Influence of subthalamic nucleus on striatal dopamine

丘脑底核对纹状体多巴胺的影响

• 批准号: 6721331
• 负责人: Thomas N Wichmann
• 金额: $ 30.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721331
• 关键词: GABA receptor; Macaca mulatta; Parkinson' s disease; autoradiography; dopamine; electrophysiology; immunocytochemistry; microdialysis; microelectrodes; neurons; neurotransmitter antagonist; receptor expression; substantia nigra; subthalamus

DESCRIPTION:(from applicant's abstract) Degeneration of the dopaminergic nigrostriatal tract results in Parkinson's disease. Over the last years, rodent studies have provided evidence that the activity of the source neurons of the nigrostriatal tract in the substantia nigra pars compacta (SNc) is modulated by afferents from the subthalamic nucleus (STN). Increased STN output, a central feature of most models of parkinsonian pathophysiology, could impact SNc function in early parkinsonism, helping to compensate for the loss of striatal dopamine by increased driving of nigrostriatal neurons. In rodents, STN and SNc are linked via excitatory glutamatergic projections, or via inhibitory pathways involving GABAergic neurons in the substantia nigra pars reticulata (SNr). Activation of the excitatory projections results in increased bursting in SNc, whereas activation of the inhibitory projections lowers the average discharge rates in SNc. Our preliminary data in primates have also demonstrated excitatory and inhibitory effects of STN stimulation on SNc activity, and have indicated that striatal DA levels may be increased with STN stimulation and reduced with STN inactivation. Effects on striatal dopamine may be explained by the direct synaptic STN-SNc interaction, by actions mediated via long loop circuits through thalamus and cortex, as well as by presynaptic mechanisms. The proposed experiments will explore the STN-SNc relationship in primates, with the general hypothesis that STN activation will result in increased burst discharges in SNc and increased dopamine levels in the striatum, while STN inactivation will result in the opposite. A combination of electrophysiologic, microdialysis and anatomic methods will be used to assess effects of transient manipulations of STN activity, induced by intra-STN injections of the GABA receptor agonist muscimol or the GABA receptor antagonist bicuculline, on the neuronal activity in SNc and SNr and on striatal dopainine levels (S.A. V 1/2). Similarly, effects of "deep brain" stimulation and lesions of STN will be studied to assess the impact of these commonly used neurosurgical interventions on SNc and SNr activity, and on striatal DA. In the case of STN lesions, the density of glutamate and GABA receptors in SNc will also be determined (immunoautoradiography) as an inverse measure of the strength of glutamatergic and GABAergic inputs to SNc. These studies will provide insight into the role of the STN-SNc interaction under normal and parkinsonian conditions and will help to understand the mechanisms of action of neurosurgical treatments aimed at SIN in parkinsonian patients.

描述：（从申请人的摘要中） 多巴胺能乳清纹状体的变性导致帕金森氏症 疾病。在过去的几年中，啮齿动物研究提供了证据 黑质区源神经元的活性 Nigra pars commacta（SNC）受到丘脑下丘脑的传入调节 核（STN）。增加STN输出，大多数模型的主要特征 帕金森氏病理生理学，可能会影响早期帕金森氏症的SNC功能， 通过增加的驾驶，帮助弥补纹状体多巴胺的损失 黑质神经元。 在啮齿动物中，STN和SNC通过兴奋性谷氨酸能预测或 通过黑质中涉及GABA能神经元的抑制途径 PARS Eticulata（SNR）。激活兴奋性预测导致 SNC的爆发增加，而抑制性投影的激活 降低SNC的平均排放率。我们在灵长类动物中的初步数据 还表现出STN刺激的兴奋性和抑制作用对 SNC活动，并表明纹状体DA水平可能会增加 STN刺激并随着STN灭活而还原。对纹状体多巴胺的影响 可以通过动作来解释直接的突触STN-SNC相互作用 通过长循环电路通过丘脑和皮层进行介导，以及 突触前机制。 提出的实验将探索灵长类动物中的STN-SNC关系， 通过一般假设，即STN激活将导致爆发增加 在SNC中排出并增加纹状体的多巴胺水平，而STN 灭活将导致相反。电生理学的组合， 微透析和解剖方法将用于评估瞬态的影响 由GABA内注射引起的STN活性的操纵 受体激动剂muscimol或GABA受体拮抗剂双瓜氨酸在 SNC和SNR的神经元活性以及纹状体多发胺水平（S.A. V 1/2）。 同样，“深脑”刺激和STN病变的影响将是 研究以评估这些常用神经外科干预的影响 在SNC和SNR活动以及纹状体DA上。在STN病变的情况下 SNC中的谷氨酸和GABA受体的密度也将确定 （免疫摄影）作为谷氨酸能强度的逆量度 和SNC的GABA能输入。 这些研究将洞悉STN-SNC相互作用的作用 在正常和帕金森氏症情况下，将有助于了解 针对帕金森尼罪的神经外科治疗的作用机制 患者。