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.

当前，人们对调节DA神经元的发射模式的生理过程有不完全的理解。 体内多巴胺能（DA）神经元特征表现出自发的，起搏器样，常规峰值以及不规则的爆发活动。 从规则到爆发模式的变化与运动位点的运动和多巴胺释放的大小有关。 尽管已经假定了兴奋性突触输入在DA爆发活性中的作用，但尚不清楚从规则到爆发的变化的基础机制尚不清楚地了解该研究建议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 dac-dace dace dae neuron的胆碱能受体活化的可能机制。我们的假设是，来自梗的pontine pontine temental核的胆碱能输入使SNC-DA神经元去除并提高其发射速率，从而有助于从丘脑下核（STN），Caine gyrus gyrus and Medial Prefront和Med nial prefront and Allatamic nicleus（STN）响应谷氨酸能输入的爆发诱导趋势。 关于乙酰胆碱对DA神经元中离子电流的影响的直接信息和机制的影响很少，通过这些信息，DA神经元中离子电流的胆碱能调节可能会促进爆发。 在这项研究中，细胞内电流夹具和全细胞贴片夹记录将用于大鼠脑切片和急性解离的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，发射行为以及与STN刺激的相互作用的影响。 将解决以下具体目标：1。检查在起搏器样的去极化和毕竟的超极化（AHP）期间胆碱能受体激活对Ca2+进入的影响； 2。检查毒蕈碱受体激活引起的静息膜电位的去极化的离子机制； 3。确定胆碱能受体介导的膜电位变化是否可以调节谷氨酸引起的爆发。重要的是要更好地了解乙酰胆碱在SNC-DA神经元发射行为的调节中的作用，该行为随后影响SNC靶结构中的多巴胺释放。 拟议研究的结果可能会产生与症状表达和运动障碍（例如帕金森氏病）中的症状表达和药理操作有关的临床后果。