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Neurobiology of Disease Jan 2018Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders,...
Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders, olfactory disturbances appear early and are considered as prodromal symptoms of the disease. In addition, pathological protein aggregates affect olfactory regions prior to other regions, suggesting that the olfactory system might be particularly vulnerable to neurodegenerative diseases. Exposed to the external environment, the olfactory epithelium and olfactory bulb allow pathogen and toxin penetration into the brain, a process that has been proposed to play a role in neurodegenerative diseases. Determining whether the olfactory bulb could be a starting point of pathology and of pathology spread is crucial to understanding how neurodegenerative diseases evolve. We argue that pathological changes following environmental insults contribute to the initiation of protein aggregation in the olfactory bulb, which then triggers the spread of the pathology within the brain by a templating mechanism in a prion-like manner. We review the evidence for the early involvement of olfactory structures in neurodegenerative diseases and the relationship between neuropathology and olfactory function. We discuss the vulnerability and putative underlying mechanisms by which pathology could be initiated in the olfactory bulb, from the entry of pathogens (promoted by increased permeability of the olfactory epithelium with aging or inflammation) to the sensitivity of the olfactory system to oxidative stress and inflammation. Finally, we review changes in protein expression and neural excitability triggered by pathogenic proteins that can promote pathogenesis in the olfactory bulb and beyond.
Topics: Animals; Humans; Neurodegenerative Diseases; Olfaction Disorders; Olfactory Bulb; Olfactory Mucosa
PubMed: 28011307
DOI: 10.1016/j.nbd.2016.12.013 -
Chemical Senses May 2020Both canonical olfactory sensory neurons (OSNs) and sensory neurons belonging to the guanylate cyclase D (GCD) "necklace" subsystem are housed in the main olfactory...
Both canonical olfactory sensory neurons (OSNs) and sensory neurons belonging to the guanylate cyclase D (GCD) "necklace" subsystem are housed in the main olfactory epithelium, which is continuously bombarded by toxins, pathogens, and debris from the outside world. Canonical OSNs address this challenge, in part, by undergoing renewal through neurogenesis; however, it is not clear whether GCD OSNs also continuously regenerate and, if so, whether newborn GCD precursors follow a similar developmental trajectory to that taken by canonical OSNs. Here, we demonstrate that GCD OSNs are born throughout adulthood and can persist in the epithelium for several months. Phosphodiesterase 2A is upregulated early in the differentiation process, followed by the sequential downregulation of β-tubulin and the upregulation of CART protein. The GCD and MS4A receptors that confer sensory responses upon GCD neurons are initially expressed midway through this process but become most highly expressed once CART levels are maximal late in GCD OSN development. GCD OSN maturation is accompanied by a horizontal migration of neurons toward the central, curved portions of the cul-de-sac regions where necklace cells are concentrated. These findings demonstrate that-like their canonical counterparts-GCD OSNs undergo continuous renewal and define a GCD-specific developmental trajectory linking neurogenesis, maturation, and migration.
Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Cyclic Nucleotide Phosphodiesterases, Type 2; Down-Regulation; Female; Guanylate Cyclase; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Nerve Tissue Proteins; Neurogenesis; Olfactory Mucosa; Olfactory Receptor Neurons; Tubulin; Up-Regulation
PubMed: 32333759
DOI: 10.1093/chemse/bjaa027 -
Journal of Anatomy Apr 1999Conventional histochemistry and the binding patterns of 22 biotinylated lectins were examined for characterisation of glycoconjugates in the components of the olfactory...
Conventional histochemistry and the binding patterns of 22 biotinylated lectins were examined for characterisation of glycoconjugates in the components of the olfactory mucosa of the armadillo Chaetophractus villosus. The mucous lining the olfactory epithelium showed binding sites for DSL, WGA, STL, LEL, PHA-E and JAC. Only the basilar processes of the supporting cells stained for Con-A and S-Con A. The olfactory receptor neurons stained with LEL, LCA, Con A, S-Con A, JAC and PNA. The layer of basal cells did not react with any of the lectins studied. Bowman's glands in the lamina propria showed subpopulations of acinar cells reacting with SBA, S-WGA, WGA, STL, Con A, PSA, PNA, SJA, VVA, JAC and S-Con A, but in our optical studies with lectins we were unable to differentiate between mucous and serous cells in the way that is possible on electron microscopy. The ducts of Bowman's glands were labelled with S-WGA, STL, LEL, PHA-E, BSL-I and JAC. This histochemical study on the glycoconjugates of the olfactory mucosa in the order Xenarthra provides a basis for further experimental investigations.
Topics: Acetylglucosamine; Animals; Armadillos; Female; Fucose; Galactose; Glycoconjugates; Histocytochemistry; Lectins; Male; Mannose; Olfactory Mucosa
PubMed: 10386777
DOI: 10.1046/j.1469-7580.1999.19430395.x -
Journal of Anatomy Nov 2019Olfactory ensheathing glia (OEG) are found in the olfactory mucosa, nerve and bulb, and provide in vivo ensheathment for the unmyelinated olfactory axons within the...
Olfactory ensheathing glia (OEG) are found in the olfactory mucosa, nerve and bulb, and provide in vivo ensheathment for the unmyelinated olfactory axons within the central and peripheral nervous system domains. OEG cells are able to migrate long distances within the neuropil of the central nervous system. Because gangliosides such as 9-O-acetyl GD3 have crucial regulatory roles in neuronal migration during development, we analyzed whether OEG in organotypical cultures are revealed by anti-9-O-acetyl GD3 and/or gangliosides are recognized by the A2B5 antibody (G-A2B5), and whether these gangliosides are involved in OEG migration. Our results showed that all OEG migrating out of a section of olfactory bulb onto a laminin substrate bound to the 9-O-acetyl GD3 and A2B5 antibodies, and that 2',3'-cyclic nucleotide phosphodiesterase (CNPase) colocalized with 9-O-acetyl GD3 and with G-A2B5. Additionally, we showed that the immune blockade of 9-O-acetyl GD3 or G-A2B5 reduced the migration of OEG on laminin, and that 9-O-acetyl GD3 and G-A2B5 colocalized with the β1-integrin subunit. We also confirmed the phenotype of in-vitro-grown OEG cells derived from adult rats, showing that they express CNPase, and also α-smooth muscle actin, which is not expressed by Schwann cells. Our data showed that the gangliosides 9-O-acetyl GD3 and G-A2B5 participate in the migratory activity of OEG cells, and that the β1-integrin subunit colocalizes with these gangliosides. These results suggest a new role for β1-integrin and gangliosides in the polarized migration of OEG cells, and provide new information on the molecules controlling OEG motility and behavior.
Topics: Animals; Cell Movement; Gangliosides; Integrin beta1; Neuroglia; Olfactory Bulb; Olfactory Mucosa; Rats; Rats, Wistar; Schwann Cells
PubMed: 31373393
DOI: 10.1111/joa.13057 -
Cell Reports Jun 2020Sensory information is selectively or non-selectively enhanced and inhibited in the brain, but it remains unclear whether and how this occurs at the most peripheral...
Sensory information is selectively or non-selectively enhanced and inhibited in the brain, but it remains unclear whether and how this occurs at the most peripheral level. Using in vivo calcium imaging of mouse olfactory bulb and olfactory epithelium in wild-type and mutant animals, we show that odors produce not only excitatory but also inhibitory responses in olfactory sensory neurons (OSNs). Heterologous assays indicate that odorants can act as agonists to some but inverse agonists to other odorant receptors. We also demonstrate that responses to odor mixtures are extensively suppressed or enhanced in OSNs. When high concentrations of odors are mixed, widespread antagonism suppresses the overall response amplitudes and density. In contrast, a mixture of low concentrations of odors often produces synergistic effects and boosts the faint odor inputs. Thus, odor responses are extensively tuned by inhibition, antagonism, and synergy at the most peripheral level, contributing to robust sensory representations.
Topics: Animals; Axons; Biological Assay; Mice, Transgenic; Odorants; Olfactory Mucosa; Olfactory Receptor Neurons; Presynaptic Terminals; Receptors, Odorant
PubMed: 32610120
DOI: 10.1016/j.celrep.2020.107814 -
Experimental Physiology Feb 2012In vertebrate olfactory transduction, a Ca(2+)-dependent Cl(-) efflux greatly amplifies the odorant response. The binding of odorants to receptors in the cilia of... (Review)
Review
In vertebrate olfactory transduction, a Ca(2+)-dependent Cl(-) efflux greatly amplifies the odorant response. The binding of odorants to receptors in the cilia of olfactory sensory neurons activates a transduction cascade that involves the opening of cyclic nucleotide-gated channels and the entry of Ca(2+) into the cilia. The Ca(2+) activates a Cl(-) current that, in the presence of a maintained elevated intracellular Cl(-) concentration, produces an efflux of Cl(-) ions and amplifies the depolarization. In this review, we summarize evidence supporting the hypothesis that anoctamin 2/TMEM16B is the main, or perhaps the only, constituent of the Ca(2+)-activated Cl(-) channels involved in olfactory transduction. Indeed, studies from several laboratories have shown that anoctamin 2/TMEM16B is expressed in the ciliary layer of the olfactory epithelium, that there are remarkable functional similarities between currents in olfactory sensory neurons and in HEK 293 cells transfected with anoctamin 2/TMEM16B, and that knockout mice for anoctamin 2/TMEM16B did not show any detectable Ca(2+)-activated Cl(-) current. Finally, we discuss the involvement of Ca(2+)-activated Cl(-) channels in the transduction process of vomeronasal sensory neurons and the physiological role of these channels in olfaction.
Topics: Animals; Chloride Channels; Humans; Membrane Proteins; Olfactory Mucosa; Olfactory Receptor Neurons; Signal Transduction; Smell
PubMed: 21890523
DOI: 10.1113/expphysiol.2011.058230 -
Physiological Reviews Apr 1998Considerable progress has been made in the understanding of transduction mechanisms in olfactory receptor neurons (ORNs) over the last decade. Odorants pass through a... (Review)
Review
Considerable progress has been made in the understanding of transduction mechanisms in olfactory receptor neurons (ORNs) over the last decade. Odorants pass through a mucus interface before binding to odorant receptors (ORs). The molecular structure of many ORs is now known. They belong to the large class of G protein-coupled receptors with seven transmembrane domains. Binding of an odorant to an OR triggers the activation of second messenger cascades. One second messenger pathway in particular has been extensively studied; the receptor activates, via the G protein Golf, an adenylyl cyclase, resulting in an increase in adenosine 3',5'-cyclic monophosphate (cAMP), which elicits opening of cation channels directly gated by cAMP. Under physiological conditions, Ca2+ has the highest permeability through this channel, and the increase in intracellular Ca2+ concentration activates a Cl- current which, owing to an elevated reversal potential for Cl-, depolarizes the olfactory neuron. The receptor potential finally leads to the generation of action potentials conveying the chemosensory information to the olfactory bulb. Although much less studied, other transduction pathways appear to exist, some of which seem to involve the odorant-induced formation of inositol polyphosphates as well as Ca2+ and/or inositol polyphosphate -activated cation channels. In addition, there is evidence for odorant-modulated K+ and Cl- conductances. Finally, in some species, ORNs can be inhibited by certain odorants. This paper presents a comprehensive review of the biophysical and electrophysiological evidence regarding the transduction processes as well as subsequent signal processing and spike generation in ORNs.
Topics: Animals; Humans; Olfactory Mucosa; Olfactory Receptor Neurons; Signal Transduction
PubMed: 9562035
DOI: 10.1152/physrev.1998.78.2.429 -
International Forum of Allergy &... Nov 2013Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). The pathophysiology of inflammatory olfactory dysfunction likely involves both conductive and...
BACKGROUND
Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). The pathophysiology of inflammatory olfactory dysfunction likely involves both conductive and sensorineural components. To study the interaction of CRS-associated inflammatory cytokines with the olfactory epithelium (OE), a transgenic mouse model was developed that allows temporally-controlled local gene expression. Interferon-gamma (IFN-γ) is a prototypical T helper 1 (Th1) cytokine linked to nonpolypoid CRS (CRSsNP), as well as sinonasal viral and bacterial infections. In this study, the effects of chronic IFN-γ expression on olfactory histology and function were investigated.
METHODS
IFN-γ secretion by olfactory sustentacular cells was induced in the transgenic mouse. Viability and gross behavior were unaffected. Mice were euthanized after 6 weeks of IFN-γ expression, and olfactory tissue was studied by histology, immunohistochemistry, and electro-olfactography (EOG). Findings were compared with uninduced littermates.
RESULTS
IFN-γ expression did not result in alteration of the normal histologic architecture of the neuroepithelium or lamina propria. However, EOG recordings demonstrated a significant decrease in odorant responses after IFN-γ expression. In addition, a marked increase in submucosal CD45-positive cells was observed, the majority of which were CD3-positive and CD4-positive lymphocytes.
CONCLUSION
Chronic IFN-γ expression in the mouse OE results in diminished odorant responsiveness, despite the absence of inflammatory tissue damage. This suggests a direct effect of IFN-γ on olfactory neuron function that may underlie olfactory loss in CRSsNP or viral infections. The infiltration of submucosal lymphocytes raises the possibility that other downstream cytokines also contribute to olfactory dysfunction.
Topics: Animals; CD3 Complex; CD4 Antigens; Case-Control Studies; Disease Models, Animal; Interferon-gamma; Leukocyte Common Antigens; Mice; Mice, Transgenic; Mucous Membrane; Nasal Lavage Fluid; Olfactory Mucosa
PubMed: 24106006
DOI: 10.1002/alr.21226 -
The Journal of Veterinary Medical... Apr 2011Nitric oxide (NO) is a free radical and produced from L-arginine by nitric oxide synthase (NOS). Since NO is recently suggested to be involved in olfactory perception,...
Nitric oxide (NO) is a free radical and produced from L-arginine by nitric oxide synthase (NOS). Since NO is recently suggested to be involved in olfactory perception, the expression of eNOS, an isoform of NOS, was examined in the rat olfactory epithelium. The activity of NADPH-diaphorase was also examined as a marker of NOS. In the dorsomedial region of the nasal cavity, intensely positive reactions for NADPH-diaphorase were observed in the entire cytoplasm of sensory cells (olfactory cells). By immunohistochemistry, intensely positive reactions for eNOS were also found in the dorsomedial region of the nasal cavity. These reactions were observed on the free border of the olfactory epithelium. By immunoelectron microscopy, positive reactions for eNOS were found in the cilia of olfactory cells. In addition, in situ hybridization analysis of the olfactory epithelium revealed the expression of eNOS mRNA in the olfactory cells. These results indicate the presence of eNOS in the olfactory cells of the rat, and differential expression of eNOS in the olfactory epithelium depending on the regions of the nasal cavity. In addition, NO produced by eNOS may be involved in olfactory perception in the cilia of olfactory cells.
Topics: Animals; Gene Expression Regulation, Enzymologic; Male; NADH Dehydrogenase; Nitric Oxide Synthase Type III; Olfactory Mucosa; Rats; Rats, Wistar
PubMed: 21068516
DOI: 10.1292/jvms.10-0353 -
Scientific Reports Mar 2017Social factors play a critical role in a panoply of health processes, including, as recently demonstrated, olfaction. Here, we investigated sex-dependent differences in...
Social factors play a critical role in a panoply of health processes, including, as recently demonstrated, olfaction. Here, we investigated sex-dependent differences in the relationship between social lives and ability to identify odors in a large sample of nationally representative older US adults (n = 3005, National Social Life and Aging Project (NSHAP)). Social life was measured by the number of friends and close relatives as well as frequency of socializing. We here confirm the association between social lives and olfactory function and extend the notion by showing specifically that olfactory identification ability is modulated by sex in older adults. The connection between olfactory performance and social lives could reflect social modulation of aging as has been reported for health in general. Future studies are necessary to elucidate the precise mechanisms underlying this association and sex difference.
Topics: Aged; Aged, 80 and over; Female; Humans; Life; Male; Middle Aged; Olfactory Mucosa; Sex Factors
PubMed: 28327569
DOI: 10.1038/srep45118