NEUROSCIENCE

神经科学

• 批准号: 6669253
• 负责人: JOSEPH A WHITTAKER
• 金额: $ 38.82万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6669253
• 关键词: G protein; acetylcholine; biological signal transduction; calcium indicator; calcium ion; calcium metabolism; cooperative study; dopamine; electrophysiology; iontophoresis therapy; laboratory rat; membrane potentials; muscarinic receptor; neuroregulation; neurosciences; potassium chloride; receptor expression; substantia nigra; tegmentum; voltage /patch clamp

Previous studies have demonstrated that cholinergic projection neurons from the brainstem pedunculopontine nucleus (PPN) modulate the excitability and firing rate of substantia nigra pars compacta (SNc) dopamine (DA) neurons. However, the underlying mechanisms by which acetylcholine (ACh) exerts its influence on DA cells remain unclear. We are interested in the role of cholinergic afferents in regulating DA cell electrical activity. Specifically, our goal is to understand the functional consequences of changes in afferent firing activity associated with muscarinic receptor activation during phasic (rapid) and sustained (tonic) stimulation. It is hypothesized that changes in membrane potential and calcium dynamics associated with DA neuron activation are differentially modulated by rapid (phasic) and sustained (tonic) muscarinic receptor stimulation. Using whole-cell voltage clamp recordings in acutely isolated DA neurons, the effects of phasic and tonic muscarine application (to mimic PPN output activity) on membrane potential and intracellular calcium dynamics will be assessed. The involvement of the interplay between calcium entry and release from intracellular stores will be investigated on the basis of the following specific aims: 1) To examine the effect of phasic muscarine receptor activation on whole-cell membrane currents and calcium dynamics; 2) to determine if the magnitude of the calcium rise in response to muscarinic receptor activation of DA neurons is dependent on basal intracellular calcium levels; and, 3) to determine the second messenger mechanisms associated with rapid muscarinic receptor activation of DA neurons. SNc DA activity is known to be highly regulated by afferent inputs and the delicate balance between the hyperpolarizing and depolarizing reponses of DA cells to ACh may be critical in the regulation of SNc activity and subsequent DA delivery to striatal targets. Findings from this study could have significant implications in understanding and developing treatments for movement and behavioral dysfunctions.

先前的研究表明，来自脑干的胆碱能投射神经元 花梗核（PPN）调节黑质Nigra pars comcacta（SNC）多巴胺（DA）神经元的兴奋性和发射速率。但是，乙酰胆碱（ACH）对DA细胞的影响的潜在机制尚不清楚。我们对胆碱能传入在调节DA细胞电活动中的作用感兴趣。具体而言，我们的目标是了解在阶段（快速）和持续（滋补）刺激期间与毒蕈碱受体激活相关的传入发射活性变化的功能后果。假设与DA神经元激活相关的膜电位变化和钙动力学的变化是通过快速（阶段）和持续（补品）毒蕈碱的差异调节的。 受体刺激。使用急性分离的DA神经元中的全细胞电压夹记录，将评估阶段性和滋补毒疗法（模拟PPN输出活性）对膜电位和细胞内钙动力学的影响。将根据以下特定目的研究钙进入和从细胞内存储中释放之间的相互作用的参与：1）检查体质毒arine受体激活对全细胞膜电流和钙动力学的影响； 2）确定DA神经元的毒蕈碱受体激活的钙升高是否取决于基础细胞内钙水平； 3）确定与DA神经元快速的毒蕈碱受体激活相关的第二种信使机制。已知SNC DA活性受到传入输入的高度调节，并且DA细胞对ACH的超极化和去极化的重新化之间的微妙平衡对于调节SNC活性至关重要 并随后将DA传递到纹状体靶标。这项研究的发现可能对理解和发展行为和行为功能障碍的治疗具有重要意义。