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.

当前在神经生理药物学部分中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。多巴胺能神经元系统的功能障碍与许多神经系统疾病的病因有关，包括帕金森氏病，迟发性运动障碍，亨廷顿郡骗子和注意力不足多动障碍。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，我们一直在研究这一假设，并探讨基底神经节输出对丘脑皮层环中活性的功能失调的后果。 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。 神经生理学的证据强烈支持这样的假设，即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。 这些变化促进了皮质振荡活性向下游部位的传播，并有助于基底神经节输出核中功能障碍振荡活性的出现。在该模型中，在2007财年中的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如何影响丘脑皮层环以及下游部位的活性，例如花梗核核（PPN）。 a）PPN与基底神经节，丘脑和运动皮层具有牢固的连接，并且是减轻帕金森病中医学上棘手的阿肯西尼州的深度脑刺激（DBS）的新目标。在第07财年，我们使用运动皮层局部场电位（LFP）活性作为参考研究了多巴胺损失对PPN的峰值时间的影响。观察结果表明，PPN活性相对于运动皮层的时机受到DA细胞病变的极大影响，这与从基底神经节输出核对PPN抑制性振荡输入增加的主要作用一致。这些发现突出了PD患者可能涉及运动功能障碍和PPN DBS功效的过程。 b）部分研究人员还在探索振荡和同步的基础神经节输出对the和感觉运动皮层的发射模式，以及在尿素 - 尿素 - 氨基化的6- hohda phate的6- hohda lisepationed hoptical pocification thal pocifififiestam thal thal的thalamus核核和甲状腺核核和运动核中的影响。从这些区域中的多巴胺质量，非仪器和控制半球记录了单个单位和局部电位活动，并且正在检查STN深脑刺激（DBS）对扣带和副阴性活性的影响。与基础神经节核中的观察结果相反，迄今为止的结果表明，多巴胺的单侧耗竭不会在麻醉大鼠中在病变和未变形的半球中的前扣带回或感觉运动皮层中的射击模式可靠。然而，副副活性的变化支持以下假设：丘脑中的峰值时间受到基底神经节的同步超极化输入的影响，并受到STN的深脑刺激的强烈调节。 2）DBS在帕金森氏病中DBS在STN中的疗效将注意力集中在STN中功能失调的发射模式的作用上。 β频率范围（8-18 Hz）中的振荡活性特别感兴趣，因为在DBS电极放置期间，在Bradykinetic Parkinsonian患者中的LFP记录显示在此频率范围内显着活性，这通过多巴胺受体刺激剂降低。 在07财年寻求了促进STN中β范围活性出现和STN产量潜在意义的机制的洞察力。 a）导致帕金森氏病的醒着的大鼠模型支持多巴胺丧失后STN和GP在β范围活性中增加同步的作用，并表明在降低多巴胺受体刺激的条件下，GP对STN活性产生了更大的影响。这些观察结果与以下假设一致：纹状体多巴胺的改变会导致清醒动物以及麻醉大鼠的皮质发射模式向下游核的传播增加。结果还显示了多巴胺受体刺激对完整和病变大鼠GP-STN关系的不同步作用。 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和GP。 结果表明，在运动活动和多巴胺系统功能改变的情况下，SNPR中β功率的变化比速率变化更一致。这种行为范式将有助于进一步探测SNPR中峰值活动与β功率之间的关系以及SNPR中记录的β活动的源/重要性。 3）与多巴胺细胞病变的作用相反，导致多巴胺受体刺激增加的治疗导致多动症。该行为状态与基底神经节输出之间的相关性在07财年中也在醒着的行为大鼠中进行了探索。 我们已经检查了醒着表现的动物的皮质 - 基质神经节网络的功能，目的是了解从皮质到基底神经节输出核在开放环境中自由移动的动物中多巴胺能调节的作用。 甲基苯甲酸酯是一种间接多巴胺激动剂，显着增加了运动活性以及前额叶皮层SNPR相干性，以前与先前与运动活性相关的频率范围，在发射模式的研究中，海马和前额叶皮层。 结果将这种相关性扩展到皮质 - 基质神经节电路，并表明甲基化甲酯诱导的儿茶酚胺外排的增加可在6-12 Hz范围内促进这些电路中的神经同步。 4）在07财年开始了协作研究，以探讨功能磁共振成像（fMRI）激活在感觉脱落后与重组相关的原代体体皮质激活的神经生理机制。这些研究的目的是进一步了解影响恢复可能性的半球间可塑性的过程。 rsults表明，在诺普神经支配后，剥夺皮质中的中间神经元活动有所增加。皮质抑制增加可能会影响中风和受伤后的康复程度。