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的主要代谢物维甲酸对神经系统功能的影响。维甲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。我们研究了无脊椎动物Lymneea stagnalis中枢神经系统(CNS)中维甲酸信号的这些方面，其中包括维甲酸、维甲酸受体和维甲酸代谢酶。维甲酸受体是核受体，通常作为配体激活的转录因子。然而，现在已经证实，在脊椎动物和无脊椎动物的中枢神经系统中，它们也可以在轴突生长、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促进我们对维甲酸的这些非基因组作用的了解和理解。与大多数脊椎动物不同，成年软体动物的神经元可以再生。生长锥体位于正在生长的轴突的顶端，在轴突发育或再生的过程中引导这些过程到达它们的目标。培养的软体动物再生运动神经元的生长锥大而结实，已被证明以一种非基因组方式对维甲酸产生诱人的转向反应。在下一个赠款周期中，我们将重点研究局部蛋白质合成在生长锥对维甲酸的反应中的作用，重点关注维甲酸受体是否以及如何在局部合成或运输，以及特定的microRNA在生长锥行为期间可以负向调节局部蛋白质合成的作用。我们还将开始研究维甲酸在体内的轴突寻路作用。使用软体动物来研究维甲酸对细胞的影响的另一个优点是，位于中枢神经系统表面的许多神经元可以单独识别出已知的递质、突触伙伴和功能。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，如呼吸或摄食。这些行为也可以通过训练来改变，我们已经证明了维甲酸及其受体在记忆形成过程中是重要的。我们还确定，维甲酸可以快速调节对细胞激活和神经递质释放至关重要的离子通道。在下一个授予周期中，我们将确定维甲酸如何以非基因组方式影响离子通道活动和细胞激发，以及这是否对突触传递有直接影响。我们研究维甲酸对突触变化和学习记忆的影响，范围从分析培养中单个或突触配对的细胞，到整个动物的行为。这些研究将强调维甲酸在神经系统中的新的非基因组作用，在重要的过程中，如轴突生长和突触可塑性。

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.