Synaptic regulation of single substantia nigra pars reticulata neurons

单个黑质网状部神经元的突触调节

• 批准号: 7880626
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 27.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880626
• 关键词: Action Potentials; Affect; Agonist; Applications Grants; Axon; Basal Ganglia; Bradykinesia; Brain; Brain region; Cell Nucleus; Cells; Chronic; Complex; Data; Deep Brain Stimulation; Denervation; Disease; Dopamine; Dopamine Receptor; Electric Stimulation; Electron Microscopy; Excitatory Postsynaptic Potentials; Frequencies; Functional disorder; Gait abnormality; Globus Pallidus; Glutamates; Goals; Human; Incidence; Laboratories; Ligands; Mediating; Mental Depression; Metabotropic Glutamate Receptors; Modeling; Motor; Movement; Muscle Rigidity; Neurons; Neurotransmitters; Operative Surgical Procedures; Output; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Play; Rattus; Recurrence; Regulation; Reporting; Role; STN stimulation; Seizures; Series; Site; Slice; Solutions; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Synaptic Potentials; System; Techniques; Testing; Tremor; Work; brain pathway; dopaminergic neuron; gamma-Aminobutyric Acid; improved; interest; nerve supply; neurophysiology; novel; pars compacta; public health relevance; receptor; research study; synaptic depression; transmission process

DESCRIPTION (provided by applicant): The subthalamic nucleus (STN) plays an important role in movement control by exerting its excitatory influence on the substantia nigra pars reticulata (SNR), a major output structure of the basal ganglia. In Parkinson's disease, increased bursting activity in the subthalamonigral pathway is thought to contribute to motor symptoms such as rigidity, bradykinesia and tremor. Preliminary data from our lab show that focal electrical stimulation of the STN evokes an initial monosynaptic EPSC followed by a series of late EPSCs superimposed on a slow inward shift in holding current that lasts 200 - 500 ms. Results thus far support the hypothesis that this complex EPSC is generated by activation of recurrent axon collaterals within the STN. Because STN stimulation evokes a burst of action potentials when recording under current-clamp, the complex EPSC may represent a novel mechanism for promoting burst firing in SNR neurons. In contrast, STN stimulation only evokes monophasic EPSCs in substantia nigra pars compacta (SNC) dopamine neurons, which suggests that the STN output to SNR may differ from the STN output to SNC dopamine neurons. The major goals of our proposed studies are to characterize the neurophysiology of complex EPSCs and their regulation by neurotransmitter systems. Experiments will use standard whole-cell patch pipette recording techniques to record from neurons in the rat brain slice. Complex EPSCs will be evoked in SNR neurons by focal electrical stimulation of the STN, and drug solutions will be delivered to specific regions of the brain slice using a fast-flow microapplicator. Planned experiments will use antidromic stimulation techniques of the SNR and SNC to characterize recurrent, polysynaptic connections within the STN. Other experiments will investigate sites of action and characterize receptor pharmacology for the regulation of complex EPSCs by GABA and dopamine receptor ligands. In conjunction with neurophysiological experiments, brain slices will also be used to document recurrent axonal collateral innervation of STN neurons using electron microscopy. Due to the importance of the subthalamonigral pathway in regulating firing pattern of SNR neurons, results of these studies may have important implications for the pathophysiology and possible treatment of Parkinson's disease. PUBLIC HEALTH RELEVANCE: Many studies suggest that excessive bursting activity in the brain pathway from subthalamic nucleus to substantia nigra pars reticulata contributes to symptoms of Parkinson's disease as well as the propagation of some types of seizures. Our studies show that activation of the subthalamonigral pathway causes long-lasting depolarization and bursts of action potentials in reticulata neurons recorded in the rat brain slice. By characterizing how synaptic connections and modulatory transmitter systems regulate this pathway, our studies may provide useful information to improve the therapy of these human disorders.

描述（由申请人提供）：底丘脑核（STN）通过对基底神经节的主要输出结构黑质网状部（SNR）发挥兴奋性影响，在运动控制中发挥重要作用。在帕金森病中，突发活动增加 丘脑下通路被认为会导致运动症状，如强直、运动迟缓和震颤。我们实验室的初步数据表明，STN 的局灶性电刺激会引发初始单突触 EPSC，随后是一系列后期 EPSC，叠加在持续 200 - 500 ms 的缓慢向内移动的保持电流上。迄今为止的结果支持这样的假设：这种复杂的 EPSC 是由 STN 内的轴突侧枝循环激活而产生的。因为 STN 刺激会引起 在电流钳下记录时会出现动作电位的爆发，复杂的 EPSC 可能代表了一种促进 SNR 神经元爆发放电的新机制。相反，STN 刺激仅唤起黑质致密部 (SNC) 多巴胺神经元中的单相 EPSC，这表明 STN 输出到 SNR 可能与 STN 输出到 SNC 多巴胺神经元不同。我们提出的研究的主要目标是表征复杂 EPSC 的神经生理学及其神经递质系统的调节。实验将使用标准的全细胞贴片吸管记录技术来记录大鼠脑切片中的神经元。通过 STN 的局部电刺激，将在 SNR 神经元中诱发复杂的 EPSC，并使用快速流动的微涂药器将药物溶液输送到脑切片的特定区域。计划中的实验将使用 SNR 和 SNC 的逆向刺激技术来表征 STN 内反复出现的多突触连接。其他实验将研究 GABA 和多巴胺受体配体调节复杂 EPSC 的作用位点并表征受体药理学。结合 神经生理学实验中，脑切片也将用于通过电子显微镜记录 STN 神经元的反复轴突侧支神经支配。由于丘脑下通路在调节 SNR 神经元放电模式中的重要性，这些研究结果可能对帕金森病的病理生理学和可能的治疗具有重要意义。公共卫生相关性：许多研究表明，大脑通路中的过度爆发活动 丘脑底核到黑质网状部会导致帕金森病的症状以及某些类型癫痫发作的传播。我们的研究表明，丘脑下通路的激活会导致大鼠脑切片中记录的网状神经元持久去极化和动作电位爆发。通过表征突触连接和调节递质系统如何调节该通路，我们的研究可能为改善这些人类疾病的治疗提供有用的信息。