Nicotinic receptor mediated neurotransmission in the central nervous system

烟碱受体介导的中枢神经系统神经传递

• 批准号: RGPIN-2018-04581
• 负责人: Nashmi, Raad
• 金额: $ 3.64万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660673
• 关键词: Nicotinic; receptor; mediated; neurotransmission; central

The transmission of information between neurons in the brain is governed by the release of chemicals called “neurotransmitters” which bind to ion channels located on the surface of neurons. Cholinergic neurons are a class of neurons that produce and release the neurotransmitter acetylcholine. Cholinergic neurotransmission mediated by neuronal nicotinic acetylcholine receptors plays a fundamental role in enhancing cognitive function, sensory perception and motor responses. We do not yet have a clear understanding how precisely these receptors in different regions of the brain function in mediating communication between neurons. This research program will examine in detail how nicotinic receptors function in the brain using a combination of electrophysiology and a powerful new technology called optogenetics that uses blue light to activate specific neurons in the brain of mice, which were genetically engineered to express exogenous blue light gated ion channels called channelrhodopsin. We will record in the substantia nigra, a brain region important for voluntary movement, and examine in detail the plasticity of ACh release and postsynaptic nicotinic responses. We will also record from the hippocampus, a brain region important for memory, and ascertain the function of nicotinic receptors in modulating the activity of action potential propagation along axons and also whether presynaptic nicotinic receptors can facilitate glutamate release. Since nicotinic receptors are calcium permeable, nicotinic receptors fused to a genetically encoded calcium indicator (GCaMP) would allow us to monitor nicotinic receptor activity by imaging instead of performing electrophysiology. This novel technology would greatly enhance the field. Our lab has already made some nicotinic receptor-GCaMP constructs and will image their activity in neurons in brain tissue. This research will allow us to better understand the basic fundamental role of nicotinic receptors in communication between neurons in the brain and give insight how nicotinic receptor activity can control or modify certain behaviours such as movement or memory. The graduate students will acquire top-notch technical skills and mentoring necessary for the training of the next generation of scientists and professors in Canada.

大脑中神经元之间的信息传输是由称为“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。 胆碱能神经元是一类产生和释放神经递质乙酰胆碱的神经元。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认知功能、感觉知觉和运动反应中起着重要作用。 我们还没有清楚地了解这些受体在大脑不同区域中如何精确地调节神经元之间的通信。 这项研究计划将详细研究尼古丁受体如何在大脑中发挥作用，使用电生理学和一种强大的新技术称为光遗传学，该技术使用蓝光激活小鼠大脑中的特定神经元，这些神经元经过基因工程改造，表达外源性蓝光门控离子通道，称为通道视紫红质。我们将记录在黑质，一个重要的大脑区域的自愿运动，并详细检查乙酰胆碱释放和突触后烟碱反应的可塑性。我们还将记录海马体（一个对记忆很重要的脑区）的记录，并确定烟碱受体在调节沿着轴突的动作电位传播活动中的功能，以及突触前烟碱受体是否能促进谷氨酸的释放。由于烟碱受体是钙渗透性的，因此与遗传编码的钙指示剂（GCaMP）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。 我们的实验室已经制造了一些烟碱受体-GCaMP结构，并将在脑组织的神经元中成像它们的活性。这项研究将使我们能够更好地了解烟碱受体在大脑神经元之间通信中的基本作用，并了解烟碱受体活性如何控制或改变某些行为，如运动或记忆。 研究生将获得顶尖的技术技能和指导，为加拿大下一代科学家和教授的培训所必需。