CHOLINERGIC MODULATION OF NIGRAL DOPAMINE NEURONS

黑质多巴胺神经元的胆碱能调节

• 批准号: 6540127
• 负责人: JOSEPH A WHITTAKER
• 金额: $ 26.75万
• 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/6540127
• 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还不完全了解。 多巴胺能神经元在体内表现出自发的、起搏器样的、有规律的放电以及不规则的爆发放电活动。 从常规到爆发式放电模式的变化与运动以及黑质纹状体靶点多巴胺释放的幅度有关。 虽然兴奋性突触输入在DA爆发活动中的作用已经被假定，但从常规到爆发放电变化的机制还不清楚。本研究的主要目的是阐明胆碱能受体激活可以调节谷氨酸诱导的SNc-DA神经元爆发放电的可能离子机制。这是我们的假设，从脚脑桥被盖核的胆碱能输入去极化SNc-DA神经元，并增加其放电率，从而有助于突发放电诱导的倾向，以响应丘脑底核（ESTA），扣带回，内侧前额叶区的多巴胺能输入。 关于乙酰胆碱对DA神经元离子电流的影响以及DA神经元离子电流的胆碱能调制可能促进突发放电的机制，目前缺乏直接的信息。 在本研究中，细胞内电流钳和全细胞膜片钳记录将被用于大鼠脑片和急性分离的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、分离离子电流、放电行为以及与突触刺激的相互作用的影响。 具体目标如下：1。研究胆碱能受体激活对类起搏器除极和后超极化过程中钙内流的影响。探讨毒蕈碱受体激活引起静息膜电位去极化的离子机制。确定胆碱能受体介导的膜电位变化和AHP是否可以调节谷氨酸诱导的爆发式放电。更好地理解乙酰胆碱在SNc-DA神经元放电行为的调制中的作用是重要的，所述SNc-DA神经元放电行为随后影响SNc靶结构中的多巴胺释放。 拟议研究的结果可能与运动和行为障碍（如帕金森病）的症状表达和药理学操作相关的临床后果。