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（申请人提供）：丘脑底核（STN）通过对基底神经节的主要输出结构黑质网状部（SNR）的兴奋性影响，在运动控制中发挥重要作用。在帕金森氏症中