Synaptic control of sensory transduction

感觉神经元检测光、触觉和化学物质等刺激，并将这些信号传输到中枢神经系统，在那里信息被处理并用于改变行为。来自不同感觉器官的信息由外周和中枢神经系统优先处理和整合，以便在每种情况下最基本的信息获得最高的优先级。这个过程的一个基本部分是由感觉神经元细胞膜上的特定受体蛋白检测到的化学信使对感觉神经元的调制。这种调节可能会使感觉神经元变得更敏感或更不敏感，这取决于化学信使和涉及的受体类型。我的实验室主要对感觉神经元对机械刺激的调节感兴趣，例如触摸、振动或身体的位置。我们使用了一个令人兴奋的无脊椎动物模型，一种大型蜘蛛，它全身都有非常发达的机械感觉器官。一些蜘蛛感觉神经元如此之大，以至于我们可以做任何脊椎动物和大多数无脊椎动物都不可能做的实验。我们已经开发了几种方法，帮助研究这些神经元是如何工作的，以及它们的敏感性是如何被化学信使改变的。基因测序技术的最新进展使我们能够确定蜘蛛神经组织中所有转录基因的核苷酸序列。我们已经确定了编码检测化学信使的受体蛋白的基因，以及编码用于细胞内信号传递的蛋白质的基因。这项研究计划集中在生物胺、章鱼胺和酪胺激活的一组受体上。这些化学信使作为神经激素、神经递质和神经调节剂发挥作用，几乎影响无脊椎动物的所有生理过程，类似于人类密切相关的肾上腺素能受体。我们将使用专门的计算机软件来研究蜘蛛生物胺受体与其他动物的受体之间的关系。当基因在培养的永生细胞中人工表达时，生物胺受体的信号特性已经被研究过了。我们认为，更重要的是了解这些受体在真实动物中的功能，在这些动物中可以观察到特定的细胞和行为反应。我们将使用细胞内记录等实验工具来了解感觉神经元中的信息传输是如何被这些化学信使改变的。光学方法帮助我们观察细胞内信号分子浓度的变化。它们将被用来研究生物胺激活或抑制的信号通路。每个受体在不同感觉器官中的具体位置将使用荧光标记的分子探针进行探索。我们正在开发一种新的方法，通过基因沉默受体和信号分子，这样我们就可以调查它们功能的缺失如何影响神经元。我们致力于解决的问题和我们使用的方法的组合是独一无二的，将在一个具有广泛兴趣的领域提供新的知识。生物胺是无脊椎动物中研究最深入的化学信使，在脊椎动物中的作用类似于肾上腺素和去甲肾上腺素。在人脑中，章鱼胺浓度降低是帕金森氏症的一个标志。酪胺会干扰一些抗抑郁药物，导致高血压。无脊椎动物的递质受体也是控制剂的靶标，有些对野生动物和人类有害。更好地了解生物胺及其受体的功能是至关重要的。

Sensory neurons detect stimuli such as light, touch and chemicals, and transmit these signals to the central nervous system where the information is processed and used to modify behavior. Information from different sensory organs is prioritized and integrated by the peripheral and central nervous systems so that the most essential messages in each situation get the highest preference. A fundamental part of this process is modulation of sensory neurons by chemical messengers that are detected by specific receptor proteins on the cell membranes of the sensory neurons. Such modulation may make sensory neurons more or less sensitive, depending on the chemical messenger and the types of receptors involved. My laboratory is mainly interested in modulation of sensory neurons that respond to mechanical stimuli, such as touch, vibration or position of the body. We use an exciting invertebrate animal model, a large spider that has extremely well developed mechanical sense organs all over its body. Some spider sensory neurons are so large that we can do experiments that are impossible in any vertebrate and most invertebrate preparations. We have developed several methods that have helped to investigate how these neurons work and how their sensitivity is modified by chemical messengers. Recent advances in gene sequencing technology have allowed us to determine the nucleotide sequences of all transcribed genes in the spider nervous tissue. We have identified genes that code receptor proteins that detect chemical messengers and also genes that code proteins used in intracellular signalling. This research proposal concentrates on a group of receptors that are activated by biogenic amines, octopamine and tyramine. These chemical messengers function as neurohormones, neurotransmitters and neuromodulators and affect almost all physiological processes in invertebrates, similarly to the closely related adrenergic receptors in humans. We will investigate the relationships of spider biogenic amine receptors to receptors in other animals using specialized computer software. Biogenic amine receptor signalling properties have previously been studied when the genes have been artificially expressed in immortal cells in culture. We believe that it is more important to understand how these receptors function in real living animals where the specific cellular and behavioral responses can be observed. We will use experimental tools such as intracellular recordings to learn how the information transmission in sensory neurons is modified by these chemical messengers. Optical methods help us to observe changes in intracellular concentrations of signalling molecules. They will be used to investigate the signalling pathways that are activated or inhibited by biogenic amines. Specific locations of each receptor in various sensory organs will be explored using fluorescently labeled molecular probes. We are in the process of developing a new method to genetically silence the receptor and signalling molecules, so that we can investigate how the lack of their function affects the neurons. The problems we aim to solve and combination of methods we use are unique and will provide new knowledge in a field with a broad interest. Biogenic amines are the most intensely investigated chemical messengers in invertebrates and function in similar roles to adrenaline and noradrenaline in vertebrates. In human brain, reduced octopamine concentration is a marker for Parkinson`s disease. Tyramine interferes with some antidepressants causing very high blood pressure. Invertebrate transmitter receptors are also targets of control agents, and some are harmful to wildlife and humans. Better understanding of how biogenic amines and their receptors function is vitally important.