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

我的研究计划的主要目的是研究维生素A的必需代谢物维甲酸对神经系统功能的影响。视黄酸是神经系统发育和再生的重要分子，也是成人大脑学习和记忆的重要分子。我们研究了含类视黄酮、类视黄酮受体和类视黄酮代谢酶的无脊椎软体动物淋巴藻中枢神经系统（CNS）中类视黄酮信号的这些方面。类视黄醛受体是核受体，通常作为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的中枢神经系统中，它们也可以在神经突起生长，突触可塑性，学习和记忆过程中发挥重要的非基因组作用。我的研究项目的主要目标之一是提高我们对类维生素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，成年软体动物的神经元可以再生。生长锥位于生长的神经突的尖端，在发育或再生的轴突寻路过程中引导这些过程到达它们的目标。培养的软体动物lynaea再生运动神经元的生长锥大而健壮，并且已被证明以非基因组方式对类维甲酸做出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视黄醇的反应中的作用，重点关注类视黄醇受体是否以及如何在局部合成或运输，以及在生长锥行为中可以负调控局部蛋白质合成的特定microRNA的作用。我们也将开始研究类维生素a在体内的轴突寻路效应。使用软体动物来检查类维甲酸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。我们可以培养和/或电记录参与特定行为的单个已识别神经元，如呼吸或进食。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重要的离子通道。在下一个资助周期，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性和细胞放电，以及这是否对突触传递有直接影响。我们的研究考察类维生素a对突触变化和学习记忆的影响，范围将从单个或突触配对细胞的分析，到整个动物的行为。这些研究将突出维甲酸在神经系统中的新的非基因组作用，在神经突生长和突触可塑性等重要过程中。

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.