Morphology of the Human Olfactory Analyzer

The sense of smell provides people with valuable information about the biochemical environment and their own body. Olfactory disorders occur in pathologies of the nasal cavity, liver cirrhosis, psychological and endocrine diseases. Smell affects various psychological aspects of people's lives, forming positive and negative emotional memories associated with smells. With the dysfunction of the olfactory analyzer, a person will not do the analysis whether the food is good, will not be able to feel the presence of poisonous gases in the air, bad breath. This puts a person in an awkward position and increases the risk of social isolation. The purpose of the study was to highlight the components of the normal structure and functioning of the human olfactory analyzer. Identification of odors in the environment and from one's own body is provided by the olfactory analyzer. Primary odors as camphor, floral, fruity, spicy, tarry, burnt and putrid in different quantities form secondary odors. Aromas are composed of volatile molecules called odorants. The smallest amount of odorant that causes an odor sensation is called the odor threshold. In people with coronavirus disease the sense of smell temporarily disappears (anosmia); it is reduced (hyposmia) in liver cirrhosis and rhinitis, and in Alzheimer's disease and schizophrenia besides hyposmia there is olfactory hallucination (phantosmia). Olfactory dysfunction adversely affects children's cognitive abilities. Fragrances change emotions and behavior. Aromas are used to regulate the physical and psychological state of the patient. Volatile molecules of fragrances penetrate through the layer of mucus that covers the olfactory epithelium located in the olfactory region of the nasal mucosa. The olfactory epithelium consists of olfactory, supportive and basal epitheliocytes, as well as secretory cells of the olfactory glands. Olfactory cells are modified nerve cells that have a body, an axon, and a dendrite, which ends with a receptor in the form of olfactory cilia. Volatile molecules interact with the olfactory cilia and then with the receptor protein, which is located on the olfactory cell bodies. In humans, olfactory cells have 350 receptor proteins. One type of receptor can register molecules of several different odorants. Molecules of the same odorant can activate several different receptors simultaneously. The nerve impulse from the olfactory cells (bodies of I neurons) reaches the nerve cells (bodies of II neurons) of the olfactory bulbs via their central outgrowths (olfactory filaments). Axons of nerve cells of olfactory bulbs continue to bodies of III neurons, which are located in subcortical centers of the brain (almond-shaped body, nuclei of the transparent septum). In human, to analyze a particular odor, axons from bodies of III neurons continue to cortex, namely to the area of the uncus of the parahippocampal gyrus

A Genetic Platform for Functionally Profiling Odorant Receptors Ex Vivo Using Olfactory Cilia.

The molecular basis for odor perception in humans remains a black box as odorant receptors (ORs) are notoriously difficult to study outside of their native environment. Efforts toward OR expression and functional profiling in heterologous systems have been met with limited success due to poor efficiency of cell surface expression and consequently reduced G-protein signal amplification. We previously reported a genetic strategy in mice to increase the number of sensory neurons expressing specific ORs, which transforms the 10 million neurons of the mouse nose into a bioreactor producing large quantities of fully functional OR protein. We now describe the isolation of cilia from these bioreactors for two human ORs. Cilia are known to contain all components of the olfactory signal transduction machinery and can be placed into an ex vivo well-plate assay to rapidly measure robust, reproducible odor-specific responses. Our OR1A1 and OR5AN1 isolated cilia reveal 10-100fold more sensitivity than existing assays. Tissue from a single animal produces up to 4,000 384-well assay wells, and isolated olfactory cilia can be stored frozen and thus preserved for long term usage. This pipeline offers a sensitive, highly scalable ex vivo odor screening platform that opens the door for decoding human olfaction.

Potential therapeutic targets for olfactory dysfunction in ciliopathies beyond single gene replacement

Olfactory dysfunction is a common disorder in the general population. There are multiple causes, one of which being ciliopathies, an emerging class of human hereditary genetic disorders characterized by multiple symptoms due to defects in ciliary biogenesis, maintenance, and/or function. Mutations/deletions in a wide spectrum of ciliary genes have been identified to cause ciliopathies. Currently, besides symptomatic therapy, there is no available therapeutic treatment option for olfactory dysfunction caused by ciliopathies. Multiple studies have demonstrated that targeted gene replacement can restore the morphology and function of olfactory cilia in olfactory sensory neurons and further re-establish the odor-guided behaviors in animals. Therefore, targeted gene replacement could be potentially used to treat olfactory dysfunction in ciliopathies. However, due to the potential limitations of single gene therapy for polygenic mutation-induced diseases, alternative therapeutic targets for broader curative measures need to be developed for olfactory dysfunction, and also for other symptoms in ciliopathies. Here we review the current understanding of ciliogenesis and maintenance of olfactory cilia. Furthermore, we emphasize signaling mechanisms that may be involved in the regulation of olfactory ciliary length and highlight potential alternative therapeutic targets for the treatment of ciliopathy induced dysfunction in the olfactory system and even in other ciliated organ systems.

Heterotrimeric kinesin-2 motor subunit, KLP68D, localises Drosophila odour receptor coreceptor in the distal domain of the olfactory cilia

Ciliary localisation of the odour receptor coreceptor (Orco) is essential for insect olfaction. Here, we show that in the Drosophila antenna Orco enters the bipartite cilia expressed on the olfactory sensory neurons in two discrete, one-hour intervals after the adult eclosion. Genetic analyses suggest that the heterotrimeric kinesin-2 is essential for Orco transfer from the base into the cilium. Using in vitro pulldown assay, we show that Orco binds to the C-terminal tail domain of KLP68D, the β-subunit of kinesin-2. Reduced Orco enrichment decreases electrophysiological response to odours and loss of olfactory behaviour. Finally, we show that kinesin-2 function is necessary to compact Orco to an approximately four-micron stretch at the distal portion of the ciliary outer-segment bearing singlet microtubule filaments. Altogether, these results highlight an independent, tissue-specific regulation of Orco entry at specific developmental stages and its localisation to a ciliary subdomain by kinesin-2.Graphical AbstractAuthor SummaryJana, Jain, Dutta et al., show that the odour receptor coreceptor only enters the cilia expressed on olfactory sensory neurons at specified developmental stages requiring heterotrimeric kinesin-2. The motor also helps to localise the coreceptor in a compact, environment-exposed domain at the ciliary outer-segment.Highlights:Odorant receptor coreceptor (Orco) selectively enters the olfactory cilia.Orco localises in a specific domain at the distal segment of the olfactory cilium.Orco/ORx binds to the C-terminal tail domain of the kinesin-2β motor subunit.Orco entry across the transition zone and its positioning require Kinesin-2.

The Caenorhabditis elegans Tubby homolog dynamically modulates olfactory cilia membrane morphogenesis and phospholipid composition

Plasticity in sensory signaling is partly mediated via regulated trafficking of signaling molecules to and from primary cilia. Tubby-related proteins regulate ciliary protein transport; however, their roles in remodeling cilia properties are not fully understood. We find that the C. elegans TUB-1 Tubby homolog regulates membrane morphogenesis and signaling protein transport in specialized sensory cilia. In particular, TUB-1 is essential for sensory signaling-dependent reshaping of olfactory cilia morphology. We show that compromised sensory signaling alters cilia membrane phosphoinositide composition via TUB-1-dependent trafficking of a PIP5 kinase. TUB-1 regulates localization of this lipid kinase at the cilia base in part via localization of the AP-2 adaptor complex subunit DPY-23. Our results describe new functions for Tubby proteins in the dynamic regulation of cilia membrane lipid composition, morphology, and signaling protein content, and suggest that this conserved family of proteins plays a critical role in mediating cilia structural and functional plasticity.

The C. elegans Tubby homolog dynamically modulates olfactory cilia membrane morphogenesis and phospholipid composition

ABSTRACTPlasticity in sensory signaling is partly mediated via regulated trafficking of signaling molecules to and from primary cilia. Tubby-related proteins regulate ciliary protein transport; however, their roles in remodeling of cilia properties are not fully understood. We find that the C. elegans TUB-1 Tubby homolog regulates membrane morphogenesis and signaling protein transport in specialized sensory cilia. In particular, TUB-1 is essential for sensory signaling-dependent reshaping of olfactory cilia morphology. We show that compromised sensory signaling alters cilia membrane phosphoinositide composition via TUB-1-dependent trafficking of a PIP5 kinase. TUB-1 regulates localization of this lipid kinase at the cilia base in part via localization of the AP-2 adaptor complex subunit DPY-23. Our results describe new functions for Tubby proteins in the dynamic regulation of cilia membrane lipid composition, morphology, and signaling protein content, and suggest that this conserved family of proteins plays a critical role in mediating cilia structural and functional plasticity.