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: 7525652
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 26.64万
• 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/7525652
• 关键词: Action Potentials; Affect; Agonist; Appendix; Axon; Basal Ganglia; Bradykinesia; Brain; Brain region; Cell Nucleus; Cells; Chronic; Complex; Condition; Data; Deep Brain Stimulation; Denervation; Disease; Dopamine; Dopamine Receptor; Electric Stimulation; Electron Microscopy; Electrons; Excitatory Postsynaptic Potentials; Fire - disasters; Functional disorder; Gait abnormality; Generations; Globus Pallidus; Glutamates; Goals; Histological Techniques; Human; Incidence; Interneurons; Label; Laboratories; Ligands; Mediating; Microscopic; Modeling; Motor; Movement; Muscle Rigidity; Nerve; Neurons; Neurotransmitters; Operative Surgical Procedures; Output; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Play; Public Health; Rattus; Recurrence; Regulation; Reporting; Role; Role playing therapy; Seizures; Series; Site; Slice; Solutions; Standards of Weights and Measures; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Supervision; Symptoms; Synapses; Synaptic Potentials; Synaptic Transmission; System; Techniques; Testing; Thinking; Tremor; Work; biocytin; brain pathway; dopaminergic neuron; gamma-Aminobutyric Acid; improved; interest; nerve supply; neurophysiology; novel; pars compacta; receptor; research study; 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）：丘脑下核（STN）通过对基底神经节的主要输出结构发挥刺激作用，在运动控制中起重要作用。在帕金森氏病中，增加了活动的爆发活动 据认为，丘脑下腔途径会导致运动症状，例如僵硬，颤音和震颤。我们实验室的初步数据表明，对STN的局灶性电刺激唤起了初始单突触EPSC，然后在持续200-500毫秒内的持续200-500毫秒内的一系列晚期EPSC中叠加在慢速内向移位上。到目前为止，结果支持以下假设：这种复杂的EPSC是通过STN内复发轴突侧支激活而产生的。因为STN刺激引起了 复杂的EPSC在电流夹下记录时发出的动作电位可能代表了促进SNR神经元中爆发的新机制。相比之下，STN刺激仅引起Nigra pars compacta（SNC）多巴胺神经元中的单相EPSC，这表明SNR的STN输出可能从STN输出到SNC多巴胺神经元有所不同。我们提出的研究的主要目标是表征复杂EPSC的神经生理及其对神经递质系统的调节。实验将使用标准的全细胞贴片移液器记录技术来记录大鼠脑切片中的神经元。复杂的EPSC将通过对STN的局灶性电刺激在SNR神经元中诱发，并且使用快速流动微应用程序将药物溶液传递到脑切片的特定区域。计划的实验将使用SNR和SNC的抗原刺激技术来表征STN内反复发作的多突触连接。其他实验将研究作用部位，并表征GABA和多巴胺受体配体调节复杂EPSC的受体药理学。结合 神经生理实验，脑切片也将用于使用电子显微镜记录STN神经元的复发性轴突侧支神经。由于亚丘脑途径在调节SNR神经元的发射模式中的重要性，这些研究的结果可能对帕金森氏病的病理生理学和可能治疗可能具有重要意义。公共卫生相关性：许多研究表明，大脑通道中的过度爆发活动 丘脑下核的核核Nigra pars nigiculata有助于帕金森氏病的症状以及某些类型的癫痫发作的传播。我们的研究表明，亚丘脑下途径的激活导致持久的去极化和在大鼠脑切片中记录的网状神经元中的作用电位爆发。通过表征突触连接和调节发射器系统如何调节这一途径，我们的研究可以提供有用的信息来改善这些人类疾病的治疗。