Immunological status of the olfactory bulb in a murine model of Toll-like receptor 3-mediated upper respiratory tract inflammation

Background Postviral olfactory dysfunction (PVOD) following a viral upper respiratory tract infection (URI) is one of the most common causes of olfactory disorders, often lasting for over a year. To date, the molecular pathology of PVOD has not been elucidated. Methods A murine model of Toll-like receptor 3 (TLR3)-mediated upper respiratory tract inflammation was used to investigate the impact of URIs on the olfactory system. Inflammation was induced via the intranasal administration of polyinosinic–polycytidylic acid (poly(I:C), a TLR3 ligand) to the right nostril for 3 days. Peripheral olfactory sensory neurons (OSNs), immune cells in the olfactory mucosa, and glial cells in the olfactory bulb (OB) were analyzed histologically. Proinflammatory cytokines in the nasal tissue and OB were evaluated using the quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Results In the treated mice, OSNs were markedly reduced in the olfactory mucosa, and T cell and neutrophil infiltration therein was observed 1 day after the end of poly(I:C) administration. Moreover, there was a considerable increase in microglial cells and slight increase in activated astrocytes in the OB. In addition, qPCR and ELISA revealed the elevated expression of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma both in the OB and nasal tissue. Conclusions Taken together, the decreased peripheral OSNs, OB microgliosis, and elevated proinflammatory cytokines suggest that immunological changes in the OB may be involved in the pathogenesis of PVOD.

Study of the glial cytoarchitecture of the developing olfactory bulb of a shark using immunochemical markers of radial glia

During development of the olfactory bulb (OB), glial cells play key roles in axonal guiding/targeting, glomerular formation and synaptic plasticity. Studies in mammals have shown that radial glial cells and peripheral olfactory glia (olfactory ensheathing cells, OECs) are involved in the development of the OB. Most studies about the OB glia were carried out in mammals, but data are lacking in most non-mammalian vertebrates. In the present work, we studied the development of the OB glial system in the cartilaginous fish Scyliorhinus canicula (catshark) using antibodies against glial markers, such as glial fibrillary acidic protein (GFAP), brain lipid-binding protein (BLBP), and glutamine synthase (GS). These glial markers were expressed in cells with radial morphology lining the OB ventricle of embryos and this expression continues in ependymal cells (tanycytes) in early juveniles. Astrocyte-like cells were also observed in the granular layer and surrounding glomeruli. Numerous GS-positive cells were present in the primary olfactory pathway of embryos. In the developmental stages analysed, the olfactory nerve layer and the glomerular layer were the regions with higher GFAP, BLBP and GS immuno-reactivity. In addition, numerous BLBP-expressing cells (a marker of mammalian OECs) showing proliferative activity were present in the olfactory nerve layer. Our findings suggest that glial cells of peripheral and central origin coexist in the OB of catshark embryos and early juveniles. These results open the path for future studies about the differential roles of glial cells in the catshark OB during embryonic development and in adulthood.

Estrogens regulate early embryonic development of the olfactory sensory system via estrogen-responsive glia

ABSTRACT Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.

Map-independent representation of an aggression-promoting social cue in the main olfactory pathway

While the olfactory system is required for proper social behaviors, the molecular basis for how social cues are detected via the main olfactory pathway of mammals is not well-characterized. Trimethylamine is a volatile, sex-specific odor found in adult male mouse urine that selectively activates main olfactory sensory neurons that express trace amine-associated receptor 5 (TAAR5). Here we show that trimethylamine, acting via TAAR5, elicits state-dependent attraction or aversion in male mice and drives inter-male aggression. Genetic knockout of TAAR5 significantly reduces aggression-related behaviors, while adding trimethylamine augments aggressive behavior towards juvenile males. We further show that transgenic expression of TAAR5 specifically in olfactory sensory neurons rescues aggressive behaviors in knockout mice, despite extensive remapping of TAAR5 projections to the olfactory bulb. Our results identify a specific main olfactory input that detects a prominent male-specific odor to induce inter-male aggression in a mammalian species and reveal that apparently innate behavioral responses are independent of patterned glomerular input to the olfactory bulb.

Effects of COVID-19 on the human central olfactory system: a natural pre-post experiment

Reduced olfactory function is the symptom with the highest prevalence in COVID-19 with nearly 70% of individuals with COVID-19 experiencing partial or total loss of their sense of smell at some point during the disease. The exact cause is not known but beyond peripheral damage, studies have demonstrated insults to both the olfactory bulb and central olfactory brain areas. However, these studies often lack both baseline pre-COVID-19 assessments and a control group and could therefore simply reflect preexisting risk factors. Right before the COVID-19 outbreak, we completed an olfactory focused study including structural MR brain images and a full clinical olfactory test. Opportunistically, we invited participants back one year later, including 9 participants who had experienced mild to medium COVID-19 (C19+) and 12 that had not (C19-), thereby creating a pre-post controlled natural experiment with a control group. Despite C19+ participants reporting subjective olfactory dysfunction, few showed signs of objectively altered function one year later. Critically, all but one individual in the C19+ group had reduced olfactory bulb volume with an average volume reduction of 14.3%, but this did not amount to a significant between group difference compared to the control group (2.3% reduction) using inference statistics. No morphological differences in cerebral olfactory areas were found but we found stronger functional connectivity between olfactory brain areas in the C19+ croup at the post measure. Taken together, these data suggest that COVID-19 might cause a long-term reduction in olfactory bulb volume but with no discernible differences in cerebral olfactory regions.

Ginsenoside Rd Attenuates Tau Phosphorylation in Olfactory Bulb, Spinal Cord, and Telencephalon by Regulating Glycogen Synthase Kinase 3β and Cyclin-Dependent Kinase 5

Objective. Ginseng is a plant of the family Acanthopanaceae. It has been used for thousands of years in China. It is known as the king of hundred herbs. It was recorded first in Shennong Baicao Jing. It has been found that ginsenoside Rd is a neuroprotective agent. This article aims to explore the protective roles of ginsenoside Rd in Alzheimer’s disease. Rd, a Chinese herb, may be a promising treatment drug for Alzheimer’s disease (AD) and is also reported to be related to several pathological changes, including the deposition of Aβ and tau hyperphosphorylation in AD as it decreases the deposition of tau hyperphosphorylation in APP transgenic mice. Methods. In this study, APP transgenic mice were pretreated with 10 mg/kg Rd for six months, and the effect of Rd on neuropathological deficits in the olfactory bulb, spinal cord, and telencephalon of APP transgenic mice was investigated. The phosphorylation levels of tau (S199/202, S396, S404, and Tau5) and the activities of the proteins glycogen synthase kinase 3β (Tyr216) and cyclin-dependent kinase 5 (P25/P35) were measured. Results. The pretreatment of Rd effectively decreased the production and deposition of hyperphosphorylated tau (S199/202, S396, and S404) protein by depressing the expression of glycogen synthase kinase 3β (GSK-3β/Tyr216) and cyclin-dependent kinase 5 (CDK5/P25). Conclusion. These findings suggest that ginsenoside Rd could improve the pathological changes of AD in the olfactory bulb, spinal cord, and telencephalon, which further demonstrated the potential therapeutic effect of Rd in early AD.