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International Journal of Molecular... Aug 2023One of the most prevalent causes of olfactory loss includes traumatic brain injury with subsequent shearing of olfactory axons at the level of the cribriform plate...
One of the most prevalent causes of olfactory loss includes traumatic brain injury with subsequent shearing of olfactory axons at the level of the cribriform plate (anterior skull base). Scar tissue at this level may prevent axonal regrowth toward the olfactory bulb. Currently, there is no cure for this debilitating and often permanent condition. One promising therapeutic concept is to implant a synthetic scaffold with growth factors through the cribriform plate/scar tissue to induce neuroregeneration. The first step toward this goal is to investigate the optimum conditions (growth factors, extracellular matrix proteins) to boost this regeneration. However, the lack of a specifically tailored in vitro model and an automated procedure for quantifying axonal length limits our ability to address this issue. The aim of this study is to create an automated quantification tool to measure axonal length and to determine the ideal growth factors and extracellular proteins to enhance axonal regrowth of olfactory sensory neurons in a mouse organotypic 2D model. We harvested olfactory epithelium (OE) of C57BL/6 mice and cultured them during 15 days on coverslips coated with various extracellular matrix proteins (Fibronectin, Collagen IV, Laminin, none) and different growth factors: fibroblast growth factor 2 (FGF2), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), retinoic acid (RA), transforming growth factor β (TGFβ), and none. We measured the attachment rate on coverslips, the presence of cellular and axonal outgrowth, and finally, the total axonal length with a newly developed automated high-throughput quantification tool. Whereas the coatings did not influence attachment and neuronal outgrowth rates, the total axonal length was enhanced on fibronectin and collagen IV ( = 0.001). The optimum growth factor supplementation media to culture OE compared to the control condition were as follows: FGF2 alone and FGF2 from day 0 to 7 followed by FGF2 in combination with NGF from day 7 to 15 ( < 0.0001). The automated quantification tool to measure axonal length outperformed the standard Neuron J application by reducing the average analysis time from 22 to 3 min per specimen. In conclusion, robust regeneration of murine olfactory neurons in vitro can be induced, controlled, and efficiently measured using an automated quantification tool. These results will help advance the therapeutic concept closer toward preclinical studies.
Topics: Animals; Mice; Mice, Inbred C57BL; Olfactory Receptor Neurons; Fibronectins; Cicatrix; Fibroblast Growth Factor 2; Nerve Growth Factor; Axons; Extracellular Matrix Proteins; Collagen Type IV; Culture Media
PubMed: 37629041
DOI: 10.3390/ijms241612863 -
Journal of Neuroinflammation Dec 2023The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's...
BACKGROUND
The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD.
METHODS
To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air-liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing.
RESULTS
Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation.
CONCLUSIONS
The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.
Topics: Humans; SARS-CoV-2; COVID-19; Anosmia; Neuroinflammatory Diseases; Alzheimer Disease; Olfactory Mucosa
PubMed: 38098019
DOI: 10.1186/s12974-023-02979-4 -
Physiological Reviews Jan 2022The biological olfactory system is the sensory system responsible for the detection of the chemical composition of the environment. Several attempts to mimic biological... (Review)
Review
The biological olfactory system is the sensory system responsible for the detection of the chemical composition of the environment. Several attempts to mimic biological olfactory systems have led to various artificial olfactory systems using different technical approaches. Here we provide a parallel description of biological olfactory systems and their technical counterparts. We start with a presentation of the input to the systems, the stimuli, and treat the interface between the external world and the environment where receptor neurons or artificial chemosensors reside. We then delineate the functions of receptor neurons and chemosensors as well as their overall input-output (I/O) relationships. Up to this point, our accounts of the systems go along similar lines. The next processing steps differ considerably: whereas in biology the processing step following the receptor neurons is the "integration" and "processing" of receptor neuron outputs in the olfactory bulb, this step has various realizations in electronic noses. For a long period of time, the signal processing stages beyond the olfactory bulb, i.e., the higher olfactory centers, were little studied. Only recently has there been a marked growth of studies tackling the information processing in these centers. In electronic noses, a third stage of processing has virtually never been considered. In this review, we provide an up-to-date overview of the current knowledge of both fields and, for the first time, attempt to tie them together. We hope it will be a breeding ground for better information, communication, and data exchange between very related but so far little-connected fields.
Topics: Animals; Humans; Odorants; Olfactory Bulb; Olfactory Receptor Neurons; Sensory Receptor Cells; Smell; Vertebrates
PubMed: 34254835
DOI: 10.1152/physrev.00036.2020 -
Cancer Research Communications Jun 2023Olfactory neuroblastoma is a rare tumor arising from the olfactory cleft region of the nasal cavity. Because of the low incidence of this tumor, as well as an absence of...
UNLABELLED
Olfactory neuroblastoma is a rare tumor arising from the olfactory cleft region of the nasal cavity. Because of the low incidence of this tumor, as well as an absence of established cell lines and murine models, understanding the mechanisms driving olfactory neuroblastoma pathobiology has been challenging. Here, we sought to apply advances from research on the human olfactory epithelial neurogenic niche, along with new biocomputational approaches, to better understand the cellular and molecular factors in low- and high-grade olfactory neuroblastoma and how specific transcriptomic markers may predict prognosis. We analyzed a total of 19 olfactory neuroblastoma samples with available bulk RNA-sequencing and survival data, along with 10 samples from normal olfactory epithelium. A bulk RNA-sequencing deconvolution model identified a significant increase in globose basal cell (GBC) and CD8 T-cell identities in high-grade tumors (GBC from ∼0% to 8%, CD8 T cell from 0.7% to 2.2%), and significant decreases in mature neuronal, Bowman's gland, and olfactory ensheathing programs, in high-grade tumors (mature neuronal from 3.7% to ∼0%, Bowman's gland from 18.6% to 10.5%, olfactory ensheathing from 3.4% to 1.1%). Trajectory analysis identified potential regulatory pathways in proliferative olfactory neuroblastoma cells, including PRC2, which was validated by immunofluorescence staining. Survival analysis guided by gene expression in bulk RNA-sequencing data identified favorable prognostic markers such as SOX9, S100B, and PLP1 expression.
SIGNIFICANCE
Our analyses provide a basis for additional research on olfactory neuroblastoma management, as well as identification of potential new prognostic markers.
Topics: Mice; Humans; Animals; Esthesioneuroblastoma, Olfactory; Olfactory Mucosa; Olfactory Pathways; Nose Neoplasms; RNA
PubMed: 37377616
DOI: 10.1158/2767-9764.CRC-23-0013 -
Sensors (Basel, Switzerland) Jan 2023A new hypothesis for the mechanism of olfaction is presented. It begins with an odorant molecule binding to an olfactory receptor. This is followed by the quantum...
A new hypothesis for the mechanism of olfaction is presented. It begins with an odorant molecule binding to an olfactory receptor. This is followed by the quantum biology event of inelastic electron tunneling as has been suggested with both the vibration and swipe card theories. It is novel in that it is not concerned with the possible effects of the tunneled electrons as has been discussed with the previous theories. Instead, the high energy state of the odorant molecule in the receptor following inelastic electron tunneling is considered. The hypothesis is that, as the high energy state decays, there is fluorescence luminescence with radiative emission of multiple photons. These photons pass through the supporting sustentacular cells and activate a set of olfactory neurons in near-simultaneous timing, which provides the temporal basis for the brain to interpret the required complex combinatorial coding as an odor. The Luminescence Hypothesis of Olfaction is the first to present the necessity of or mechanism for a 1:3 correspondence of odorant molecule to olfactory nerve activations. The mechanism provides for a consistent and reproducible time-based activation of sets of olfactory nerves correlated to an odor. The hypothesis has a biological precedent: an energy feasibility assessment is included, explaining the anosmia seen with COVID-19, and can be confirmed with existing laboratory techniques.
Topics: Humans; Smell; Luminescence; COVID-19; Olfactory Receptor Neurons; Odorants; Receptors, Odorant
PubMed: 36772376
DOI: 10.3390/s23031333 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Apr 2020The olfactory epithelium(OE) is the neuro-epithelial tissue that can be regenerated after damage in the nervous system. However, certain factors, such as... (Review)
Review
The olfactory epithelium(OE) is the neuro-epithelial tissue that can be regenerated after damage in the nervous system. However, certain factors, such as neurodegenerative diseases, head trauma, viral infections, etc. , can lead to olfactory dysfunction, affecting patients' physical and mental health, quality of life and risk identification, and even increase patient mortality. Therefore, it is important to clarify the mechanism of OE regeneration regulation and to find new treatment methods. This review is based on OE and the composition of olfactory stem cells, physiological and pathological olfactory sensory neurons regeneration regulation and treatment of olfactory disorders.
Topics: Humans; Olfactory Mucosa; Olfactory Receptor Neurons; Quality of Life; Regeneration; Smell
PubMed: 32842240
DOI: 10.13201/j.issn.2096-7993.2020.04.024 -
Journal of Neurochemistry May 2021Olfactory disorders have been increasingly reported in individuals infected with SARS-CoV-2, the virus causing the coronavirus disease 2019 (COVID-19). Losing the sense... (Review)
Review
Olfactory disorders have been increasingly reported in individuals infected with SARS-CoV-2, the virus causing the coronavirus disease 2019 (COVID-19). Losing the sense of smell has a strong impact on the quality of life, since it may lead to malnutrition, weight loss, food poisoning, depression, and exposure to dangerous chemicals. Individuals who suffer from anosmia (inability to smell) also cannot sense the flavor of food, which is a combination of taste and smell. Interestingly, infected individuals have reported sudden loss of smell with no congested nose, as is frequently observed in common colds or other upper respiratory tract infections. These observations suggest that SARS-CoV-2 infection leads to olfactory loss through a distinct mechanism, which is still unclear. This article provides an overview of olfactory loss and the recent findings relating to COVID-19. Possible mechanisms of SARS-CoV-2-induced olfactory loss are also discussed.
Topics: COVID-19; Humans; Olfaction Disorders; Olfactory Receptor Neurons; Virus Diseases
PubMed: 32970861
DOI: 10.1111/jnc.15197 -
Frontiers in Neuroscience 2021Resection of the olfactory mucosa (OM) is sometimes unavoidable during surgery; however, it is not known whether the OM can completely recover thereafter. The aim of...
Resection of the olfactory mucosa (OM) is sometimes unavoidable during surgery; however, it is not known whether the OM can completely recover thereafter. The aim of this study was to uncover whether the OM fully recovers after mucosal resection and describe the process of OM regeneration. 8-week-old male Sprague-Dawley rats ( = 18) were subjected to OM resection at the nasal septum; six rats were euthanized for histological examination 0, 30, and 90 days after surgery. Immunohistochemistry was performed to identify olfactory receptor neuron (ORN) lineage cells [mature and immature ORNs and ORN progenitors, and olfactory ensheathing cells (OECs)], as well as dividing and apoptotic cells. Squamous and respiratory metaplasia and inflammatory cell infiltration were also assessed. On day 30 after resection, the mucosa had regenerated, and mainly contained thin nerve bundles, basal cells, and immature ORNs, with a few mature ORNs and OECs. On day 90, the repaired nasal mucosa had degenerated into stratified squamous or ciliated pseudostratified columnar epithelia, with reducing ORNs. The lamina propria contained numerous macrophages. Partial regeneration was observed within 1 month after OM resection, whereas subsequent degeneration into squamous and respiratory epithelia occurred within 3 months. Given the poor persistence of ORNs and OECs, OM resection is likely to result in olfactory impairment. Overall, surgeons should be cautious not to injure the OM during surgery.
PubMed: 34354563
DOI: 10.3389/fnins.2021.695653 -
International Journal of Molecular... Apr 2022Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and it is involved in several fundamental functions in the central and peripheral nervous...
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and it is involved in several fundamental functions in the central and peripheral nervous systems, and in sensory organs. BDNF regulates the chemosensory systems of mammals and is consistently expressed in those organs. In zebrafish, the key role of BDNF in the biology of the hair cells of the inner ear and lateral line system has recently been demonstrated. However, only some information is available about its occurrence in the olfactory epithelium, taste buds, and cutaneous isolated chemosensory cells. Therefore, this study was undertaken to analyze the involvement of BDNF in the chemosensory organs of zebrafish during the larval and adult stages. To identify cells displaying BDNF, we compared the cellular pattern of BDNF-displaying cells with those immunoreactive for calretinin and S100 protein. Our results demonstrate the localization of BDNF in the sensory part of the olfactory epithelium, mainly in the ciliated olfactory sensory neurons in larvae and adult zebrafish. Intense immunoreaction for BDNF was also observed in the chemosensory cells of oral and cutaneous taste buds. Moreover, a subpopulation of olfactory sensory neurons and chemosensory cells of olfactory rosette and taste bud, respectively, showed marked immunopositivity for calcium-binding protein S100 and calretinin. These results demonstrate the possible role of BDNF in the development and maintenance of olfactory sensory neurons and sensory cells in the olfactory epithelium and taste organs of zebrafish during all stages of development.
Topics: Animals; Brain-Derived Neurotrophic Factor; Calbindin 2; Larva; Mammals; Olfactory Mucosa; S100 Proteins; Taste Buds; Zebrafish
PubMed: 35563087
DOI: 10.3390/ijms23094696 -
The Journal of Neuroscience : the... Nov 2023In the mammalian nose, two chemosensory systems, the trigeminal and the olfactory mediate the detection of volatile chemicals. Most odorants are able to activate the...
In the mammalian nose, two chemosensory systems, the trigeminal and the olfactory mediate the detection of volatile chemicals. Most odorants are able to activate the trigeminal system, and vice versa, most trigeminal agonists activate the olfactory system as well. Although these two systems constitute two separate sensory modalities, trigeminal activation modulates the neural representation of an odor. The mechanisms behind the modulation of olfactory response by trigeminal activation are still poorly understood. We addressed this question by looking at the olfactory epithelium (OE), where olfactory sensory neurons (OSNs) and trigeminal sensory fibers co-localize and where the olfactory signal is generated. Our study was conducted in a mouse model. Both sexes, males and females, were included. We characterize the trigeminal activation in response to five different odorants by measuring intracellular Ca changes from primary cultures of trigeminal neurons (TGNs). We also measured responses from mice lacking TRPA1 and TRPV1 channels known to mediate some trigeminal responses. Next, we tested how trigeminal activation affects the olfactory response in the olfactory epithelium using electro-olfactogram (EOG) recordings from wild-type (WT) and TRPA1/V1-knock out (KO) mice. The trigeminal modulation of the olfactory response was determined by measuring responses to the odorant, 2-phenylethanol (PEA), an odorant with little trigeminal potency after stimulation with a trigeminal agonist. Trigeminal agonists induced a decrease in the EOG response to PEA, which depended on the level of TRPA1 and TRPV1 activation induced by the trigeminal agonist. This suggests that trigeminal activation can alter odorant responses even at the earliest stage of the olfactory sensory transduction. Most odorants reaching the olfactory epithelium (OE) can simultaneously activate olfactory and trigeminal systems. Although these two systems constitute two separate sensory modalities, trigeminal activation can alter odor perception. Here, we analyzed the trigeminal activity induced by different odorants proposing an objective quantification of their trigeminal potency independent from human perception. We show that trigeminal activation by odorants reduces the olfactory response in the olfactory epithelium and that such modulation correlates with the trigeminal potency of the trigeminal agonist. These results show that the trigeminal system impacts the olfactory response from its earliest stage.
Topics: Male; Humans; Female; Mice; Animals; Smell; Olfactory Receptor Neurons; Olfactory Mucosa; Odorants; Mice, Knockout; Phenylethyl Alcohol; Mammals
PubMed: 37813571
DOI: 10.1523/JNEUROSCI.0489-23.2023