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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742237
• 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.

我的研究计划的主要目的是研究维生素A（视黄酸）基本代谢产物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。我们研究了无脊椎动物软体动物，lymnaea stagnalis中中枢神经系统（CNS）中类视黄素信号传导的这些方面，其中含有类视黄素，类视网膜样子受体和类维生素类似的代谢酶。类视感受体是核受体，通常充当配体激活的转录因子。但是，在脊椎动物和无脊椎动物中，它也已经建立了很好的确定，它们在神经突生长过程中以及突触可塑性，学习和记忆期间也可以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促进我们对视视视网想的这些非基因组行为的了解和理解。与大多数脊椎动物不同，成年的软体动物神经元可以再生。生长锥位于生长神经突的尖端，在发育或再生过程中轴突探路期间，将这些过程引导到其靶标。软体动物淋巴结培养的再生动物神经元的生长锥很大，健壮，并且已被证明会以非基因组方式对视视网膜类似的有吸引力的转向反应做出反应。在下一个赠款周期中，我们将重点关注局部蛋白质合成在生长锥对类维生素类动物的反应中的作用，重点是局部合成或运输类维生素类受体，以及特定microRNA的作用，以及在生长锥行为过程中负面调节局部蛋白质的作用。我们还将开始研究类体内类视黄素的轴突探路作用。使用软体动物检查类维生素类动物的细胞效应的另一个优点是，许多位于中枢神经系统表面的神经元可以单独识别，具有已知的发射器，突触伙伴和功能。我们可以从涉及特定行为（例如呼吸或喂养）的单个鉴定神经元中培养和/或电气记录。这些行为也可以通过训练来修改，我们已经表明，类维生素类动物及其受体在记忆形成过程中很重要。我们还确定，类视视视感素可以快速调节对细胞发射和神经递质释放重要的离子通道。在下一个赠款周期中，我们将确定类维生素类动物如何以非基因组方式影响离子通道活性和细胞射击，以及这是否对突触传播有直接影响。我们的研究研究了类视黄素对突触变化，学习和记忆的影响，范围从对培养物中的单个或突触配对细胞的分析到整个动物行为。这些研究将在神经系统中，在神经突生长和突触可塑性等重要过程中重点介绍视黄酸在神经系统中的新型非基因组作用。