Dynamic Aspects of Olfactory Signal Transduction

描述（由申请人提供）：动物生活在一个不断变化和复杂的气味信号环境中，这些气味信号通过吸入的空气传递给鼻腔中的嗅觉受体神经元（orn）。嗅觉神经识别气味，并将气味刺激转化为动作电位，传递给大脑中的第一个中继站——嗅球。这是通过激活气味受体来实现的，通过G蛋白偶联级联和嗅觉纤毛上离子通道的打开以及随后的去极化，导致cAMP的产生。气味特异性是通过在给定的ORN中只表达一种气味受体来提供的，而在小鼠中有1000种不同的受体，在人类中有350种。嗅觉信号转导的大多数主要成分已经被确定。我们的目标是确定是什么限制和控制了嗅觉转导成分相互作用的动力学，这是如何控制动作电位的产生和编码的，以及对行为的影响，特别是对气味的辨别和嗅探的开始。利用电生理技术，我们将研究小鼠的嗅觉如何传导气味刺激。使用快速、重复的刺激来模拟高频、嗅探驱动的气味传递，我们将确定orn是否仅仅报告这些气味浓度的快速变化，还是实际上它们自己以刺激频率依赖的方式积极地处理这些信息。我们将确定嗅觉标记蛋白在嗅觉转导动力学中的功能作用（其功能自1972年发现以来一直未被发现），以及确定不同气味受体在塑造气味诱导反应的时间过程中的作用。快速和精确的嗅觉转导的重要性将通过对转基因小鼠的行为测试来研究气味识别的速度和准确性权衡。监测主动嗅觉探索期间的呼吸频率将使我们能够确定ORN动力学的贡献以及外周与中枢对控制呼吸和嗅探频率变化的影响。

DESCRIPTION (provided by applicant): Animals live in an environment of constantly changing and complex odorous signals, which are delivered by the inhaled air to olfactory receptor neurons (ORNs) in the nasal cavity. ORNs recognize odorants and convert odorant stimulation into action potentials to be conveyed to the first relay station in the brain, the olfactory bulb. This is achieved by activation of odorant receptors, leading to cAMP generation via a G protein-coupled cascade and the opening of ion channels present on the olfactory cilia and subsequent depolarization. Odorant specificity is provided by the expression of only one type of odorant receptor in a given ORN out of ~1000 different receptors in mice and 350 in humans. Most major components of olfactory signal transduction have been identified. Our goal is to determine what limits and controls the kinetics with which olfactory transduction components interact, how this controls action potential generation and coding and what the behavioral implications are for, in particular, odorant discrimination and initiation of sniffing. Using electrophysiological techniques, we will investigate how mouse ORNs transduce odorant stimulation. Using rapid, repetitive stimulation designed to simulate high-frequency, sniffing-driven odorant delivery, we will establish whether ORNs merely report these rapid changes in odorant concentration or if in fact they themselves actively process this information in a stimulation-frequency-dependent manner. We will determine the functional role in olfactory transduction kinetics of olfactory marker protein (the function of which has not been found since its discovery in 1972) as well as determining the role of different odorant receptors in shaping the time-course of the odorant-induced response. The importance of fast and precise olfactory transduction will be studied using behavioral testing on genetically altered mice to investigate speed-accuracy tradeoff in odorant identification. Monitoring the breathing frequency during active olfactory exploration will allow us to establish the contribution of ORN kinetics and peripheral-versus-central influence on controlling changes in breathing and sniffing rates.