Nicotinic receptor mediated neurotransmission in the CNS

中枢神经系统中烟碱受体介导的神经传递

• 批准号: 355822-2013
• 负责人: Nashmi, Raad
• 金额: $ 2.19万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527911
• 关键词: Nicotinic; receptor; mediated; neurotransmission; CNS

The transmission of information between neurons in the brain is governed by the release of chemicals called "neurotranmitters" which bind to ion channels located on the surface of neurons. Cholinergic neurotransmission mediated by neuronal nicotinic acetylcholine receptors plays a fundamental role in enhancing cognitive function such as attention and memory. We do not yet have a clear understanding where exactly these receptors are located in the brain and how precisely they function in mediating communication between neurons. This research program will examine in detail how nicotinic receptors function in the brain using electrophysiology, imaging and genetically engineered mice including a nicotinic gain-of-function mouse line that the applicant has produced. We have also produced mice with fluorescently tagged nicotinic receptors which would allow us to accurately image the receptors on individual neurons. This proposal will examine the function and localization of these receptors in specific neurons in brain regions important for cognition (attention and memory). We will also examine how nicotinic receptor expression are regulated by cellular processes such as phosphorylation by protein kinases. We propose that protein kinase C can modify nicotinic receptors at specific sites to affect either their expression levels, their movement inside the cell or their function. Furthermore, we will also produce novel technologies to advance the study of nicotinic receptors. Using molecular biological approaches we will produce nicotinic receptors bound to a fluorescent protein that is calcium sensitive (GCaMP5G). Since nicotinic receptors are calcium permeable, nicotinic receptors fused to GCaMP5G would allow us to monitor nicotinic receptor activity by imaging instead of performing electrophysiology. This novel technology would greatly enhance the field. Nicotinic receptors are known not only to enhance attention and memory but are also implicated in other brain regions in enhancing sensory perception and reward. This grant examines the basic fundamental role of nicotinic receptors in mediating communication between neurons in the brain.

大脑神经元之间的信息传递是由称为“神经递质”的化学物质的释放控制的，这些化学物质与位于神经元表面的离子通道结合。 由神经元烟碱乙酰胆碱受体介导的胆碱能神经传递在增强注意力和记忆等认知功能中发挥着重要作用。 我们还不清楚这些受体到底位于大脑中的什么位置，以及它们在介导神经元之间的通信方面的精确程度如何。 该研究计划将利用电生理学、成像和基因工程小鼠（包括申请人生产的烟碱功能获得性小鼠品系）详细研究烟碱受体如何在大脑中发挥作用。 我们还培育了带有荧光标记烟碱受体的小鼠，这将使我们能够准确地对单个神经元上的受体进行成像。 该提案将检查这些受体在对认知（注意力和记忆）很重要的大脑区域的特定神经元中的功能和定位。 我们还将研究烟碱受体表达如何受细胞过程（例如蛋白激酶磷酸化）的调节。 我们认为蛋白激酶 C 可以修饰特定位点的烟碱受体，从而影响它们的表达水平、它们在细胞内的运动或它们的功能。 此外，我们还将开发新技术来推进烟碱受体的研究。 使用分子生物学方法，我们将产生与钙敏感荧光蛋白 (GCaMP5G) 结合的烟碱受体。 由于烟碱受体具有钙渗透性，与 GCaMP5G 融合的烟碱受体将使我们能够通过成像而不是进行电生理学来监测烟碱受体活性。 这项新技术将极大地增强该领域的实力。 众所周知，烟碱受体不仅可以增强注意力和记忆力，而且还与其他大脑区域增强感官知觉和奖励有关。 该资助研究了烟碱受体在介导大脑神经元之间的通信中的基本作用。