Nicotinic receptor mediated neurotransmission in the CNS

大脑中神经元之间的信息传输是由一种名为“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相结合。神经型烟碱型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方面起着基础性作用。我们还不清楚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起到的精确作用。这项研究计划将使用电生理学、成像和基因工程小鼠，包括申请人培育的尼古丁功能获得性小鼠系，详细研究尼古丁受体在大脑中的功能。我们还制造了带有荧光标记的尼古丁受体的小鼠，这将使我们能够准确地对单个神经元上的受体进行成像。这项提议将研究这些受体在大脑中对认知(注意力和记忆)重要的区域中特定神经元的功能和定位。我们还将研究尼古丁受体的表达如何受到细胞过程的调节，例如蛋白激酶的磷酸化。我们认为蛋白激酶C可以修饰特定部位的烟碱受体，以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尼古丁受体的研究。使用分子生物学方法，我们将产生与钙敏感的荧光蛋白(GCaMP5G)结合的尼古丁受体。由于尼古丁受体是钙渗透性的，将尼古丁受体融合到GCaMP5G将使我们能够通过成像来监测尼古丁受体的活动，而不是进行电生理。这项新技术将极大地增强这一领域。众所周知，尼古丁受体不仅可以增强注意力和记忆力，而且还与大脑其他区域有关，可以增强感觉知觉和奖励。这项资助研究了尼古丁受体在调节大脑神经元之间的交流中的基本基础作用。

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.