SYNAPTIC PHARMACOLOGY OF SINGLE SUBTHALAMIC NEURONS

产品说明：（改编自申请人的摘要）电生理学研究将在大鼠脑切片中进行，以检查对丘脑底神经元的兴奋性和抑制性输入的特征。 将正常大鼠的记录与用6-羟基多巴胺（6-OHDA）处理的大鼠和左旋多巴处理的动物的记录进行比较，这将允许深入了解帕金森病。具体目标1是致力于表征电压依赖性电流和多巴胺对底丘脑神经元在体外膜特性的影响。 这些研究将解决这一假设，即长期刺激丘脑底神经元降低其活动，因为持续失活的电压门控钙电流或脱敏的谷氨酸受体。 该假设将具体说明该区域的刺激“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丘脑底和黑质网状神经元突触电流的影响。 选择多巴胺和乙酰胆碱是合乎逻辑的，因为这些递质可能在正常情况下产生作用。 有一个特定的假设要解决，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。实验将解决这一假设的方式不像具体目标1那样明确。具体目标3将确定负责底丘脑神经元爆发放电的离子机制。 还将检查通过多巴胺能操纵的调节。 理解爆发性放电的重要性在于，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将清楚地与理解运动障碍和帕金森症有关。具体目标4是基于之前的研究，表明多巴胺耗尽/左旋多巴治疗都对基底神经节中的GABA和毒蕈碱受体产生慢性影响。 因此，假设该处理将影响底丘脑和黑质网状神经元中的突触电位。 因此，将在体外检查用6-羟基多巴胺损伤或用左旋多巴处理的大鼠的底丘脑核和黑质网状物中的突触变化。

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.