SYNAPTIC PHARMACOLOGY OF SINGLE SUBTHALAMIC NEURONS

单个底丘脑神经元的突触药理学

• 批准号: 2848632
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 17.32万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2848632
• 关键词: 6 hydroxydopamine; Parkinson's disease; acetylcholine; action potentials; brain electrical activity; calcium flux; dihydroxyphenylalanine; disease /disorder model; dopamine; dopamine receptor; electrical property; experimental brain lesion; fluorescent dye /probe; glutamate receptor; immunocytochemistry; laboratory rat; neuropharmacology; receptor sensitivity; substantia nigra; subthalamus; synapses; tissue /cell culture; voltage /patch clamp; voltage gated channel

DESCRIPTION: (adapted from applicant's abstract) Electrophysiological studies will be conducted in rat brain slices to examine the characteristics of excitatory and inhibitory inputs to subthalamic neurons. Recordings in normal rats will be compared to those of rats treated with 6-hydroxydopamine (6-OHDA) and levodopa-treated animals, which will allow insight into Parkinson's disease. Specific aim 1 is devoted to characterization of voltage-dependent currents and effects of dopamine on membrane properties of subthalamic neurons in vitro. These studies will address the hypothesis that prolonged stimulation of subthalamic neurons reduces their activity because of persistent inactivation of voltage-gated calcium currents or desensitization of glutamate receptors. This hypothesis will specifically address how stimulation of this region "deep brain stimulation "may yield a clinical effect. Specific aim 2 will examine the effects of dopamine, ACh, and other transmitters on synaptic currents in both subthalamic and substantia nigra - reticulata neurons. The choice of dopamine and acetylcholine is logical given that these transmitters are likely to have effects normally. There is a specific hypothesis to be addressed, that is, chronic dopamine depletion and levodopa treatment, akin to Parkinonism, would alter receptor pharmacology. The manner that the experiment will address this hypothesis is not as clear as in specific aim 1. Specific aim 3 will identify ionic mechanisms that are responsible for burst firing in subthalamic neurons. Modulation by dopaminergic manipulations will be examined also. The importance of understanding burst firing is that this type of activity is more likely than single discharge to influence target neurons. Understanding the output of the subthalamic nucleus will clearly have relevance for understanding movement disorders and Parkinsonism. Specific aim 4 is based on previous studies showing that dopamine depletion/levodopa treatment both have chronic effects on GABA and muscarinic receptors in the basal ganglia. Thus it is hypothesized that this treatment will influence the synaptic potentials in both the subthalamic and substantia nigra- reticulata neurons. Therefore, rats which are lesioned with 6-hydroxydopamine or treated with levodopa will be examined in vitro for synaptic changes in the subthalamic nucleus and substantia nigra-reticulata.

描述：（改编自申请人的摘要）将在大鼠脑切片中进行电生理学研究，以检查底丘脑神经元的兴奋性和抑制性输入的特征。 正常大鼠的记录将与接受 6-羟基多巴胺 (6-OHDA) 治疗的大鼠和左旋多巴治疗的动物的记录进行比较，这将有助于深入了解帕金森病。具体目标 1 致力于表征电压依赖性电流以及多巴胺对体外丘脑神经元膜特性的影响。 这些研究将解决这样的假设：由于电压门控钙电流持续失活或谷氨酸受体脱敏，长时间刺激底丘脑神经元会降低其活性。 该假设将具体解决刺激该区域的“深部脑刺激”如何产生临床效果。具体目标 2 将检查多巴胺、乙酰胆碱和其他递质对底丘脑和黑质网状神经元突触电流的影响。 考虑到这些递质可能正常发挥作用，选择多巴胺和乙酰胆碱是合乎逻辑的。 有一个具体的假设需要解决，即慢性多巴胺耗竭和左旋多巴治疗（类似于帕金森病）会改变受体药理学。该实验解决这一假设的方式并不像具体目标 1 中那样明确。具体目标 3 将确定负责丘脑底神经元爆发放电的离子机制。 还将检查多巴胺能操作的调节。 了解突发放电的重要性在于，这种类型的活动比单次放电更有可能影响目标神经元。 了解丘脑底核的输出显然与了解运动障碍和帕金森症相关。具体目标 4 基于先前的研究，表明多巴胺消耗/左旋多巴治疗均对基底神经节中的 GABA 和毒蕈碱受体产生慢性影响。 因此，假设这种治疗将影响丘脑底神经元和黑质网状神经元的突触电位。 因此，用6-羟基多巴胺损伤或用左旋多巴治疗的大鼠将在体外检查丘脑底核和黑质网状体的突触变化。