CHOLINERGIC MODULATION OF NIGRAL DOPAMINE NEURONS

黑质多巴胺神经元的胆碱能调节

• 批准号: 6494279
• 负责人: JOSEPH A WHITTAKER
• 金额: $ 26.01万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6494279
• 关键词: brain electrical activity; calcium flux; cholinergic agents; cingulate gyrus; dopamine; electrical measurement; electrical potential; glutamates; laboratory rat; membrane potentials; muscarinic receptor; neural information processing; nicotinic receptors; potassium ion; prefrontal lobe /cortex; substantia nigra; subthalamus; tegmentum; tissue /cell culture; voltage /patch clamp

Currently there is an incomplete understanding of the physiological processes which regulate firing patterns in DA neurons. Dopaminergic (DA) neurons in vivo characteristically exhibit spontaneous, pacemaker-like, regular spiking as well as irregular burst-firing activity. The change from regular to burst-firing mode has been associated with movement as well as with the magnitude of dopamine release at nigrostriatal target sites. Although a role for excitatory synaptic inputs in DA bursting activity has been postulated, the mechanisms underlying the change from regular to burst-firing are not clearly understood The main goal of this research proposal is to elucidate possible ionic mechanisms by which cholinergic receptor activation can modulate glutamate-induced burst-firing in SNc-DA neurons. It is our hypothesis that cholinergic input from the peduncular pontine tegmental nucleus depolarizes SNc-DA neurons and increases their firing rate, thereby contributing to the tendency for burst-firing induction in response to glutamatergic input from the subthalamic nucleus (STN), cingulate gyrus, and medial prefrontal area. There is a paucity of direct information regarding the effects of acetylcholine on ion currents in DA neurons and mechanisms by which cholinergic modulation of ion currents in DA neurons may facilitate burst-firing. In this study, intracellular current clamp and whole-cell patch clamp recordings will be utilized in rat brain slices and acutely dissociated SNc neurons. The effects of postsynaptic muscarinic and nicotinic receptor activation on neuronal membrane potential, isolated ion currents, firing behavior, and interactions with STN stimulation will be assessed. The following specific aims will be addressed: 1. To examine the effect of cholinergic receptor activation on Ca2+ entry during the pacemaker-like depolarization and afterhyperpolarization (AHP); 2. To examine the ionic mechanism(s) underlying the depolarization of the resting membrane potential induced by muscarinic receptor activation; 3. To determine if cholinergic receptor-mediated changes in membrane potential and AHP can modulate burst-firing induced by glutamate. It is important to better understand the role of acetylcholine in the modulation of SNc-DA neuronal firing behavior which subsequently influences dopamine release in SNc target structures. Results from the proposed studies may have clinical consequences relevant to symptomatic expression and pharmacological manipulations in motor and behavioral disorders such as Parkinson's disease.

目前，对调节 DA 神经元放电模式的生理过程尚不完全了解。 体内多巴胺能（DA）神经元的特征是表现出自发的、类似起搏器的、有规律的尖峰以及不规则的突发放电活动。 从常规模式到突发模式的变化与运动以及黑质纹状体目标部位多巴胺释放的程度有关。 尽管兴奋性突触输入在 DA 爆发活动中的作用已被假设，但从常规放电变为爆发放电的机制尚不清楚。本研究提案的主要目标是阐明胆碱能受体激活可调节 SNc-DA 神经元中谷氨酸诱导的爆发放电的可能离子机制。我们的假设是，来自脑桥脚被盖核的胆碱能输入使 SNc-DA 神经元去极化并增加其放电率，从而有助于响应来自丘脑底核 (STN)、扣带回和内侧前额叶区的谷氨酸能输入而诱导爆发放电。 关于乙酰胆碱对 DA 神经元中离子流的影响以及 DA 神经元中离子流的胆碱能调节可能促进爆发放电的机制，缺乏直接信息。 在本研究中，细胞内电流钳和全细胞膜片钳记录将用于大鼠脑切片和急性分离的 SNc 神经元。 将评估突触后毒蕈碱和烟碱受体激活对神经元膜电位、孤立离子电流、放电行为以及与 STN 刺激的相互作用的影响。 将解决以下具体目标： 1. 研究起搏器样去极化和后超极化（AHP）过程中胆碱能受体激活对 Ca2+ 进入的影响； 2. 检查毒蕈碱受体激活引起的静息膜电位去极化的离子机制； 3. 确定胆碱能受体介导的膜电位和 AHP 变化是否可以调节谷氨酸诱导的爆发。更好地了解乙酰胆碱在调节 SNc-DA 神经元放电行为中的作用非常重要，该行为随后影响 SNc 靶结构中多巴胺的释放。 拟议研究的结果可能会产生与帕金森病等运动和行为障碍的症状表现和药理学操作相关的临床后果。