Physical exercise prevents behavioral alterations in a reserpine-treated zebrafish: A putative depression model.

Major depressive disorder (MDD) has increasingly reached the world population with an expressive increase in recent years due to the COVID-19 pandemic. Here we used adult zebrafish (Danio rerio) as a model to verify the effects of reserpine on behavior and neurotransmitter levels. We observed an increase in the immobile time and time spent in the bottom zone of the tank in reserpine-exposed animals. The results demonstrated a decrease in distance traveled and velocity. Reserpine exposure did not induce changes in memory and social interaction compared to the control group. We also evaluated the influence of exposure to fluoxetine, a well-known antidepressant, on the behavior of reserpine-exposed animals. We observed a reversal of behavioral alterations caused by reserpine. To verify whether behavioral alterations in the putative depression model induced by reserpine could be prevented, the animals were subjected to physical exercise for 6 weeks. The results showed a protective effect of the physical exercise against the behavioral changes caused by reserpine in zebrafish. In addition, we observed a reduction in dopamine and serotonin levels and an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the brain. Physical exercise was able to prevent the changes in dopamine and serotonin levels, reinforcing that the preventive effect promoted by physical exercise is related to the modulation of neurotransmitter levels. Our findings showed that reserpine was effective in the induction of a putative depression model in zebrafish and that physical exercise may be an alternative to prevent the effects induced by reserpine.

Pedicularis resupinata Extract Prevents Depressive-like Behavior in Repeated Corticosterone-Induced Depression in Mice: A Preliminary Study.

Excessive corticosterone (CORT), resulting from a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, is associated with cognitive impairment and behavioral changes, including depression. In Korean oriental medicine, Pedicularis resupinata is used for the treatment of inflammatory diseases such as rheumatoid arthritis. However, the antidepressant properties of P. resupinata have not been well characterized. Here, the antidepressant-like effects of P. resupinata extract (PRE) were evaluated in terms of CORT-induced depression using in vivo models. HPLC confirmed that acteoside, a phenylethanoid glycoside, was the main compound from PRE. Male ICR mice (8 weeks old) were injected with CORT (40 mg/kg, i.p.) and orally administered PRE daily (30, 100, and 300 mg/kg) for 21 consecutive days. Depressive-like behaviors were evaluated using the open-field test, sucrose preference test, passive avoidance test, tail suspension test, and forced swim test. Treatment with a high dose of PRE significantly alleviated CORT-induced, depressive-like behaviors in mice. Additionally, repeated CORT injection markedly reduced brain-derived neurotrophic factor levels, whereas total glucocorticoid receptor (GR) and GR phosphorylation at serine 211 were significantly increased in the mice hippocampus but improved by PRE treatment. Thus, our findings suggest that PRE has potential antidepressant-like effects in CORT-induced, depressive-like behavior in mice.

Dual hit mouse model to examine the long-term effects of maternal immune activation and post-weaning social isolation on schizophrenia endophenotypes.

Evidence suggests that early life adversity, such as maternal immune activation (MIA), can alter brain development in the offspring and confer increased risk for psychopathology and psychiatric illness in later life. In this study, the long-term effects of MIA, post-weaning social isolation, and the combination were assessed on behavioural and immunological profiles in adult male and female offspring. On gestation day 12.5, pregnant mice were weighed and injected with either polyinosinic:polycytidylic acid (5 mg/kg) or saline and cytokines levels were assayed 3 hrs later to confirm immune activation. The behaviour and immunological profiles of male and female offspring were examined in adolescence (P34-36), and adulthood (P55-80). MIA induced an increase in the pro-inflammatory cytokine IL-6 in pregnant dams three hours after administration (p < 0.001) that correlated with a decrease in body temperature (p < 0.05). The effect of MIA on the immunological phenotype of the offspring was evident in adolescence, but not in adulthood. MIA selectively induced hypoactivity in adolescent males, a phenotype that persisted until adulthood, but had no effect on cognition in males or females. In contrast, social isolation stress from adolescence resulted in impaired sociability (p < 0.05) and increased anxiety (p < 0.05) particularly in adult females. There was no synergistic effect of the dual-hit on immune parameters, sociability, anxiety or cognitive behaviours. Given the negative impact and sex-dependent effects of SI stress on locomotor and anxiety-like behaviour, future investigations should examine whether the health risks of social isolation, such as that experience during the COVID-19 pandemic, are mediated through increased anxiety.

Lack of social touch alters anxiety-like and social behaviors in male mice.

The importance of social interactions has been reported in a variety of animal species. In human and rodent models, social isolation is known to alter social behaviors and change anxiety or depression levels. During the coronavirus pandemic, although people could communicate with each other through other sensory cues, social touch was mostly prohibited under different levels of physical distancing policies. These social restrictions inspired us to explore the necessity of physical contact, which has rarely been investigated in previous studies on mouse social interactions. We first conducted a long-term observation to show that pair-housed mice in a standard laboratory cage spent nearly half the day in direct physical contact with each other. Furthermore, we designed a split-housing condition to demonstrate that even with free access to visual, auditory, and olfactory social signals, the lack of social touch significantly increased anxiety-like behaviors and changed social behaviors. There were correspondingly higher levels of the pro-inflammatory cytokine interleukin-6 in the hippocampus in mice with no access to physical contact. Our study demonstrated the necessity of social touch for the maintenance of mental health in mice and could have important implications for human social interactions.

Recovery of anosmia in hamsters infected with SARS-CoV-2 is correlated with repair of the olfactory epithelium.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for a pandemic affecting billions of people worldwide. Apart from the extreme global economic impact, the pandemic will likely have a lasting impact through long-term sequelae not yet fully understood. Fully understanding the mechanisms driving the various symptoms and sequelae of SARS-CoV-2 infection will allow for the eventual development of therapeutics to prevent or treat such life-altering symptoms. In this study, we developed a behavioral test of anosmia in SARS-CoV-2-infected hamsters. We find a moderately strong correlation between the level of anosmia and the score of histological damage within the olfactory epithelium. We also find a moderately strong correlation between the level of anosmia and the thickness of the olfactory epithelium, previously demonstrated to be severely damaged upon infection. Thus, this food-searching behavioral test can act as a simple and effective screening method in a hamster model for various therapeutics for SARS-CoV-2-related anosmia.

Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation.

Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and ∆9-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg/kg/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.

Spatiotemporal interactions of a novel mesocarnivore community in an urban environment before and during SARS-CoV-2 lockdown.

Studying species interactions and niche segregation under human pressure provides important insights into species adaptation, community functioning and ecosystem stability. Due to their high plasticity in behaviour and diet, urban mesocarnivores are ideal species for studying community assembly in novel communities. We analysed the spatial and temporal species interactions of an urban mesocarnivore community composed of the red fox Vulpes vulpes and the marten Martes sp. as native species, the raccoon Procyon lotor as invasive species, and the cat Felis catus as a domestic species in combination with human disturbance modulated by the SARS-CoV-2 lockdown effect that happened while the study was conducted. We analysed camera trap data and applied a joint species distribution model to understand not only the environmental variables influencing the detection of mesocarnivores and their use intensity of environmental features but also the species' co-occurrences while accounting for environmental variables. We then assessed whether they displayed temporal niche partitioning based on activity analyses, and finally analysed at a smaller temporal scale the time of delay after the detection of another focal species. We found that species were more often detected and displayed a higher use intensity in gardens during the SARS-CoV-2 lockdown period, while showing a shorter temporal delay during the same period, meaning a high human-induced spatiotemporal overlap. All three wild species spatially co-occurred within the urban area, with a positive response of raccoons to cats in detection and use intensity, whereas foxes showed a negative trend towards cats. When assessing the temporal partitioning, we found that all wild species showed overlapping nocturnal activities. All species displayed temporal segregation based on temporal delay. According to the temporal delay analyses, cats were the species avoided the most by all wild species. To conclude, we found that although the wild species were positively associated in space, the avoidance occurred at a smaller temporal scale, and human pressure in addition led to high spatiotemporal overlap. Our study sheds light to the complex patterns underlying the interactions in a mesocarnivore community both spatially and temporally, and the exacerbated effect of human pressure on community dynamics.

Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage.

The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR); however, it has been never tested in any kind of "clinically" relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, "IV-effects" of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 µg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure.

A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke.

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood-brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.

Effects of long-term social isolation on central, behavioural and metabolic parameters in middle-aged mice.

Social isolation gained discussion momentum due to the COVID-19 pandemic. Whereas many studies address the effects of long-term social isolation in post-weaning and adolescence and for periods ranging from 4 to 12 weeks, little is known about the repercussions of adult long-term social isolation in middle age. Thus, our aim was to investigate how long-term social isolation can influence metabolic, behavioural, and central nervous system-related areas in middle-aged mice. Adult male C57Bl/6 mice (4 months-old) were randomly divided into Social (2 cages, n = 5/cage) and Isolated (10 cages, n = 1/cage) housing groups, totalizing 30 weeks of social isolation, which ended concomitantly with the onset of middle age of mice. At the end of the trial, metabolic parameters, short-term memory, anxiety-like behaviour, and physical activity were assessed. Immunohistochemistry in the hippocampus (ΔFosB, BDNF, and 8OHDG) and hypothalamus (ΔFosB) was also performed. The Isolated group showed impaired memory along with a decrease in hippocampal ΔFosB at dentate gyrus and in BDNF at CA3. Food intake was also affected, but the direction depended on how it was measured in the Social group (individually or in the group) with no alteration in ΔFosB at the hypothalamus. Physical activity parameters increased with chronic isolation, but in the light cycle (inactive phase), with some evidence of anxiety-like behaviour. Future studies should better explore the timepoint at which the alterations found begin. In conclusion, long-term social isolation in adult mice contributes to alterations in feeding, physical activity pattern, and anxiety-like behaviour. Moreover, short-term memory deficit was associated with lower levels of hippocampal ΔFosB and BDNF in middle age.

PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior.

Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic stress disorder (PTSD), and suicide, which share a strong neuroinflammatory etiopathogenetic component. The peroxisome-proliferator activated receptor (PPAR)-α, a newly discovered target involved in emotional behavior regulation, is a ligand-activated nuclear receptor and a transcription factor that, following stimulation by endogenous or synthetic ligands, may induce neuroprotective effects by modulating neuroinflammation, and improve anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. How stress affects epigenetic mechanisms with downstream effects on inflammation and emotional behavior remains poorly understood. We studied the effects of 4-week social isolation, using a mouse model of PTSD/suicide-like behavior, on hippocampal PPAR-α epigenetic modification. Decreased PPAR-α expression in the hippocampus of socially isolated mice was associated with increased levels of methylated cytosines of PPAR-α gene CpG-rich fragments and deficient neurosteroid biosynthesis. This effect was associated with increased histone deacetylases (HDAC)1, methyl-cytosine binding protein (MeCP)2 and decreased ten-eleven translocator (TET)2 expression, which favor hypermethylation. These alterations were associated with increased TLR-4 and pro-inflammatory markers (e.g., TNF-α,), mediated by NF-κB signaling in the hippocampus of aggressive mice. This study contributes the first evidence of stress-induced brain PPAR-α epigenetic regulation. Social isolation stress may constitute a risk factor for inflammatory-based psychiatric disorders associated with neurosteroid deficits, and targeting epigenetic marks linked to PPAR-α downregulation may offer a valid therapeutic approach.

Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia.

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.

COVID-19 suppression of human mobility releases mountain lions from a landscape of fear.

Humans have outsized effects on ecosystems, in part by initiating trophic cascades that impact all levels of the food chain.1,2 Theory suggests that disease outbreaks can reverse these impacts by modifying human behavior,3,4 but this has not yet been tested. The COVID-19 pandemic provided a natural experiment to test whether a virus could subordinate humans to an intermediate link in the trophic chain, releasing a top carnivore from a landscape of fear. Shelter-in-place orders in the Bay Area of California led to a 50% decline in human mobility, which resulted in a relaxation of mountain lion aversion to urban areas. Rapid changes in human mobility thus appear to act quickly on food web functions, suggesting an important pathway by which emerging infectious diseases will impact not only human health but ecosystems as well.

Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats.

Based on several lines of evidence, numerous investigators have suggested that acetaminophen exposure during early development can induce neurological disorders. We had previously postulated that acetaminophen exposure early in life, if combined with antioxidants that prevent accumulation of NAPQI, the toxic metabolite of acetaminophen, might be innocuous. In this study, we administered acetaminophen at or below the currently recommended therapeutic dose to male laboratory rat pups aged 4-10 days. The antioxidants cysteine and mannitol were included to prevent accumulation of NAPQI. In addition, animals were exposed to a cassette of common stress factors: an inflammatory diet, psychological stress, antibiotics, and mock infections using killed bacteria. At age 37-49 days, observation during introduction to a novel conspecific revealed increased rearing behavior, an asocial activity, in animals treated with acetaminophen plus antioxidants, regardless of their exposure to oxidative stress factors (2-way ANOVA; P < 0.0001). This observation would suggest that the initial hypothesis is incorrect, and that oxidative stress mediators do not entirely eliminate the effects of acetaminophen on neurodevelopment. This study provides additional cause for caution when considering the use of acetaminophen in the pediatric population, and provides evidence that the effects of acetaminophen on neurodevelopment need to be considered both in the presence and in the absence of oxidative stress.

Neurobehavioral, neurochemical and synaptic plasticity perturbations during postnatal life of rats exposed to chloroquine in-utero.

Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15-20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats.

Transient prenatal ruxolitinib treatment suppresses astrogenesis during development and improves learning and memory in adult mice.

Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms. The drug targets the JAK/STAT signalling pathway, which is critical in regulating the gliogenesis process during nervous system development. In the study, we assessed the effect of non-maternal toxic dosages of ruxolitinib (0-30 mg/kg/day between E7.5-E20.5) on the brain of the developing mouse embryos. While the pregnant mice did not show any apparent adverse effects, the Gfap protein marker for glial cells and S100ß mRNA marker for astrocytes were reduced in the postnatal day (P) 1.5 pups' brains. Gfap expression and Gfap+ cells were also suppressed in the differentiating neurospheres culture treated with ruxolitinib. Compared to the control group, adult mice treated with ruxolitinib prenatally showed no changes in motor coordination, locomotor function, and recognition memory. However, increased explorative behaviour within an open field and improved spatial learning and long-term memory retention were observed in the treated group. We demonstrated transplacental effects of ruxolitinib on astrogenesis, suggesting the potential use of ruxolitinib to revert pathological conditions caused by gliogenic-shift in early brain development such as Down and Noonan syndromes.

Social contact behaviors are associated with infection status for Trichuris sp. in wild vervet monkeys (Chlorocebus pygerythrus).

Social grooming in the animal kingdom is common and serves several functions, from removing ectoparasites to maintaining social bonds between conspecifics. We examined whether time spent grooming with others in a highly social mammal species was associated with infection status for gastrointestinal parasites. Of six parasites detected, one (Trichuris sp.) was associated with social grooming behaviors, but more specifically with direct physical contact with others. Individuals infected with Trichuris sp. spent significantly less time grooming conspecifics than those not infected, and time in direct contact with others was the major predictor of infection status. One model correctly predicted infection status for Trichuris sp. with a reliability of 95.17% overall when the variables used were time spent in direct contact and time spent grooming others. This decrease in time spent grooming and interacting with others is likely a sickness behavior displayed by individuals with less energy or motivation for non-essential behaviors. This study emphasizes the possible links between host behavior and parasitic infections and highlights the need for an understanding of a study population's parasitic infections when attempting to interpret animal behavior.

Delta-range coupling between prefrontal cortex and hippocampus supported by respiratory rhythmic input from the olfactory bulb in freely behaving rats.

Respiratory rhythm (RR) during sniffing is known to couple with hippocampal theta rhythm. However, outside of the short sniffing bouts, a more stable ~ 2 Hz RR was recently shown to rhythmically modulate non-olfactory cognitive processes, as well. The underlying RR coupling with wide-spread forebrain activity was confirmed using advanced techniques, creating solid premise for investigating how higher networks use this mechanism in their communication. Here we show essential differences in the way prefrontal cortex (PFC) and hippocampus (HC) process the RR signal from the olfactory bulb (OB) that may support dynamic, flexible PFC-HC coupling utilizing this input. We used inter-regional coherences and their correlations in rats, breathing at low rate (~ 2 Hz), outside of the short sniffing bouts. We found strong and stable OB-PFC coherence in wake states, contrasting OB-HC coherence which was low but highly variable. Importantly, this variability was essential for establishing PFC-HC synchrony at RR, whereas variations of RRO in OB and PFC had no significant effect. The findings help to understand the mechanism of rhythmic modulation of non-olfactory cognitive processes by the on-going regular respiration, reported in rodents as well as humans. These mechanisms may be impaired when nasal breathing is limited or in OB-pathology, including malfunctions of the olfactory epithelium due to infections, such as in Covid-19.