Limb structure; Maintenance; Medial; Midbrain structure; Modeling; Motor; Motor Cortex; Movement; Mus; Muscle; Neurons; Neurotransmitters; Output; Parafascicular Nucleus; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Peripheral nerve injury; Pharmacology; Physiology; Pontine structure; Posture; Preparation; Procedures; Rattus; Recovery; Research Personnel; Rest; Rodent Model; Role; Sensory; Shoulder; Side; Signal Transduction; Site; Somatosensory Cortex; Stroke; Structure of subthalamic nucleus; Substantia nigra structure; Thalamic Nuclei; Thalamic structure; Therapeutic Agents; Time; Training; United States National Institutes of Health; Urethane; Vibrissae; Walking; Work; awake; axon growth; dopaminergic neuron; in vivo; information processing; insight; interest; neurophysiology; novel; prevent; receptor; response; stroke recovery; transmission process

Current focus in the NPS is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. The Sections 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 and the effects of these alterations on sites receiving basal ganglia input, such as the thalamus and peduncular pontine nucleus (PPN). We have also initiated studies to explore the consequences of deep brain stimulation (DBS) of the peduncular pontine nucleus(PPN) and subthalamic nucleus (STN) on motor cortex activity. In addition, through collaborations with researchers working in the Mouse Imaging Facility (MIF) at NIH, we have investigated the neurophysiological correlates of functional magnetic resonance imaging (fMRI) changes in cortex in animal models of stroke and sensory denervation. 1) Section Researchers in previous years have used a rodent model of Parkinsons disease, the urethane-anesthetized rat with unilateral lesion of midbrain dopamine neurons, to investigate how dopamine cell death brings about alterations in neuronal firing patterns in basal ganglia output. Our studies have strongly supported the hypothesis that loss of striatal dopamine enhances transmission of cortical firing patterns to downstream sites via the striatal-pallidal pathway, contributing to the emergence of dysfunctional oscillatory activity in the basal ganglia output nuclei as well as in downstream sites such as the PPN. Further studies in the anesthetized rat model in FY 2009 have been directed at determining whether synchronized and oscillatory activity in basal ganglia output affects activity in thalamocortical loops. a) In contrast to the changes observed in the PPN firing patterns after dopamine cell lesion, Section researchers showed in FY 2009 that spike trains in the ventroanterior-ventrolateral (VAVL) nucleus and the parafascicular nucleus (PFN) of the thalamus are not affected as hypothesized by loss of dopamine. It has been predicted that changes in basal ganglia output after dopamine cell lesion should influence VAVL and PFN activity and impact cortical function. Results do not support the view that robust increases in oscillatory activity in basal ganglia output following dopamine loss drive changes in oscillatory activity in either VAVL or PFN thalamic nuclei. Studies are underway to further investigate the effects of basal ganglia output on activity in the ventral medial (VM) nucleus of the thalamus in normal and dopamine lesioned animals. 2) The efficacy of DBS in the STN and GPi in Parkinsons disease has focused attention on the role of dysfunctional firing patterns in the basal ganglia in this disorder. Oscillatory activity in the beta frequency range (8-35 Hz) is of special interest as LFP recordings in bradykinetic parkinsonian patients during DBS electrode placement show prominent activity in this frequency range, which is reduced by dopamine receptor stimulants. However, these clinical observations raise many questions difficult to address in patients, including the extent to which beta activity is differentially expressed in the intact vs. dopamine-depleted state, what drives the increase in beta, whether STN beta activity affects spike timing in basal ganglia output, how beta activity correlates with difficulties in gait, and what the functionally significant consequences of increased basal ganglia beta output are at downstream sites, such as the PPN and motor thalamus. Insight into these questions has been sought in studies in an awake behaving rat model of Parkinsons disease in FY09. a) 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. Neurophysiological recordings support the hypothesis that loss of dopamine is associated with increased LFP activity and neuronal spiking in the low beta (12 25 Hz) frequency range in the basal ganglia output during periods when the rats are at rest and inattentive to their environment. Data further suggest that dysfunctional expression of high beta (25 40 Hz) activity in basal ganglia output is associated with alert states and is evident at a slightly higher peak frequency during impaired walking. b) The same rat model was used to study how basal ganglia output is differentially expressed in the dopamine -depleted state before and after chronic l-dopa treatment. Acute treatment with l-dopa restores walking to control levels in the circular treadmill and reduces high beta frequency to levels comparable to those in the intact hemisphere. After chronic treatment with l-dopa, rats exhibited pronounced rotational behavior associated with marked decreases in SNpr firing rate in the dopamine-depleted hemisphere and subsequently, limb dyskinesias associated with more variable changes in SNpr rate and pattern with significant coherence with limb dyskinesia activity. c) Changes in motor cortex network function in conjunction with deep brain stimulation are underway in the urethane-anesthetized rodent model of Parkinsons disease in FY 08. Section researchers are comparing the effects of STN and PPN DBS on motor cortex activity in the rodent model of Parkinsons disease to help understand the immediate and persistent effects of these therapies in the anesthetized model, with plans to extend these studies in the awake behaving rat model of Parkinsons disease. 3) Collaborative studies are on-going in FY09 to explore the neurophysiological mechanisms underlying observations of functional magnetic resonance imaging (fMRI) activation of primary somatosensory cortex associated with reorganization following sensory deafferentation and response to stroke. To date, in vivo electrophysiological recordings and juxtacellular neuronal labeling in somatosensory cortex in urethane anesthetized rats with peripheral nerve injury have shown that deafferentation is specifically accompanied by elevated responsiveness of inhibitory interneurons, a change that is reflected in the fMRI signal but not the evoked local field potential responses. In addition, preparations have begun in FY 2009 to extend correlative studies with the MIF facility to include investigation of neurophysiological changes in cortex associated with unilateral deafferentation of the whiskers, comparing results with changes observed above with peripheral nerve injury. In addition, the section is investigating changes in cortical activity associated with recovery from stroke, focusing on oscillatory activity in the ultraslow frequency range which may facilitate axon growth and rewiring associated with recovery.

NP的当前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。几种不同大鼠制剂中的神经生理学研究 - 局部麻醉，固定和人为呼吸的大鼠，自由移动大鼠和全身麻醉的大鼠 - 提供了正常水平的多巴胺受体刺激的证据，以防止出现不适当地同步和振动性神经启发性，并在振动性的启发性上增加，并在振动性上增加了20.多巴胺受体刺激增强了这些功能失调模式的表达。在过去的一年中，我们一直在探索帕金森氏病动物模型中基底神经节输出功能失调改变的细节，以及这些改变对接受基底神经节输入的地点的影响，例如丘脑和花梗蓬托核（PPN）。 我们还开始了研究，以探索脚踏板庞然核（PPN）和丘脑下核（STN）对运动皮层活性的深脑刺激（DB）的后果。 此外，通过与NIH的小鼠成像设施（MIF）的研究人员的合作，我们研究了中风和感官神经动物模型中功能磁共振成像（fMRI）变化的神经生理学相关性。 1）前几年的研究人员使用了帕金森氏病的啮齿动物模型，帕金森氏病（尿烷 - 麻醉的大鼠）具有单侧脑多巴胺神经元的单侧病变，研究了多巴胺细胞死亡如何使基底神经节输出中神经元射击模式的变化改变。我们的研究强烈支持了这样的假设：纹状体多巴胺的丧失通过纹状体 - 帕利德途径增强了皮质发射模式向下游部位的传播，这有助于在基底神经节输出核以及下游场所中的基础神经节输出核中功能障碍振荡活性的出现。在2009财年的麻醉大鼠模型中，进一步研究旨在确定基底神经节输出中的同步和振荡活性是否会影响丘脑皮层环的活性。 a）与多巴胺细胞病变后的PPN放电模式中观察到的变化相反，研究人员在2009年表明，尖峰在腹膜内外侧（VAVL）核和副核酸核（PFN）中训练，而thalamus却没有受到thalamus的影响。 据预测，多巴胺细胞病变后基底神经节输出的变化应影响VAVL和PFN活性并影响皮层功能。 结果不支持这样的观点，即多巴胺损失驱动器在VAVL或PFN丘脑核中的振荡活性变化后，基底神经节输出的振荡活性的强劲增加。正在进行研究以进一步研究基底神经节输出对正常和多巴胺病变动物丘脑腹侧内侧（VM）核的活性的影响。 2）DBS在STN和GPI中对帕金森氏病的功效集中在基础神经节中功能失调的发射模式在这种疾病中的作用。 β频率范围（8-35 Hz）中的振荡活性是特别感兴趣的，因为在DBS电极放置期间，头肌运动帕金森患者的LFP记录显示出在此频率范围内的显着活性，这通过多巴胺受体刺激剂降低。然而，这些临床观察结果引发了许多难以解决的患者，包括在完整与多巴胺缺乏的状态下差异表达的β活动的程度，是什么推动了β的增加，STNβ活动是否会影响基底神经节的峰值时间，是否会在基础上增加beta活性，与基础上的困难相关，以及在盖伊特上的困难，降低了群体的影响，降低了群体的影响。 PPN和马达丘脑。在09财年的帕金森病大鼠模型中，已经寻求对这些问题的见解。 A）训练大鼠在新型的旋转跑步机中行走，而肩部肌肉的EMG活性和基底神经节输出中的神经元活性。在单方面损失多巴胺后，大鼠在旋转跑步机上逆时针行走，但在顺时针行走时倾向于冻结，因为这需要受影响的一侧对步态和姿势进行更苛刻的调整。 神经生理记录支持以下假设：在大鼠静止且对环境不集中的时期，在低β（12 25 Hz）频率范围内，多巴胺的丧失与低β（12 25 Hz）频率范围的LFP活性和神经元尖峰有关。数据进一步表明，基底神经节输出中高β（25 40 Hz）活性的功能失调与警报状态相关，并且在行走受损时，在峰值较高的峰值频率下显而易见。 b）使用相同的大鼠模型来研究如何在慢性L -DOPA处理之前和之后在多巴胺消耗状态中差异表达的基底神经节输出。 使用L-DOPA的急性处理可恢复步行到圆形跑步机中的控制水平，并将高β频率降低到与完整半球相当的水平。在用L-DOPA进行慢性治疗后，大鼠表现出明显的旋转行为，与多巴胺缺乏半球的SNPR发射速率显着降低有关，随后，Limb Dyskinesias与SNPR速率和模式的变化更大的变化相关，与Limb运动障碍活动的显着性相干相关。 c）在08财年的尿电烷 - 动工啮齿动物模型中，运动皮层网络的功能与深脑刺激的变化正在进行中。研究人员正在比较STN和PPN DBS对运动皮层对帕金斯疾病模型中的影响的影响，以帮助理解这些模型的影响，以帮助理解这些模型，以了解这些模型，以了解这些模型，以了解这些模型，这些模型在这些模型中的影响是在这些模型中的影响。帕金森病大鼠模型。 3）在09财年，协作研究正在进行中，以探讨功能磁共振成像（fMRI）激活的神经生理机制的主要体体皮质激活与感觉脱落和中风的反应后与重组相关的原发性体积皮层的激活。 迄今为止，体内电生理记录和在尿烷麻醉大鼠中具有周围神经损伤的大鼠体体感知皮层中的并置神经元标记已表明，脱eferentation特异性伴随着抑制性Interneurons的反应性升高，而抑制性Interneurons则反应了，但在FMRI中反映了eve evece the evece the Eveck eveck eveck eve the deveck eve the the eveck。 此外，在2009财年开始准备与MIF设施扩展相关研究的准备工作，包括研究与晶须单侧脱落相关的皮质的神经生理变化，将结果与上面观察到的结果与外周神经损伤进行了比较。此外，本节正在研究与中风恢复相关的皮质活性的变化，重点是在超声频率范围内的振荡活动，这可能促进轴突生长并与恢复相关。