Neurophysiology of striatal neurons after ischemia

缺血后纹状体神经元的神经生理学

• 批准号: 6571400
• 负责人: ZAO C XU
• 金额: $ 29.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6571400
• 关键词: cerebral ischemia /hypoxia; corpus striatum; dopamine; dopamine receptor; hippocampus; interneurons; laboratory rat; neural degeneration; neural transmission; neurons; neurophysiology; pathologic process; potassium channel; prosencephalon; statistics /biometry; synapses; voltage /patch clamp

DESCRIPTION (provided by applicant): Stroke is the leading cause of death and number one cause of disability in the United States. The objective of this proposal is to identify the cellular mechanisms of electrophysiological changes associated with neuronal damage in striatum after transient cerebral ischemia. Spiny neurons in striatum are highly vulnerable to cerebral ischemia. The current knowledge about the pathogenesis of neuronal injury after ischemia is mainly derived from studies on hippocampal neurons. However, the ischemic threshold and time course of cell death in striatum are different from 'those in hippocampus. The neurophysiological changes of striatal neurons following ischemia and their relationship to neuronal damage might not be the same as those of hippocampal neurons. Accumulating evidence has indicated that dopamine aggravates neuronal injury in striatum. Using intracellular recording and staining techniques in vivo, recent studies from this laboratory have demonstrated the depression of inhibitory postsynaptic potentials (IPSPs) in spiny neurons after severe cerebral ischemia. The depression of IPSPs may trigger the excitotoxic neuronal injury in striatum after ischemia. The working hypothesis of this proposal is that the depression of inhibitory components in spiny neurons after ischemia is due to the reduction of inhibitory inputs and dopamine facilitates this process by modulating the synaptic transmission and potassium conductance of striatal neurons. Using in vitro and in vivo preparations, the experiments in this proposal are designed to determine: 1) How excitatory and inhibitory synaptic transmission in spiny neurons and interneurons are altered after ischemia? 2) How dopamine modulation influences these changes? 3) Whether application of dopamine receptor agonists or antagonists protects striatal neurons after transient forebrain ischemia? The specific aims of the proposed experiments are: 1. To compare the excitatory and inhibitory inputs to spiny neurons before and after transient forebrain ischemia. 2. To examine the changes of excitatory inputs and excitability of interneurons after ischemia. 3. To investigate the effects of dopamine modulation on synaptic transmission and potassium currents in spiny neurons after ischemia. 4. To evaluate the protection of dopamine receptor agonist or antagonist on striatal neurons after transient forebrain ischemia. The results of these studies will improve understanding of mechanisms of neuronal injury upon resuscitation following cardiac arrest and provide bases for developing therapeutical interventions for stroke patients.

描述（由申请人提供）：中风是死亡的主要原因，也是美国残疾的第一原因。该提案的目的是确定与瞬时脑缺血后纹状体上与神经元损伤相关的电生理变化的细胞机制。纹状体中的棘神经元极易受到脑缺血的影响。缺血后神经元损伤发病机理的当前知识主要来自海马神经元的研究。但是，纹状体中细胞死亡的缺血阈值和时间过程与海马中的缺血阈值不同。缺血后纹状体神经元的神经生理变化及其与神经元损伤的关系可能与海马神经元的神经元不同。积累的证据表明，多巴胺加剧了纹状体中的神经元损伤。使用体内的细胞内记录和染色技术，该实验室的最新研究表明，严重的脑缺血后棘神经元中抑制性突触后潜能（IPSP）的抑制作用。 IPSP的抑郁可能会引发缺血后纹状体中的兴奋性神经元损伤。该提议的工作假设是，缺血后棘神经元中抑制性成分的抑郁症是由于抑制性输入的减少和多巴胺通过调节突触传递和Striatal神经元的钾电导而促进了这一过程。使用体外和体内制剂，该提案中的实验旨在确定：1）缺血后刺激性神经元和中间神经元的兴奋性和抑制性突触传播如何改变？ 2）多巴胺调节如何影响这些变化？ 3）多巴胺受体激动剂或拮抗剂的应用是否在瞬时前脑缺血后保护纹状体神经元？所提出的实验的具体目的是：1。将兴奋性和抑制性输入与短暂性前脑缺血之前和之后进行比较。 2。检查缺血后兴奋性输入的变化和中间神经元的兴奋性。 3。研究多巴胺调节对缺血后棘神经元突触传播和钾电流的影响。 4。评估瞬时前脑缺血后对纹状体神经元的多巴胺受体激动剂或拮抗剂的保护。这些研究的结果将提高心脏骤停后复苏后神经元损伤机制的理解，并为中风患者开发治疗干预措施提供基础。