封面故事

哺乳动物的嗅觉系统由嗅上皮、嗅球和更高级的嗅觉中枢组成。直接探测气味分子的细胞——嗅感觉神经元位于鼻腔内的嗅上皮上。嗅感觉神经元的纤毛上表达很多气味受体蛋白,这些蛋白可以检测进入鼻腔的气味分子。每个嗅感觉神经元只表达一种特定的气味受体。表达一种气味受体的嗅感觉神经元投射到嗅球中的一到两个嗅小球中,一     

嗅球对嗅觉信息的处理

哺乳动物的嗅觉系统拥有惊人的能力,它可以识别和分辨成千上万种分子结构各异的气味分子。这种识别能力是由基因决定的。近年来,分子生物学和神经生理学的研究使得我们对嗅觉识别的分子基础和嗅觉系统神经连接的认识有了质的飞跃。气味分子的识别是由一千多种气味受体完成的,鼻腔中的嗅觉感觉神经元表达这些气味受体基因。每个感觉神经元只表达一种气味受体基因。表达同种气味受体的感觉神经元投射到嗅球表面的一个或几个嗅小球中,从而在嗅球中形成一个精确的二维连接图谱。了解嗅球对气味信息的加工和处理方式是我们研究嗅觉系统信号编码的一个重要环节。文章概述并总结了有关嗅球信号处理的最新研究成果。     

“嗅觉机制”研究的新进展

人类可能会辨出近50万种不同的气味,但对于鼻腔深处发生的嗅觉的机制,仍在探索之中。以色列魏茨曼科学研究所的恩伯特·佩斯,伊曼纽尔·汉斯基等科学家对脊椎动物嗅觉机制的探索初见端倪。他们发现在做实验用的青蛙嗅纤毛中,腺苷酸环化酶的浓度非常高,当嗅纤毛受到4种不同气味的混合气体刺激时,该酶的活性增加了。科学家们认为,嗅觉敏感细胞对气味分子的反应似乎和细胞对激素的反应是相似的。他们在嗅纤毛中还发现一种和G-蛋白质大小和性质相同的蛋白质。所以,他们认为嗅觉的产生可能是以如下程序发生的:当有气味的气体分子和嗅纤毛膜上的受体分子结合后,     

2004年度诺贝尔生理学和医学奖简介

2004年诺贝尔生理学和医学奖颁发给两位美国科学家理查德·阿克塞尔(Richard Axel)和琳达·巴克(Linda Buck).他们发现嗅觉系统中一个大家族基因,这一大家族基因可以表达等量的嗅觉受体类型.这些受体位于鼻腔上皮的嗅觉神经元上,以检测不同的气味分子.     

昆虫嗅觉相关蛋白的研究进展

嗅觉是昆虫产生行为的重要物质基础,阐明昆虫嗅觉机理有助于调控昆虫行为和进行害虫治理。近年来,许多与嗅觉相关的生物活性分子和相关基因的发现和克隆,对揭示嗅觉机理具有重要作用。作者针对近年来研究较多的气味结合蛋白、化学感受蛋白、气味受体、气味降解酶以及感觉神经元膜蛋白等,就其生化特性、表达部位、分子结构、生理功能等进行了综述。     

昆虫气味认知的嗅觉神经结构及分子机制

大多数昆虫主要通过气味认知感知外界环境的变化,维持生命活动。探究昆虫气味认知的嗅觉系统神经结构及分子机制,对于完善气味认知神经生物学理论及利用其原理进行仿生学研究等有重要的科学意义。近年,关于昆虫气味认知科学研究有了很大的进展。本文从昆虫神经生物学的视角详细综述了近年关于昆虫气味认知的嗅觉神经结构、分子机制及气味信号的神经传导途径等方面的基本理论及最新研究成果。综述结果显示:昆虫对气味的认知是通过嗅觉神经系统的触角感器、触角叶(AL)、蕈形体(MB)等脑内多层信号处理神经结构来实现的。当外界气味分子进入触角感器内后,由感器内特定的气味识别蛋白(OBP)将气味分子运载到达嗅觉感受神经元(ORN)树突膜上的受体位点,气味分子与表达特定气味的受体(OR)结合产生电信号,并以动作电位的形式通过ORN的轴突传到脑内的触角叶。在触角叶经过嗅觉纤维球对气味信息选择性加工处理,再由投射神经元(PNs)将初步的识别和分类的气味信息传到蕈形体和外侧角(LH)等神经中枢,实现对气味的识别和认知。虽然,近年昆虫气味认知神经生物学的研究有了很大的进步,但是,我们认为目前的研究成果还不能完全阐明昆虫气味认知的神经机制,还有很多问题,例如,触角叶上众多的嗅觉纤维球是如何对嗅觉感受神经元传入的气味信息进行编码处理的?等有待进一步深入研究。为了搞清这些疑难问题,我们认为需要提高现有的实验技术水平,加强电生理学和分子神经生物学相结合的实验研究,从分子水平探究气味认知的神经机制可能是未来研究的热点。     

昆虫嗅觉相关蛋白及嗅觉识别机理研究概述

嗅觉是昆虫产生行为的基础之一,在长期进化的过程中昆虫形成了复杂的嗅觉系统,完成这一过程,需要有多种与嗅觉相关的蛋白参与,包括气味结合蛋白、化学感受蛋白、气味受体和感觉神经元膜蛋白等。了解昆虫感受外界信息的嗅觉机制可以帮助我们更好地理解昆虫识别配偶、天敌及寻找食物来源、产卵场地等行为特征,为进一步调控昆虫的行为、防控害虫侵袭、保护和利用有益昆虫奠定基础。本文综述了昆虫嗅觉相关的几类重要蛋白的生化特性和生理功能,并对昆虫气味分子的识别机制、气味分子在昆虫体内运输机制的最新研究进展进行了概述。     

昆虫气味受体研究进展

嗅觉在昆虫的多种行为中发挥关键作用。气味分子与嗅觉神经元树突上气味受体的结合,参与了昆虫嗅觉识别的初始过程。昆虫的嗅觉神经元表达两类气味受体： 一是传统气味受体,该类受体同源性较低,在少部分嗅觉神经元中表达; 二是Or83b家族受体,该类受体不感受气味,在不同昆虫间较为保守且在大多数嗅觉神经元中表达。目前,对于单个传统气味受体的气味分子配体特异性所知甚少; 对于Or83b家族受体,一般认为其可能具有将传统气味受体运送至嗅觉神经元树突膜上的功能。此外,有一些实验证据不支持昆虫气味受体为G蛋白偶联受体的观点。     

二维不定常嗅觉模型及其精确解

在考虑了鼻腔结构的基础上,把嗅觉反应的主要机理分成四个连续的主要过程,建立了二维不定常的嗅觉模型,利用分离变量法得到了该模型的精确解,并给出了两个无量纲参数影响气味分子在粘膜层内分布的计算结果,精确解则揭示了各生理参数之间的内在联系。理论和数值结果表明：吸气速度和嗅粘膜表面的粘液是影响嗅觉反应的两个重要因素。这些结果对进一步研究嗅觉反应机理具有一定的参考价值     

果蝇嗅觉分子机理研究进展

黑腹果蝇Drosophila melanogaster是生物学研究的重要模式生物,也是探索研究生物体嗅觉奥秘的理想材料。近年来,由于分子生物学技术在神经科学领域的广泛应用,黑腹果蝇嗅觉机理研究取得了许多重大突破, 对气味分子受体及其识别机理、 嗅觉神经电信号的产生和传递、嗅觉信息的加工、编码以及记忆等方面都有了深入的了解。研究表明, 果蝇约1 300个嗅神经元(olfactory receptor neurons, ORNs)共表达62种不同的气味受体蛋白（olfactory receptor proteins, ORs）, 用以检测和识别其所感受的所有化学气味分子。许多OR所识别的气味分子配体已鉴定出来,普通的气味（如水果的气味）由数种不同的OR组合来识别,而信息素（pheromone）分子则由单种特定的OR来检测。气味信息在嗅神经元内转换成神经电信号,嗅觉电信号沿嗅神经元的轴突传递到触角叶, 再经投射神经元（projection neurons, PNs）将信息送至高级中枢如蘑菇体（mushroom body, MB）和侧角（lateral horn, LH）,最终引发行为反应。在黑腹果蝇嗅觉信息传递通路中,某些蛋白如Dock,N-cadherin,Fruitless等起着重要作用,缺失这些蛋白会导致嗅觉异常。本文对这些研究进展作一综述。     

Complexes of porcine odorant binding protein with odorant molecules belonging to different chemical classes

Porcine odorant binding protein (pOBP) is a monomer of 157 amino acid residues, purified in abundance from pig nasal mucosa. In contrast to the observation on lipocalins as retinol binding protein (RBP), major urinary protein (MUP) or bovine odorant binding protein (bOBP), no naturally occurring ligand was found in the beta-barrel cavity of pOBP. Porcine OBP was therefore chosen as a simple model for structure/function studies with odorant molecules. In competition experiments with tritiated pyrazine, the affinity of pOBP towards several odorant molecules belonging to different chemical classes has been found to be of the micromolar order, with a 1:1 stoichiometry. The X-ray structures of pOBP complexed to these molecules were determined at resolution between 2.15 and 1.4 A. As expected, the electron density of the odorant molecules was observed into the hydrophobic beta-barrel of the lipocalin. Inside this cavity, very few specific interactions were established between the odorant molecule and the amino acid side-chains, which did not undergo significant conformational change. The high B-factors observed for the odorant molecules as well as the existence of alternative conformations reveal a non-specific mode of binding of the odorant molecules in the cavity.     

A computational study of odorant transport and deposition in the canine nasal cavity: implications for olfaction

Olfaction begins when an animal draws odorant-laden air into its nasal cavity by sniffing, thus transporting odorant molecules from the external environment to olfactory receptor neurons (ORNs) in the sensory region of the nose. In the dog and other macrosmatic mammals, ORNs are relegated to a recess in the rear of the nasal cavity that is comprised of a labyrinth of scroll-like airways. Evidence from recent studies suggests that nasal airflow patterns enhance olfactory sensitivity by efficiently delivering odorant molecules to the olfactory recess. Here, we simulate odorant transport and deposition during steady inspiration in an anatomically correct reconstructed model of the canine nasal cavity. Our simulations show that highly soluble odorants are deposited in the front of the olfactory recess along the dorsal meatus and nasal septum, whereas moderately soluble and insoluble odorants are more uniformly deposited throughout the entire olfactory recess. These results demonstrate that odorant deposition patterns correspond with the anatomical organization of ORNs in the olfactory recess. Specifically, ORNs that are sensitive to a particular class of odorants are located in regions where that class of odorants is deposited. The correlation of odorant deposition patterns with the anatomical organization of ORNs may partially explain macrosmia in the dog and other keen-scented species.     

Modeling inspiratory and expiratory steady-state velocity fields in the Sprague-Dawley rat nasal cavity

Distribution patterns of odorant molecules in the rat nasal olfactory region depend in large part on the detailed airflow patterns in the nasal cavity, which in turn depend on the anatomical structure. To investigate these flow patterns, we constructed an anatomically accurate finite element model of the right nasal cavity of the Sprague-Dawley rat based on horizontal (anterior-posterior) nasal cast cross sections. By numerically solving the fluid mechanical momentum and continuity equations using the finite element method, we studied the flow distribution and the complete velocity field for both inspiration and expiration throughout the nasal cavity under physiological flow rates of resting breathing and sniffing. Detailed velocity profiles, volumetric flow distributions, and streamline patterns for quasi-steady airflow are presented. S-shaped streamlines passing through the olfactory region are found to be less prevalent during expiratory than inspiratory flow leading to trapping and an increase in odorant molecule retention in the olfactory region during sniffing. The rat nasal velocity calculations will be used to study the distribution of odorant uptake onto the rat olfactory mucosa and compare it with the known anatomic location of some types of rat olfactory receptors.     

Numerical modeling of turbulent and laminar airflow and odorant transport during sniffing in the human and rat nose

Human sniffing behavior usually involves bouts of short, high flow rate inhalation (>300 ml/s through each nostril) with mostly turbulent airflow. This has often been characterized as a factor enabling higher amounts of odorant to deposit onto olfactory mucosa than for laminar airflow and thereby aid in olfactory detection. Using computational fluid dynamics human nasal cavity models, however, we found essentially no difference in predicted olfactory odorant flux (g/cm2 s) for turbulent versus laminar flow for total nasal flow rates between 300 and 1000 ml/s and for odorants of quite different mucosal solubility. This lack of difference was shown to be due to the much higher resistance to lateral odorant mass transport in the mucosal nasal airway wall than in the air phase. The simulation also revealed that the increase in airflow rate during sniffing can increase odorant uptake flux to the nasal/olfactory mucosa but lower the cumulative total uptake in the olfactory region when the inspired air/odorant volume was held fixed, which is consistent with the observation that sniff duration may be more important than sniff strength for optimizing olfactory detection. In contrast, in rats, sniffing involves high-frequency bouts of both inhalation and exhalation with laminar airflow. In rat nose odorant uptake simulations, it was observed that odorant deposition was highly dependent on solubility and correlated with the locations of different types of receptors.     

Numerical Simulation of Airway Dimension Effects on Airflow Patterns and Odorant Deposition Patterns in the Rat Nasal Cavity

The sense of smell is largely dependent on the airflow and odorant transport in the nasal cavity, which in turn depends on the anatomical structure of the nose. In order to evaluate the effect of airway dimension on rat nasal airflow patterns and odorant deposition patterns, we constructed two 3-dimensional, anatomically accurate models of the left nasal cavity of a Sprague-Dawley rat: one was based on high-resolution MRI images with relatively narrow airways and the other was based on artificially-widening airways of the MRI images by referencing the section images with relatively wide airways. Airflow and odorant transport, in the two models, were determined using the method of computational fluid dynamics with finite volume method. The results demonstrated that an increase of 34 µm in nasal airway dimension significantly decreased the average velocity in the whole nasal cavity by about 10% and in the olfactory region by about 12% and increased the volumetric flow into the olfactory region by about 3%. Odorant deposition was affected to a larger extent, especially in the olfactory region, where the maximum odorant deposition difference reached one order of magnitude. The results suggest that a more accurate nasal cavity model is necessary in order to more precisely study the olfactory function of the nose when using the rat.     

Experimental and numerical determination of odorant solubility in nasal and olfactory mucosa

Odorant deposition in the nasal and olfactory mucosas is dependent on a number of factors including local air/odorant flow distribution patterns, odorant mucosal solubility and odorant diffusive transport in the mucosa. Although many of these factors are difficult to measure, mucosal solubility in the bullfrog mucus has been experimentally determined for a few odorants. In the present study an experimental procedure was combined with computational fluid dynamic (CFD) techniques to further describe some of the factors that govern odorant mucosal deposition. The fraction of odorant absorbed by the nasal mucosa (eta) was experimentally determined for a number of odorants by measuring the concentration drop between odorant 'blown' into one nostril and that exiting the contralateral nostril while the subject performed a velopharyngeal closure. Odorant concentrations were measured with a photoionization detector. Odorants were delivered to the nostrils at flow rates of 3.33 and 10 l/min. The velopharyngeal closure nasal air/odorant flows were then simulated using CFD techniques in a 3-D anatomically accurate human nose modeland the mucosal odorant uptake was numerically calculated. The comparison between the numerical simulations and the experimental results lead to an estimation of the human mucosal odorant solubility and the mucosal effective diffusive transport resistance. The results of the study suggest that the increase in diffusive resistance of the mucosal layer over that of a thin layer of water seemed to be general and non-odorant-specific; however, the mucosa solubility was odorant specific and usually followed the trend that odorants with lower water solubility were more soluble in the mucosa than would be predicted from water solubility alone. The ability of this approach to model odorant movement in the nasal cavity was evaluated by comparison of the model output with known values of odorant mucosa solubility.     

How Far Does a Receptor Influence Vibrational Properties of an Odorant?

The biophysical mechanism of the sense of smell, or olfaction, is still highly debated. The mainstream explanation argues for a shape-based recognition of odorant molecules by olfactory receptors, while recent investigations suggest the primary olfactory event to be triggered by a vibrationally-assisted electron transfer reaction. We consider this controversy by studying the influence of a receptor on the vibrational properties of an odorant in atomistic details as the coupling between electronic degrees of freedom of the receptor and the vibrations of the odorant is the key parameter of the vibrationally-assisted electron transfer. Through molecular dynamics simulations we elucidate the binding specificity of a receptor towards acetophenone odorant. The vibrational properties of acetophenone inside the receptor are then studied by the polarizable embedding density functional theory approach, allowing to quantify protein-odorant interactions. Finally, we judge whether the effects of the protein provide any indications towards the existing theories of olfaction.     

Expression of a Lipocalin in Human Nasal Mucosa

A 19 kDa soluble protein was purified from human nasal mucus. Its N-terminal amino-acid sequence appeared to be identical to that of a lipocalin synthesised both in lachrymal glands and in von Ebner's glands (VEG) of circumvallate papillae. In order to verify whether this protein was synthesised in the nasal cavity or was the result of tear contamination, we adopted an immunohistochemical approach. Polyclonal antibodies, raised against a primate VEG protein, were used on sections of human nasal mucosa obtained from surgery. The results clearly indicate that the protein is synthesised in sero-mucous glands underlying the respiratory ciliated epithelium. Although ligand-binding experiments with some odorant molecules have given negative results, we cannot exclude a role of odorant solubiliser and carrier for this protein.     

Measuring smells

Olfaction consists of a set of transforms from a physical space of odorant molecules, through a neural space of information processing, and into a perceptual space of smell. Elucidating the rules governing these transforms depends on establishing valid metrics for each of the three spaces. Here we first briefly review the perceptual and neural spaces, and then concentrate on the physical space of odorant molecules. We argue that the lack of an agreed-upon odor metric poses a significant obstacle toward understanding the neurobiology of olfaction, and suggest two alternative odor metrics as possible solutions.     

Speed-accuracy tradeoff in olfaction

The basic psychophysical principle of speed-accuracy tradeoff (SAT) has been used to understand key aspects of neuronal information processing in vision and audition, but the principle of SAT is still debated in olfaction. In this study we present the direct observation of SAT in olfaction. We developed a behavioral paradigm for mice in which both the duration of odorant sampling and the difficulty of the odor discrimination task were controlled by the experimenter. We observed that the accuracy of odor discrimination increases with the duration of imposed odorant sampling, and that the rate of this increase is slower for harder tasks. We also present a unifying picture of two previous, seemingly disparate experiments on timing of odorant sampling in odor discrimination tasks. The presence of SAT in olfaction provides strong evidence for temporal integration in olfaction and puts a constraint on models of olfactory processing.