scholarly journals The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

2021 ◽  
Author(s):  
Rafal Butowt ◽  
Nicolas Meunier ◽  
Bertrand Bryche ◽  
Christopher S. von Bartheld
Keyword(s):  
Animal Models ◽  
Virus Entry ◽  
Olfactory Nerve ◽  
Olfactory Receptor Neurons ◽  
Current Evidence ◽  
Olfactory Neurons ◽  
Brain Infection ◽  
Receptor Neurons ◽  
Alternative Routes ◽  
The Brain

AbstractOne of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains.

scholarly journals Expression of the ACE2 Virus Entry Protein in the Nervus Terminalis Reveals the Potential for an Alternative Route to Brain Infection in COVID-19

2021 ◽  
Vol 15 ◽  
Author(s):  
Katarzyna Bilinska ◽  
Christopher S. von Bartheld ◽  
Rafal Butowt
Keyword(s):  
Virus Entry ◽  
Olfactory Nerve ◽  
Alternative Route ◽  
Angiotensin Converting Enzyme 2 ◽  
Nervus Terminalis ◽  
Brain Infection ◽  
Potential Alternative ◽  
Receptor Neurons ◽  
The Brain ◽  
Entry Receptor

Previous studies suggested that the SARS-CoV-2 virus may gain access to the brain by using a route along the olfactory nerve. However, there is a general consensus that the obligatory virus entry receptor, angiotensin converting enzyme 2 (ACE2), is not expressed in olfactory receptor neurons, and the timing of arrival of the virus in brain targets is inconsistent with a neuronal transfer along olfactory projections. We determined whether nervus terminalis neurons and their peripheral and central projections should be considered as a potential alternative route from the nose to the brain. Nervus terminalis neurons in postnatal mice were double-labeled with antibodies against ACE2 and two nervus terminalis markers, gonadotropin-releasing hormone (GnRH) and choline acetyltransferase (CHAT). We show that a small fraction of CHAT-labeled nervus terminalis neurons, and the large majority of GnRH-labeled nervus terminalis neurons with cell bodies in the region between the olfactory epithelium and the olfactory bulb express ACE2 and cathepsins B and L. Nervus terminalis neurons therefore may provide a direct route for the virus from the nasal epithelium, possibly via innervation of Bowman’s glands, to brain targets, including the telencephalon and diencephalon. This possibility needs to be examined in suitable animal models and in human tissues.

scholarly journals Expression of the ACE2 virus entry protein in the nervus terminalis suggests an alternative route for brain infection in COVID-19

2021 ◽  
Author(s):  
Katarzyna Bilinska ◽  
Christopher S. von Bartheld ◽  
Rafal Butowt
Keyword(s):  
Virus Entry ◽  
Olfactory Nerve ◽  
Alternative Route ◽  
Angiotensin Converting Enzyme 2 ◽  
Nervus Terminalis ◽  
Brain Infection ◽  
Receptor Neurons ◽  
The Brain ◽  
Entry Receptor ◽  
Gain Access

AbstractPrevious studies suggested that the SARS-CoV-2 virus may gain access to the brain by using a route along the olfactory nerve. However, there is a general consensus that the obligatory virus entry receptor, angiotensin converting enzyme 2 (ACE2), is not expressed in olfactory receptor neurons, and the timing of arrival of the virus in brain targets is inconsistent with a neuronal transfer along olfactory projections. We determined whether nervus terminalis neurons and their peripheral and central projections may provide an alternative route from the nose to the brain. Nervus terminalis neurons were double-labeled with antibodies against ACE2 and nervus terminalis markers in postnatal mice. We show that most nervus terminalis neurons with cell bodies in the region between the olfactory epithelium and the olfactory bulb express ACE2, and therefore may provide a direct route for the virus from the nasal epithelium and Bowman’s glands to brain targets, including the telencephalon and diencephalon.

scholarly journals Adaptive integrate-and-fire model reproduces the dynamics of olfactory receptor neuron responses in a moth

2019 ◽  
Vol 16 (157) ◽  
pp. 20190246 ◽  
Author(s):  
Marie Levakova ◽  
Lubomir Kostal ◽  
Christelle Monsempès ◽  
Philippe Lucas ◽  
Ryota Kobayashi
Keyword(s):  
Olfactory Receptor ◽  
Time Course ◽  
Olfactory Receptor Neuron ◽  
Receptor Activation ◽  
Olfactory Receptor Neurons ◽  
Response Dynamics ◽  
Spike Threshold ◽  
Olfactory Stimuli ◽  
Receptor Neurons ◽  
The Brain

In order to understand how olfactory stimuli are encoded and processed in the brain, it is important to build a computational model for olfactory receptor neurons (ORNs). Here, we present a simple and reliable mathematical model of a moth ORN generating spikes. The model incorporates a simplified description of the chemical kinetics leading to olfactory receptor activation and action potential generation. We show that an adaptive spike threshold regulated by prior spike history is an effective mechanism for reproducing the typical phasic–tonic time course of ORN responses. Our model reproduces the response dynamics of individual neurons to a fluctuating stimulus that approximates odorant fluctuations in nature. The parameters of the spike threshold are essential for reproducing the response heterogeneity in ORNs. The model provides a valuable tool for efficient simulations of olfactory circuits.

scholarly journals Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT)

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ting-hao Huang ◽  
Peter Niesman ◽  
Deepshika Arasu ◽  
Donghyung Lee ◽  
Aubrie L De La Cruz ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transgenic Animals ◽  
Genetically Engineered ◽  
Olfactory Receptor Neurons ◽  
Neuronal Circuits ◽  
Protein Fragment ◽  
Brain Circuits ◽  
Artificial Receptor ◽  
Receptor Neurons ◽  
The Brain

Understanding the computations that take place in brain circuits requires identifying how neurons in those circuits are connected to one another. We describe a technique called TRACT (TRAnsneuronal Control of Transcription) based on ligand-induced intramembrane proteolysis to reveal monosynaptic connections arising from genetically labeled neurons of interest. In this strategy, neurons expressing an artificial ligand (‘donor’ neurons) bind to and activate a genetically-engineered artificial receptor on their synaptic partners (‘receiver’ neurons). Upon ligand-receptor binding at synapses the receptor is cleaved in its transmembrane domain and releases a protein fragment that activates transcription in the synaptic partners. Using TRACT in Drosophila we have confirmed the connectivity between olfactory receptor neurons and their postsynaptic targets, and have discovered potential new connections between neurons in the circadian circuit. Our results demonstrate that the TRACT method can be used to investigate the connectivity of neuronal circuits in the brain.

scholarly journals Exercise, brain, and cognition across the life span

2011 ◽  
Vol 111 (5) ◽  
pp. 1505-1513 ◽  
Author(s):  
Michelle W. Voss ◽  
Lindsay S. Nagamatsu ◽  
Teresa Liu-Ambrose ◽  
Arthur F. Kramer
Keyword(s):  
Resistance Training ◽  
Animal Models ◽  
Life Span ◽  
Current Evidence ◽  
Brain Health ◽  
Future Directions ◽  
Exercise Type ◽  
Clinically Significant ◽  
The Brain ◽  
Human Neuroimaging

This is a brief review of current evidence for the relationships between physical activity and exercise and the brain and cognition throughout the life span in non-pathological populations. We focus on the effects of both aerobic and resistance training and provide a brief overview of potential neurobiological mechanisms derived from non-human animal models. Whereas research has focused primarily on the benefits of aerobic exercise in youth and young adult populations, there is growing evidence that both aerobic and resistance training are important for maintaining cognitive and brain health in old age. Finally, in these contexts, we point out gaps in the literature and future directions that will help advance the field of exercise neuroscience, including more studies that explicitly examine the effect of exercise type and intensity on cognition, the brain, and clinically significant outcomes. There is also a need for human neuroimaging studies to adopt a more unified multi-modal framework and for greater interaction between human and animal models of exercise effects on brain and cognition across the life span.

Functional properties of vertebrate olfactory receptor neurons

1986 ◽  
Vol 66 (3) ◽  
pp. 772-818 ◽  
Author(s):  
T. V. Getchell
Keyword(s):  
Olfactory Receptor ◽  
Olfactory Receptor Neuron ◽  
Olfactory Nerve ◽  
Sensory Transduction ◽  
Olfactory Receptor Neurons ◽  
Receptor Neuron ◽  
Olfactory Pathway ◽  
Receptor Neurons ◽  
Molecular Biological Techniques

The interaction of an odorant with the chemosensitive membrane of olfactory receptor neurons initiates a sequence of molecular and membrane events leading to sensory transduction, impulse initiation, and the transmission of sensory information to the brain. The main steps in this sequence are summarized in Figure 6. Several lines of evidence support the hypothesis that the initial molecular events and subsequent stages of transduction are mediated by odorant receptor sites and associated ion channels located in the membrane of the cilia and apical dendritic knob of the olfactory receptor neuron. Similarly, the membrane events associated with impulse initiation and propagation are mediated by voltage-gated channels located in the initial axonal segment and the axolemma. The ionic and electrical events associated with the proposed sequence have been characterized in general using a variety of experimental techniques. The identification, localization, and sequence of membrane events are consistent with the neurophysiological properties observed in specific regions of the bipolar receptor neuron. The influence of other cells in the primary olfactory pathway such as the sustentacular cells in the olfactory epithelium, the Schwann cells in the olfactory nerve, and the astrocytes in the olfactory nerve layer in the olfactory bulb on the physiological activity of the olfactory receptor neuron is an emerging area of research interests. The general principles derived from the experimental results described in this review provide only a framework that is both incomplete and of necessity somewhat speculative. As noted in the Introduction, the multidisciplinary study of the primary olfactory pathway is undergoing a renaissance of research interest. The application of modern biophysical, cell, and molecular biological techniques to the basic issues of odorant recognition and membrane excitability will clarify the speculations and lead to the establishment of new hypotheses. Three broad areas of research will benefit from such studies. First, the application of biophysical techniques will lead to a detailed characterization of the membrane properties and associated ion conductance mechanisms. Second, the isolation and biochemical characterization of intrinsic membrane and cytosolic proteins associated with odorant recognition, sensory transduction, and the subsequent electrical events will result from the utilization of cell and molecular biological techniques.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Voltage-dependent and odorant-regulated currents in isolated olfactory receptor neurons of the channel catfish.

1992 ◽  
Vol 99 (4) ◽  
pp. 505-529 ◽  
Author(s):  
T Miyamoto ◽  
D Restrepo ◽  
J H Teeter
Keyword(s):  
Action Potentials ◽  
Olfactory Receptor Neurons ◽  
Olfactory Neurons ◽  
Outward Currents ◽  
Na Currents ◽  
Voltage Dependent ◽  
Inward Currents ◽  
K Current ◽  
Receptor Neurons ◽  
K Currents

The electrical properties of olfactory receptor neurons, enzymatically dissociated from the channel catfish (Ictalurus punctatus), were studied using the whole-cell patch-clamp technique. Six voltage-dependent ionic currents were isolated. Transient inward currents (0.1-1.7 nA) were observed in response to depolarizing voltage steps from a holding potential of -80 mV in all neurons examined. They activated between -70 and -50 mV and were blocked by addition of 1 microM tetrodotoxin (TTX) to the bath or by replacing Na+ in the bath with N-methyl-D-glucamine and were classified as Na+ currents. Sustained inward currents, observed in most neurons examined when Na+ inward currents were blocked with TTX and outward currents were blocked by replacing K+ in the pipette solution with Cs+ and by addition of 10 mM Ba2+ to the bath, activated between -40 and -30 mV, reached a peak at 0 mV, and were blocked by 5 microM nimodipine. These currents were classified as L-type Ca2+ currents. Large, slowly activating outward currents that were blocked by simultaneous replacement of K+ in the pipette with Cs+ and addition of Ba2+ to the bath were observed in all olfactory neurons examined. The outward K+ currents activated over approximately the same range as the Na+ currents (-60 to -50 mV), but the Na+ currents were larger at the normal resting potential of the neurons (-45 +/- 11 mV, mean +/- SD, n = 52). Four different types of K+ currents could be differentiated: a Ca(2+)-activated K+ current, a transient K+ current, a delayed rectifier K+ current, and an inward rectifier K+ current. Spontaneous action potentials of varying amplitude were sometimes observed in the cell-attached recording configuration. Action potentials were not observed in whole-cell recordings with normal internal solution (K+ = 100 mM) in the pipette, but frequently appeared when K+ was reduced to 85 mM. These observations suggest that the membrane potential and action potential amplitude of catfish olfactory neurons are significantly affected by the activity of single channels due to the high input resistance (6.6 +/- 5.2 G omega, n = 20) and low membrane capacitance (2.1 +/- 1.1 pF, n = 46) of the cells.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Comparison of the Nasal Olfactory Organs of Various Species of Lizardfishes (Teleostei: Aulopiformes: Synodontidae) with Additional Remarks on the Brain

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
L. Fishelson ◽  
D. Golani ◽  
B. Galil ◽  
M. Goren
Keyword(s):  
Olfactory Epithelium ◽  
Olfactory Receptor ◽  
Olfactory Receptor Neurons ◽  
Adult Fish ◽  
Supporting Cells ◽  
Receptor Neurons ◽  
Olfactory Organs ◽  
Species Specific ◽  
The Brain

The olfactory organs of lizardfishes (Synodontidae) are situated in two capsules connected to the outside by incurrent and excurrent openings. The olfactory epithelium is in form of petal rosettes each composed of lamellae and a rephe, and bear olfactory receptor neurons, supporting cells and cells with kinocillia. The dimension of rosettes and lamellae, as well as the number of lamellae, increase with growth of the fish; until in adult fish these parameters remaine constant, species specific. In adultSynodusspp. andTrachinocephalus myopsthe rosettes are 3.5–4.0 mm long, with 5–8 lamellae, whereas inSauridaspp. they are 8.0 mm and possess up tp 22 lamellae. The number of ORN ranges from 2,600 on the smaller lamellae to 20,000 on the largest ones. The number of ORN/m of olfactory is ca. 30,000 inSauridaspp. Thus the rosettes ofS. macrolepiswith 20 lamellae possess a total of ca. 170,000 ORN, whereas those ofSy. variegatusandT. myopswith the average of six lamellae possess only ca. 50,000–65,000 ORN. The olfactory nerves lead from the rosettes to the olfactory balbs situated on the olfactory lobes. The differences among the species in olfactory organs are discussed in correlation with their distribution.

scholarly journals Olfactory dysfunction in coronavirus disease

2021 ◽  
pp. 94-102
Author(s):  
Aleksandra V. Tsepkolenko ◽  
Sergey M. Pukhlik
Keyword(s):  
Olfactory Receptor ◽  
Clinical Symptoms ◽  
Nasal Congestion ◽  
Specific Treatment ◽  
Olfactory Dysfunction ◽  
Olfactory Receptor Neurons ◽  
Supporting Cells ◽  
Receptor Neurons ◽  
The Brain

Olfactory dysfunction may be the only early clinical manifestation in COVID-19 patients with no other significant signs. It is typical of the disease and can be significant for testing. The purpose of the review is to provide guidance to the otorhinolaryngologist in the problem of olfactory dysfunction in SARS-CoV-2 infection. Materials and Methods: The authors analyzed the available clinical data on the problem of olfactory dysfunction in SARS-CoV-2 infection. The data of statistics, clinical symptoms and pathogenesis were studied. Toexplain anosmia in COVID-19 patients, 4 possible mechanisms are considered: nasal congestion / nasal congestion and rhinorrhea; death of olfactory receptor neurons; infiltration of the brain and damage to the olfactorycenters; damage to the supporting cells of the olfactory epithelium. The analysis of clinical cases of patients with prolonged ansomia against the background of COVID-19 was carried out. Conclusions: Smell after COVID-19 in most cases is restored without specific treatment. There are no reports of studies in patients with long-term anosmia.

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