Understanding how retinoic acid affects neurite outgrowth and synaptic function using invertebrate neurons.

了解视黄酸如何影响无脊椎动物神经元的神经突生长和突触功能。

• 批准号: RGPIN-2021-02825
• 负责人: Spencer, Gaynor
• 金额: $ 3.64万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744831
• 关键词: Understanding; how; retinoic; acid; affects

The main aim of my research program is to study the effects of the essential metabolite of Vitamin A, retinoic acid, on nervous system function. Retinoic acid is an important molecule for nervous system development and regeneration, as well as for learning and memory in the adult brain. We study these aspects of retinoid signaling in the central nervous system (CNS) of the invertebrate mollusc, Lymnaea stagnalis, which contains retinoids, retinoid receptors and retinoid metabolic enzymes. The retinoid receptors are nuclear receptors that generally act as ligand-activated transcription factors. However, it has now been well established, in both vertebrate and invertebrate CNS, that they can also exert important non-genomic effects during neurite outgrowth, and during synaptic plasticity, learning and memory. One of the main goals of my research program is to advance our knowledge and understanding of these non-genomic actions of retinoids. Unlike most vertebrate species, adult molluscan neurons can regenerate. Growth cones, located at the tips of growing neurites, guide these processes to their targets during axon pathfinding in development or regeneration. The growth cones of cultured regenerating motorneurons of the mollusc Lymnaea are large, robust and have been shown to respond with attractive turning responses to retinoids in a non-genomic manner. Over the next grant cycle, we will focus on the role of local protein synthesis in the growth cone responses to retinoids, with a focus on whether, and how, retinoid receptors are locally synthesized or trafficked, as well as the role of a specific microRNA, which can negatively regulate local protein synthesis during growth cone behaviour. We will also begin studying the axon pathfinding effects of retinoids in vivo. Another advantage of using molluscs to examine cellular effects of retinoids, is that many neurons located on the surface of the CNS are individually identifiable with known transmitters, synaptic partners and functions. We can culture and/or electrically record from single identified neurons involved in a specific behaviour, such as respiration or feeding. These behaviours can also be modified by training, and we have shown that retinoids and their receptors are important during memory formation. We have also determined that retinoids can rapidly modulate ion channels important for cell firing and neurotransmitter release. Over the next grant cycle, we will determine how retinoids affect ion channel activity and cell firing in a non-genomic manner, and whether this has direct effects on synaptic transmission. Our studies examining the effects of retinoids on synaptic changes and learning and memory, will range from analysis of single or synaptically paired cells in culture, to whole animal behaviour. These studies will highlight novel non-genomic actions of retinoic acid in the nervous system, during important processes such as neurite outgrowth and synaptic plasticity.

我的研究项目的主要目的是研究维生素 A 的必需代谢物视黄酸对神经系统功能的影响。视黄酸是神经系统发育和再生以及成人大脑学习和记忆的重要分子。我们研究无脊椎动物软体动物 Lymnaea stagnalis 中枢神经系统 (CNS) 中类维生素A信号传导的这些方面，其中含有类维生素A、类维生素A受体和类维生素A代谢酶。类视黄醇受体是核受体，通常充当配体激活的转录因子。然而，现在已经确定，在脊椎动物和无脊椎动物中枢神经系统中，它们还可以在神经突生长以及突触可塑性、学习和记忆过程中发挥重要的非基因组效应。我的研究计划的主要目标之一是增进我们对类维生素A的这些非基因组作用的认识和理解。与大多数脊椎动物不同，成年软体动物神经元可以再生。生长锥位于正在生长的神经突的尖端，在轴突发育或再生过程中引导这些过程到达其目标。培养的软体动物 Lymnaea 的再生运动神经元的生长锥大而坚固，并且已被证明以非基因组方式对类维生素A产生有吸引力的转向反应。在下一个资助周期中，我们将重点关注局部蛋白质合成在生长锥对类维生素A反应中的作用，重点关注类维生素A受体是否以及如何局部合成或运输，以及特定microRNA的作用，它可以在生长锥行为期间负面调节局部蛋白质合成。我们还将开始研究类维生素A在体内的轴突寻路效应。使用软体动物检查类维生素A的细胞效应的另一个优点是，位于中枢神经系统表面的许多神经元可以通过已知的递质、突触伙伴和功能单独识别。我们可以对涉及特定行为（例如呼吸或进食）的单个已识别神经元进行培养和/或电记录。这些行为也可以通过训练来改变，我们已经证明类维生素A及其受体在记忆形成过程中很重要。我们还确定，类维生素A可以快速调节对细胞放电和神经递质释放很重要的离子通道。在下一个资助周期中，我们将确定类维生素A如何以非基因组方式影响离子通道活动和细胞放电，以及这是否对突触传递有直接影响。我们研究类视黄醇对突触变化以及学习和记忆的影响，范围从分析培养中的单个或突触配对细胞到整个动物行为。这些研究将强调视黄酸在神经系统中在神经突生长和突触可塑性等重要过程中的新的非基因组作用。