Mechanisms and functions of dendritic dopamine release in the brain

大脑树突状多巴胺释放的机制和功能

• 批准号: RGPIN-2015-05230
• 负责人: Trudeau, LouisEric
• 金额: $ 3.28万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613429
• 关键词: Mechanisms; functions; dendritic; dopamine; release

Neurons in the brain that use the chemical messenger dopamine (DA) play a key role in the control of movement, motivated behaviors and cognition. At present, we know very little about the basic mechanisms that control DA release in the brain. Although DA release from the neurons' nerve endings (axon terminals) is well characterized and known to occur through a form of regulated exocytosis, DA is also released from the cell body and dendrites of DA neurons (STD DA release) and very little is presently known about how this occurs and what roles it plays in brain function. This integrated research program may lead to a better understanding of the role of DA neurons in movement, motivation and cognition. It will also identify a mechanism that is likely to be relevant to explain the dendritic release of other chemical messengers of the brain such as serotonin and neuropeptides. The reason we know so little about the roles of STD DA release is mainly because at the present time, there is no way to selectively block or enhance STD DA release to examine the functional and behavioral consequences.The development of a mouse model in which STD DA release is strongly reduced or blocked would represent a major advance in the field. We plan to build on our recent in vitro discoveries to establish such a mouse model. We will address the following two specific aims: Specific aim #1 : Identification of the mechanism of STD DA release. We will build on our recent discovery using DA neurons maintained in culture showing that the calcium-sensing proteins synaptotagmin 4 and synaptotagmin 7 are critical determinants of STD DA. We will detect DA release in mouse brain sections to test the hypothesis that deletion of synaptotagmin 4 and/or synaptotagmin 7 in DA neurons will severely reduce STD DA release. Specific aim #2 : Identification of the functional and behavioral roles of STD DA release. We will build on our experiments from aim 1 to obtain the first insights into the roles of STD DA release in brain function and behavor. Due to a presumed negative feedback role of STD DA release, we hypothesize that in the absence of STD DA release, the electrical activity of DA neurons will be increased. We also hypothesize that the strength of connections onto DA neurons will be altered. Finally, we will perform a thorough behavioral evaluation of these mice in which STD DA release has been reduced to identify some of the major roles of STD DA release in regulating behavior. We hypothesize that movement, motivated behaviors and spatial working memory will be altered.

大脑中使用化学信使多巴胺(DA)的神经元在控制运动、动机行为和认知方面发挥着关键作用。目前，我们对大脑中控制DA释放的基本机制知之甚少。虽然从神经元的神经末梢(轴突终末)释放DA是很好的特征，并且已知是通过一种调节的胞吐作用发生的，但DA也从DA神经元的细胞体和树突释放(STD DA释放)，目前对这一过程如何发生以及它在脑功能中扮演什么角色知之甚少。这一综合研究计划可能有助于更好地理解DA神经元在运动、动机和认知中的作用。它还将确定一种可能与解释大脑其他化学信使(如5-羟色胺和神经肽)树突释放相关的机制。之所以我们对STD DA释放的作用知之甚少，主要是因为目前还没有选择性地阻断或增强STD DA释放来检查其功能和行为后果的方法。发展一种STD DA释放强烈减少或阻断的小鼠模型将是该领域的重大进展。我们计划在我们最近的体外发现的基础上建立这样一个小鼠模型。 我们将解决以下两个具体目标： 具体目标#1：确定STD DA释放的机制。我们将以我们最近的发现为基础，使用培养中的DA神经元表明钙敏感蛋白synaptopagmin 4和synaptopagmin 7是STD DA的关键决定因素。我们将检测小鼠脑切片中DA的释放，以验证以下假设：DA神经元中突触素4和/或突触素7的缺失将严重减少STD DA的释放。 具体目标#2：确定STD DA释放的功能和行为作用。我们将在我们从目标1开始的实验的基础上，获得对STD DA释放在大脑功能和行为中的作用的第一次见解。由于推测STD DA释放的负反馈作用，我们假设在没有STD DA释放的情况下，DA神经元的电活动将增加。我们还假设，与DA神经元的连接强度将会改变。最后，我们将对这些STD DA释放减少的小鼠进行彻底的行为评估，以确定STD DA释放在调节行为中的一些主要作用。我们假设运动、动机行为和空间工作记忆会发生改变。