The sense of smell of mammals

The mammalian olfactory organs are more developed than other terrestrial vertebrates , and play a very important role in their life. Mammals use the ability to distinguish odors for orientation in space, when searching for food, as part of interspecific and intraspecific contacts ^[4] . The importance of olfaction for mammals is also indicated by the fact that the genes encoding olfactory receptor proteins form just the most extensive in their genome ^[5] . Smelling plays a role in the nutrition of mammals: pleasant odors trigger the secretion of saliva and gastric juice , and unpleasant ones warn of potential harm (for example, the unpleasant smell of spoiled food) ^[6] .

According to the degree of development of the olfactory function, mammals are divided into two groups: macro-mats with extremely acute sense of smell (most mammals) and micro-mats with moderately developed sense of smell ( primates , cetaceans , pinnipeds ) ^[7] .

The difference between these groups is clearly visible when comparing the degree of development of smell in humans and dogs . If the human nose has about 6 million olfactory cells, then the dog has about 225 million ^[8] . Many macrosmates can smell at a distance of several hundred meters and are able to find food objects underground ^[9] . It is a well-known practice to search for truffles growing in the forest under the ground with the help of specially trained search dogs and pigs , which are able to smell truffles underground at a distance of up to 20 m ^[10] .

The degree of development of smell as a whole correlates with the number of genes encoding various types of functional proteins of olfactory receptors . Macmatmatians usually have more than 1000, in many primates - about 500, in humans - only 387 (about 1-2% of the genome ^[11] ), and in the platypus - 262 ^[12] . Apparently, the worst developed sense of smell in cetaceans; they have the highest percentage of pseudogenes of olfactory receptors ^[13] .

The mammalian olfactory organs are located in the posterior upper part of the nasal cavity , where a very complex system of turbinates , especially in the macromati, arises - thin bony petals directed inside the cavity and covered with olfactory epithelium . In the nasal concha not only an olfactory analysis of the inhaled air occurs, but also its heating before entering the lungs. Among modern species of tetrapods, olfactory shells are found only in mammals, as well as in a few species of birds in which these shells arose independently ^[14] . The olfactory epithelium contains olfactory receptor cells , supporting cells secreting mucus and properties similar to glial cells, as well as basal cells, which, like stem cells , are able to divide and give rise to new functional neurons throughout the life of the animal. The size of the olfactory epithelium in mammals varies from 2-4 cm² (human) and 9.3 cm² (rabbit) to 18 cm² (dog) and 21 cm² (domestic cat). However, these values ​​do not give an idea of ​​the severity of the sense of smell, because they do not take into account the number of olfactory receptors per unit surface. The olfactory receptors are able to capture molecules of odorous substances contained in the inhaled air. Like taste receptors, they are assigned to the group of chemoreceptors . Signals of the presence of smelling substances are transmitted through the olfactory nerve to the corresponding center of the brain - the olfactory bulb or primary centers of smell of the cerebral cortex . From the latter, olfactory signals are transmitted to the hypothalamus , limbic system , reticular formation and neocortex ^{[7] [6] [15]} .

Most mammals retain the Jacobson organ as a separate section of the olfactory capsule. This organ, which is also found in bipedal and most tetrapods (the most important exceptions are birds and crocodiles ), serves mainly for the perception of pheromones . In representatives of a number of groups ( cetaceans , sirens , most bats and narrow-nosed primates , including humans ), the Jacobson organ is rudimentary or completely lost ^{[16] [17] [18]} .

The vomeronasal organ is lined with olfactory epithelium, similar to the one that covers the nasal concha. Olfactory receptor cells renew throughout life and are supported by epithelial and basal cells, but instead of cilia they have microvilli (microvilli). Receptor molecules are also represented by GPCR, but their amino acid sequence has nothing to do with nasal concha receptors. The GPCR of the vomeronasal organ is represented by two different families, each of which contains from 100 to 200 genes and developed independently. Representatives of one of these families have a long extracellular N-terminal domain, similar to the metabotropic glutamate receptor . The secondary mediator here is not cAMP, as in the nasal concha, but inositol triphosphate. Afferent fibers from the vomeronasal epithelium are projected into the additional olfactory bulb, which in most cases is located posterior to the main olfactory bulb. Like the olfactory nose, the vomeronasal epithelium is also divided into zones: different G-proteins are expressed in the apical and basal parts of the organ. These zones are preserved in projections into the additional olfactory bulb: the apical zone of the epithelium is projected into the anterior zone of the bulb, and the basal one into the posterior. Glomeruli in the additional bulb are less pronounced than in the main. In addition, instead of the spatial map of the main bulb, the representation of the additional bulb is more complex and mosaic. The additional bulb does not have projections into the cortex and is associated only with the limbic system: with the amygdala and hypothalamic nuclei, which play an important role in sexual behavior. It is possible that the additional bulb reacts only to special species-specific combinations of substances of the corresponding pheromone and simply ignores all the others ^[19] .

Olfactory cells

The olfactory receptors ( ) are bipolar neurons with one unbranched dendrite. It passes between the basal cells and ends with a slight swelling - olfactory mace . Up to 20 long cilia come out of it, which represent the sensory surface of the olfactory cell. They are usually immersed in a layer of mucus covering the epithelium and form a dense matrix with it. The olfactory cell has a dual function: the perception of the stimulus and the transmission of a nerve impulse to the brain , therefore it is a sensor neurosensor (sensory neuron). Axons that transmit signals to the central nervous system are assembled in bundles - olfactory threads . Olfactory neurons are capable of being replaced by division of basal cells ^{[20] [21]} .

The mucus in which the olfactory cilia lie contains a large number of medium-sized (20 kDa) proteins that are secreted by the glands of the nose and are found in the mucus covering not only the olfactory epithelium, but also purely respiratory. These proteins are possibly very non-selectively bound to odorous molecules (odorants) and provide their interaction with receptor cells ^[20] .

The olfactory cilia do not differ in structure from other cilia and contain the usual motionless axoneme . The olfactory cilia are very long and thin: with a length of 5 to 250 microns, they reach only 100-250 nm in diameter . They are collected in bundles of 5–40 and emerge from the clubs of the olfactory cell, increasing its sensory surface. Receptor proteins are located on the surface of the cilia. Each gene in the family of genes encoding such proteins encodes a specific variety of them, and olfactory proteins of only one species are present on the cilia of one olfactory cell; not all genes of this family, however, can be expressed (for example, about 40% of these genes are expressed in humans). For a long time, it was unclear whether the cilium responds to many types of odorants or only to one ^[11] . Now, however, it has been established that olfactory cells of the same type are specific to a particular narrow class of chemical compounds , since they recognize special structural motifs in them ^{[14] [21]} .

Regardless of specificity, the sensitivity of olfactory cells is very high: they are able to register substances at a concentration of 10 ^-4 M to 10 ^-13 M. With a cold, sensitivity decreases due to the fact that the cilia are immersed in too thick a layer of mucus ^[11] .

In addition to the olfactory cells associated with the olfactory nerve, in the nasal mucosa there are also free endings of the trigeminal nerve ; they are able to respond to some aggressive odors, for example, acid or ammonia fumes ^[21] .

Signal

The olfactory stimulus begins as follows. The odorous substance binds to the receptor in the membrane of the olfactory cell. The olfactory receptor is a G protein coupled receptor ( G protein coupled receptor ) and, like all GPCRs, contains 7 domains . Unlike other receptors of the GPCR superfamily, olfactory receptors are characterized by a large amino acid diversity in the 3, 4, and especially 5. In addition, olfactory receptors are less specific from other GPCRs: they have affinity to one degree or another to a number of stereochemically similar odorants. However, small changes in the chemical structure of the odorant may correspond to a change in the set of stimulated receptors and a change in subjective perception. Thus, the replacement of the hydroxyl group of octanol with the carboxyl group leads to a significant change in olfactory perception: instead of a smell that resembles the smell of an orange , the smell of rancidity and sweat is felt. In addition, the number of stimulated receptors and subjective perception may depend on the concentration of the odorant. For example, in a low concentration, indole has a pleasant floral aroma, and in a high one it has a disgusting putrefactive aroma ^[22] .

Binding of the odorant to the receptor activates the , which activates the adenylate cyclase enzyme , as a result of which GTP breaks down into phosphate and HDF . Adenylate cyclase converts ATP into cAMP , which binds to the cyclonucleotide-dependent cation channel in the membrane and opens the current of Na ⁺ and Ca ^{2+ ions} to the olfactory cell, thereby triggering the action potential in it, which is then transmitted to afferent neurons ^[21] . Sometimes olfactory receptors, however, do not activate adenylate cyclase, but phospholipase , and the secondary mediator is not cAMP, but inositol triphosphate and diacylglycerol . In addition, it is possible that in olfactory cells, NO is formed due to calcium activation of NO synthase , which leads to the formation of cGMP ^[23] .

Cyclonucleotide-dependent channels have six hydrophobic segments and resemble potential-dependent ion channels in structure. The difference is that the cyclonucleotide-dependent channels have a large C-terminal cytoplasmic domain that binds to secondary messengers. 2400 channels / μm² are located on the cilia (only 6 channels / μm² on the olfactory club and dendrite. In the absence of calcium, the cyclonucleotide-dependent channels are permeable to all monovalent cations : Na ⁺ > K ⁺ > Li ⁺ > Rb ⁺ > Cs ⁺ . When exposed to odorant ion currents through cyclonucleotide-dependent channels change, leading to depolarization of the cell membrane and triggering of the action potential ^[24] .

Olfactory cells of the same type transmit their signals to the same olfactory bulb, and the spatial organization of the latter topographically repeats the arrangement of receptors on the surface of the olfactory shell ^[14] . It is worth noting that one olfactory receptor can be excited by one odorous molecule ^[25] .

In 2004, Linda Buck and Richard Excel received the Nobel Prize in Physiology or Medicine for their studies of olfactory mammalian receptors ^[26] ; it was they who established the chemical nature of the olfactory receptor proteins, estimated the number of genes in the mammalian genome encoding these proteins, and substantiated the rules by which one olfactory cell expresses one kind of olfactory receptor proteins, and the same one is responsible for processing signals from all olfactory cells of the same type the glomerulus of the olfactory bulb ^{[27] [28]} .

Sensory Adaptation

Interestingly, the cyclonucleotide-dependent channels of the olfactory cilia do not , that is, they do not lose their sensitivity upon repeated presentation of the odorant. However, in olfactory cells, however, adaptation occurs. This is probably due to the entry of Ca ²⁺ ions into the cell , which either directly or through activation of calmodulin lead to the closure of ion channels and, in addition, desensitize GPCR ^[29] .

Кроме того, ответ на обонятельный стимул градуален, то есть большей концентрации одоранта соответствует больший ответ. Это связано с тем, что цАМФ увеличивает или уменьшает количество открытых циклонуклеотид-зависимые каналов. Для эффективного различения сигналов в реальном времени необходим быстрый ответ. Показано, что пик образования цАМФ наступает через 40—75 мс после воздействия пахучего вещества и через 100—500 мс падает до нуля. G-белковый каскад усиливает сигнал, благодаря чему один импульс одоранта активирует множество каналов. Впрочем, кинетика каналов достаточно медленна, и открытое состояние может отставать от импульса цАМФ на несколько миллисекунд. При продолжительной активации GPCR одорантов импульсы цАМФ обеспечивают поддержание циклонуклеотид-зависимые каналов в постоянно открытом состоянии ^[29] .

В отличие от других сенсорных систем ( зрительной , слуховой , соматосенсорной и, в меньшей степени, вкусовой ), где сенсорный эпителий регистрирует пространственную информацию, «картирующая» функция обонятельного эпителия не так выражена. Тем не менее, в нём присутствуют зачатки пространственной организации. Картирование при помощи , которая даёт возможность выявить активные клетки, показало, что в обонятельном эпителии имеются группы клеток, связанные с определёнными запахами. Так, бутанол возбуждает клетки передней области, а лимонен активирует клетки задней части слизистой. Кроме того, недавно было показано, что рецепторные клетки организованы в передне-задние полосы (так называемые зоны экспрессии ), каждая из которых содержит полный набор клеток. Судя по всему, существует 3 неперекрывающиеся зоны экспрессии, которые перекрываются с меньшей, четвёртой зоной ^[30] .

Аксоны обонятельных биполярных клеток объединяются в несколько десятков пучков, каждый из которых содержит несколько сотен или тысяч волокон. Они входят в полость черепа через отверстия решётчатой кости и объединяются в обонятельные нервы . Окончания первичных обонятельных клеток образуют синапсы с дендритами клеток обонятельных луковиц. Каждая такая клетка ( ), являющаяся сенсорным нейроном второго порядка, получает сигналы от около 1000 аксонов первичных сенсорных клеток, то есть около 1000 обонятельных аксонов конвергируют на разветвлениях апикального дендрита одной митральной клетки. Около 25 таких дендритов совместно с терминалями формируют сферические образования — гломерулы . На одной гломеруле конвергирует около 2500 обонятельных аксонов, а в обонятельной луковице кролика имеется около 2000 гломерул. Для митральных клеток характерна ритмическая активность, обусловленная вдыханием пахучих веществ. Локальные интернейроны обонятельных луковиц (перигломерулярные клетки, расположенные между гломерулами, и зернистые клетки, залегающие под митральными клетками) способны к контрастированию получаемых сигналов. На этих клетках оканчиваются пути противоположной обонятельной луковицы, лимбических структур и ретикулярной формации мозга. Система синаптических контактов в обонятельной луковицы чрезвычайно сложна, как и её химия: в ней идентифицировано около дюжины нейромедиаторов , среди которых ацетилхолин , дофамин , ГАМК и несколько нейропептидов ^[31] .

Аксоны митральных клеток образуют обонятельный тракт, ведущий к обонятельным центрам высшего порядка, который, разделяясь на несколько частей, оканчивается на лимбических структурах переднего мозга: , перегородке, пириформной и парагиппокампальной извилинах. От этих структур информация поступает в гиппокамп , миндалины , орбитофронтальную кору (напрямую или через таламус ) и ретикулярную формацию среднего мозга ^{[32] [6]} .

Распознавание конкретного запаха является результатом совместной работы рецепторов и мозга, в результате чего он представляется как комбинация «первичных запахов». В соответствии со стереохимической теорией обоняния Монкриффа — Эймура ^[33] , у человека имеется семикомпонентная система распознавания запахов, базирующаяся на различении семи первичных запахов: мускусного, камфарного, цветочного, эфирного, мятного, едкого и гнилостного (относящиеся к одной группе вещества сходны в стереомодели) ^{[34] [35]} .

У человека генетический анализ выявил несколько дюжин специфических аносмий — расстройств обонятельной системы, проявляющихся в неспособности различать определённые запахи. Например, неспособность определить запах цианида встречается с частотой 1:10, а (пахучее вещество скунса ) — 1:1000. Вероятно, аносмии обусловлены дефектами специфических обонятельных рецепторов. Многие аносмии демонстрируют менделевское наследование , однако генетика аносмий изучена плохо ^[29] .

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