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: 7594641
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 170.57万
• 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/7594641
• 关键词: Affect; Animals; Anterior; Area; Attention; Attention deficit hyperactivity disorder; Basal Ganglia; Behavioral; Behavioral Paradigm; Catecholamines; Cell Death; Cell Nucleus; Cells; Chorea; Chronic; Computer information processing; Condition; Corpus striatum structure; Deafferentation procedure; Deep Brain Stimulation; Denervation; Disease; Dopamine; Dopamine Agonists; Dopamine Receptor; EEF1A2 gene; Electrodes; Environment; Etiology; Fire - disasters; Forelimb; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Gilles de la Tourette syndrome; Goals; Hippocampus (Brain); Hyperactive behavior; Implant; Injury; Interneurons; Lead; Lesion; Maintenance; Methylphenidate; Midbrain structure; Modeling; Motor; Motor Activity; Motor Cortex; Movement; Muscle; Neurons; Neurotransmitters; Output; Oxidopamine; Parafascicular Nucleus; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Pharmacology; Physiology; Placement; Prefrontal Cortex; Preparation; Probability; Procedures; Process; Range; Rate; Rattus; Recovery; Rehabilitation therapy; Research Personnel; Rodent Model; Role; Sensory; Site; Somatosensory Cortex; Source; Stroke; Substantia nigra structure; Symptoms; System; Tardive Dyskinesia; Thalamic structure; Therapeutic Agents; Time; Training; Urethane; Walking; awake; dopamine system; dopaminergic neuron; insight; interest; nervous system disorder; neurophysiology; prevent; receptor; relating to nervous system; transmission process

Current focus in the Neurophysiological Pharmacology Section is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. Dysfunction of the dopaminergic neuronal system has been implicated in the etiology of many neurological diseases, including Parkinsons disease, tardive dyskinesia, Huntingtons chorea and attention deficit hyperactivity disorder. 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 investigating this hypothesis and exploring the consequences of dysfunctional alterations in basal ganglia output on activity in thalamocortical loops. 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. Neurophysiological evidence has strongly supported the hypothesis that loss of striatal dopamine enhances transmission of cortical firing patterns to downstream sites via the striatal-pallidal pathway. These changes facilitate transmission of cortical oscillatory activity to downstream sites and contribute to the emergence of dysfunctional oscillatory activity in the basal ganglia output nuclei. Further studies in this model in FY 2007 have been directed at determining how synchronized and oscillatory activity in basal ganglia output may affect activity in thalamocortical loops as well as in downstream sites such as the pedunculopontine nucleus (PPN). a) The PPN has robust connections with the basal ganglia, thalamus and motor cortex, and is a new target for deep brain stimulation (DBS) for the alleviation of medically intractable akinesia in Parkinsons disease. In FY 07 we have investigated the effect of dopamine loss on spike timing in the PPN using motor cortex local field potential (LFP) activity as a reference. Observations show that timing of PPN activity with respect to motor cortex is dramatically affected by DA cell lesion, consistent with a dominant effect of increased inhibitory oscillatory input to the PPN from basal ganglia output nuclei. These findings highlight processes that may be involved in motor dysfunction and PPN DBS efficacy in PD patients. b) Section researchers are also exploring the impact of oscillatory and synchronized basal ganglia output on firing patterns in the cingulate and sensorimotor cortex and in the parafascicular nucleus and motor nuclei of the thalamus in the urethane-anesthetized 6-OHDA lesioned rat to determine how dopamine loss modifies thalamocortical loop function. Single unit and local field potential activities are being recorded from the dopamine-lesioned, non-lesioned and control hemispheres in these areas, and the impact of deep brain stimulation (DBS) of the STN on cingulate and parafascicular activity is being examined. In contrast to observations in basal ganglia nuclei, the results to date show that unilateral depletion of dopamine does not robustly alter firing patterns in the anterior cingulate or sensorimotor cortices in lesioned and non-lesioned hemispheres in the anesthetized rat. However, changes in parafascicular activity supports the hypothesis that spike timing in the thalamus is affected by synchronized hyperpolarizing input from the basal ganglia and strongly modulated by deep brain stimulation of the STN. 2) The efficacy of DBS in the STN in Parkinsons disease has focused attention on the role of dysfunctional firing patterns in the STN. Oscillatory activity in the beta frequency range (8-18 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. Insight into mechanisms promoting emergence of beta range activity in the STN and potential significance of STN output in this range has been sought in FY07. a) Results in an awake behaving rat model of Parkinsons disease support a role for increased synchronization between STN and GP in the beta range activity after dopamine loss and suggest a greater impact of GP on STN activity in conditions of decreased dopamine receptor stimulation. These observations are consistent with the hypothesis that alterations in striatal dopamine lead to increased transmission of cortical firing patterns to downstream nuclei in awake animals as well as in anesthetized rats. Results also show a desynchronizing effect of dopamine receptor stimulation on GP-STN relationships in both intact and lesioned rats. b) To further explore the significance of beta range activity in the STN and GP after loss of dopamine, rats were trained to walk in the rotating treadmill and implanted bilaterally electromyogram bundles for recording muscle activity in the forelimb and with microwire bundles for chronic recording of spike and local field potential (LFP) activity in the SNpr, a basal ganglia output nucleus receiving input from the STN and GP. Results indicate that changes in beta power in the SNpr are more consistent than changes in rate in the context of alterations in motor activity and dopamine system function. This behavioral paradigm will be useful for further probing of relationships between spiking activity and beta power in SNpr and the source/significance of beta activity recorded in the SNpr. 3) In contrast to effects of dopamine cell lesion, treatments which lead to increases in dopamine receptor stimulation lead to hyperactivity. Correlations between this behavioral state and basal ganglia output have been also explored in FY07 in awake behaving rats. We have examined cortico-basal ganglia network function in the awake behaving animal, with the aim of understanding the role of dopaminergic modulation of information flow from the cortex to the basal ganglia output nuclei in freely-moving animals in an open field environment. Methylphenidate, an indirect dopamine agonist, significantly increased locomotor activity as well as prefrontal cortex SNpr coherence in a frequency range previously associated with motor activity in studies of firing pattern the hippocampus and prefrontal cortex. Results extend this correlation to the cortico-basal ganglia circuites and indicate that increased catecholamine efflux induced by methylphenidate promotes neural synchrony in these circuits in the 6-12 Hz range. 4) Collaborative studies have been initiated in FY07 to explore the neurophysiological mechanisms underlying observations of functional magnetic resonance imaging (fMRI) activation of primary somatosensory cortex associated with reorganization following sensory deafferentation. The goal of these studies is to further understand processes involved in interhemispheric plasticity which impact the probability of recovery. Rsults suggest that there is an increase in interneuron activity in the deprived cortex following forepaw denervation. Increased cortical inhibition may affect the degree of rehabilitation following stroke and injury.

神经生理药理学部分当前的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。多巴胺能神经系统的功能障碍与许多神经系统疾病的病因有关，包括帕金森病、迟发性运动障碍、亨廷顿舞蹈病和注意力缺陷多动障碍。该部门对几种不同的大鼠制剂（局部麻醉、固定和人工呼吸的大鼠、自由活动的大鼠和全身麻醉的大鼠）进行的神经生理学研究提供了证据，表明正常水平的多巴胺受体刺激可防止出现不适当的同步和振荡神经元放电活动。基底神经节网络，而多巴胺受体刺激的显着增加和减少增强了这些功能障碍模式的表达。在过去的一年中，我们一直在研究这一假设，并探索基底神经节输出功能失调改变对丘脑皮质环活动的影响。 1）部分研究人员前几年使用了帕金森病的啮齿动物模型，即中脑多巴胺神经元单侧损伤的聚氨酯麻醉大鼠，来研究多巴胺细胞死亡如何导致基底神经节输出中神经元放电模式的改变。 神经生理学证据强烈支持这样的假设：纹状体多巴胺的丧失增强了皮质放电模式通过纹状体-苍白球通路向下游部位的传递。 这些变化促进皮质振荡活动向下游位点的传递，并导致基底神经节输出核中出现功能失调的振荡活动。 2007 财年对该模型的进一步研究旨在确定基底神经节输出的同步和振荡活动如何影响丘脑皮质环以及桥脚核 (PPN) 等下游部位的活动。 a) PPN 与基底神经节、丘脑和运动皮层有牢固的联系，是缓解帕金森病中难以治愈的运动不能的深部脑刺激 (DBS) 的新靶点。在 07 财年，我们使用运动皮层局部场电位 (LFP) 活动作为参考，研究了多巴胺损失对 PPN 尖峰时间的影响。观察表明，运动皮层的 PPN 活动时间受到 DA 细胞损伤的显着影响，这与基底神经节输出核对 PPN 的抑制性振荡输入增加的主导效应一致。这些发现强调了可能涉及 PD 患者运动功能障碍和 PPN DBS 疗效的过程。 b) 该部门的研究人员还在探索振荡和同步基底神经节输出对乌拉坦麻醉的 6-OHDA 损伤大鼠的扣带皮层和感觉运动皮层以及丘脑束旁核和运动核的放电模式的影响，以确定多巴胺如何损失会改变丘脑皮质环路功能。正在从这些区域的多巴胺损伤、非损伤和控制半球记录单个单位和局部场电位活动，并且正在检查 STN 的深部脑刺激 (DBS) 对扣带皮和束旁活动的影响。与基底神经节核中的观察结果相反，迄今为止的结果表明，多巴胺的单侧消耗不会强烈改变麻醉大鼠病变和非病变半球的前扣带皮层或感觉运动皮层的放电模式。然而，束旁活动的变化支持了这样的假设：丘脑的尖峰时间受到来自基底神经节的同步超极化输入的影响，并受到 STN 的深部脑刺激的强烈调节。 2) DBS 在 STN 中对帕金森病的疗效引起了人们对 STN 中功能失调的放电模式的作用的关注。 β 频率范围 (8-18 Hz) 中的振荡活动特别令人感兴趣，因为在 DBS 电极放置过程中运动迟缓的帕金森病患者的 LFP 记录显示在此频率范围内有显着的活动，但多巴胺受体兴奋剂会降低该频率范围的活动。 2007 财年，人们一直在寻求深入了解促进 STN 中出现 β 范围活动的机制以及该范围内 STN 输出的潜在意义。 a) 帕金森病大鼠清醒行为模型的结果支持多巴胺丧失后 STN 和 GP 在 β 范围活性中同步性增强的作用，并表明在多巴胺受体刺激减少的情况下 GP 对 STN 活性的影响更大。这些观察结果与以下假设一致：在清醒的动物以及麻醉的大鼠中，纹状体多巴胺的改变导致皮质放电模式向下游核的传递增加。结果还表明，多巴胺受体刺激对完整大鼠和病变大鼠的 GP-STN 关系具有去同步作用。 b) 为了进一步探讨多巴胺丧失后 STN 和 GP 中 β 范围活动的意义，训练大鼠在旋转跑步机上行走，并植入双侧肌电图束以记录前肢的肌肉活动，并用微丝束长期记录SNpr 中的尖峰和局部场电位 (LFP) 活动，SNpr 是基底神经节输出核，接收来自 STN 和 GP 的输入。 结果表明，在运动活动和多巴胺系统功能改变的背景下，SNpr β 功率的变化比速率的变化更加一致。这种行为范式将有助于进一步探讨 SNpr 中的尖峰活动和 β 功率之间的关系以及 SNpr 中记录的 β 活动的来源/意义。 3) 与多巴胺细胞损伤的影响相反，导致多巴胺受体刺激增加的治疗会导致多动症。 2007 财年，我们还在清醒行为的大鼠中探索了这种行为状态与基底神经节输出之间的相关性。 我们检查了清醒行为动物的皮质基底神经节网络功能，目的是了解在开放场地环境中自由移动的动物中，多巴胺能调节从皮质到基底神经节输出核的信息流的作用。 哌醋甲酯是一种间接多巴胺激动剂，在海马和前额皮质放电模式研究中，显着增加了运动活动以及前额皮质 SNpr 的一致性，该频率范围先前与运动活动相关。 结果将这种相关性扩展到皮质基底节回路，并表明哌醋甲酯诱导的儿茶酚胺流出增加可促进这些回路在 6-12 Hz 范围内的神经同步。 4) 合作研究已于 2007 财年启动，旨在探索功能性磁共振成像 (fMRI) 观察初级体感皮层激活与感觉传入神经阻滞后重组相关的神经生理学机制。这些研究的目的是进一步了解影响恢复概率的半球间可塑性过程。 结果表明，前爪去神经后，被剥夺的皮质中的中间神经元活动增加。皮质抑制的增加可能会影响中风和受伤后的康复程度。