Nicotinic receptor mediated neurotransmission in the CNS

大脑中神经元之间的信息传递是由一种叫做“神经递质”的化学物质的释放控制的，这种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起着重要作用。 我们还没有清楚地了解这些受体在大脑中的确切位置，以及它们在神经元之间的沟通中的精确功能。 该研究计划将使用电生理学、成像和基因工程小鼠（包括申请人生产的烟碱功能获得小鼠系）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的烟碱受体的小鼠，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）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的表达是如何通过细胞过程如蛋白激酶磷酸化来调节的。 我们认为蛋白激酶C可以在特定位点修饰烟碱受体，从而影响其表达水平、细胞内运动或功能。 此外，我们还将开发新技术，以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的荧光蛋白（GCaMP5G）结合的烟碱受体。 由于烟碱受体是钙渗透性的，因此与GCaMP5G融合的烟碱受体将允许我们通过成像而不是进行电生理学来监测烟碱受体活性。 这项新技术将大大提高该领域。 已知尼古丁受体不仅能增强注意力和记忆力，而且还涉及其他大脑区域，以增强感官知觉和奖励。 这项资助研究了烟碱受体在介导大脑神经元之间的通讯中的基本作用。

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.