Regions Of Olfactory Bulb Research Articles

Telencephalic eversion in embryos and early larvae of four teleost species.

The telencephalon of ray-finned fishes undergoes eversion, which is very different to the evagination that occurs in most other vertebrates. Ventricle morphogenesis is key to build an everted telencephalon. Thus, here we use the apical marker zona occludens 1 to understand ventricle morphology, extension of the tela choroidea and the eversion process during early telencephalon development of four teleost species: giant danio (Devario aequipinnatus), blind cavefish (Astyanax mexicanus), medaka (Oryzias latipes), and paradise fish (Macroposus opercularis). In addition, by using immunohistochemistry against tubulin and calcium-binding proteins, we analyze the general morphology of the telencephalon, showing changes in the location and extension of the olfactory bulb and other telencephalic regions from 2 to 5 days of development. We also analyze the impact of abnormal eye and telencephalon morphogenesis on eversion, showing that cyclops mutants do undergo eversion despite very dramatic abnormal eye morphology. We discuss how the formation of the telencephalic ventricle in teleost fish, with its characteristic shape, is a crucial event during eversion.

Pathological features and molecular signatures of early olfactory dysfunction in 3xTg-AD model mice.

Olfactory dysfunction is known to be an early manifestation of Alzheimer's disease (AD). However, the underlying mechanism, particularly the specific molecular events that occur during the early stages of olfactory disorders, remains unclear. In this study, we utilized transcriptomic sequencing, bioinformatics analysis, and biochemical detection to investigate the specific pathological and molecular characteristics of the olfactory bulb (OB) in 4-month-old male triple transgenic 3xTg-AD mice (PS1M146V/APPSwe/TauP301L). Initially, during the early stages of olfactory impairment, no significant learning and memory deficits were observed. Correspondingly, we observed significant accumulation of amyloid-beta (Aβ) and Tau pathology specifically in the OB, but not in the hippocampus. In addition, significant axonal morphological defects were detected in the olfactory bulb, cortex, and hippocampal brain regions of 3xTg-AD mice. Transcriptomic analysis revealed a significant increase in the expression of neuroinflammation-related genes, accompanied by a significant decrease in neuronal activity-related genes in the OB. Moreover, immunofluorescence and immunoblotting demonstrated an activation of glial cell biomarkers Iba1 and GFAP, along with a reduction in the expression levels of neuronal activity-related molecules Nr4a2 and FosB, as well as olfaction-related marker OMP. In sum, the early accumulation of Aβ and Tau pathology induces neuroinflammation, which subsequently leads to a decrease in neuronal activity within the OB, causing axonal transport deficits that contribute to olfactory disorders. Nr4a2 and FosB appear to be promising targets for intervention aimed at improving early olfactory impairment in AD.

Evaluation of peripheral and central olfactory pathways in HIV-infected patients by MRI

To investigate peripheral and central olfactory pathways using cranial magnetic resonance imaging (MRI) in human immunodeficiency virus (HIV)-infected patients. The cranial MRI images of 37 HIV-infected adult patients and 37 adults without HIV infection having normal cranial MRI results were included in the study. In both groups, olfactory bulb (OB) volume and olfactory sulcus (OS) depth; and insular gyrus and corpus amygdala areas were measured using cranial MRI. In the HIV group, disease duration, HIV RNA, and CD4 lymphocyte count and levels as a percentage were also recorded. The HIV group had significantly lower bilateral OB volumes, insular gyrus and corpus amygdala areas compared to the control group. The HIV group showed positive correlations between OB volumes, OS depths, insular gyrus, and corpus amygdala areas bilaterally. Increases in OB volumes and OS depths were associated with an increase in the insular gyrus area. The corpus amygdala and insular gyrus areas increased similarly. There was no significant correlation between age, gender, disease duration, CD4 lymphocyte count and per cent, HIV RNA values, and the measurement values of the central and peripheral olfactory regions. A decrease in olfactory regions of OB, insular gyrus, and corpus amygdala in HIV-infected patients shows that HIV infection may cause olfactory impairment. There is no correlation between disease duration and olfactory impairment. It may be related to neuroinflammation, HIV-related brain atrophy, acquired immunodeficiency syndrome (AIDS) dementia complex, or neurocognitive impairment, which are the other explanations for the olfactory impairment in HIV. The possible toxicity from antiretroviral therapy (ART) may be another cause that should be investigated further.

Heterogeneous Damage to the Olfactory Epithelium in Patients with Post-Viral Olfactory Dysfunction.

Post-viral olfactory dysfunction (PVOD) is a neurogenic disorder caused by a common cold virus. Based on the homology of deduced amino acid sequences, olfactory sensory neurons (OSNs) in both mice and humans express either class I or class II odorant receptor genes encoding class I and class II OSNs. The purpose of this study was to determine whether OSN damage in PVOD occurs uniformly in both neuron types. The characteristics of PVOD patients were compared with those of patients with chronic rhinosinusitis (CRS) or post-traumatic olfactory dysfunction (PTOD). Briefly, subjects underwent orthonasal olfaction tests using five different odors (T&T odors) and a retronasal olfaction test using a single odor (IVO odor). The regions in the mouse olfactory bulb (OB) activated by the T&T and the IVO odors were also examined. Multivariate analysis of 307 cases of olfactory dysfunction (PVOD, 118 cases; CRS, 161 cases; and PTOD, 28 cases) revealed that a combination of responses to the IVO odor, but not to the T&T odors, is characteristic of PVOD, with high specificity (p < 0.001). Imaging analysis of GCaMP3 mice showed that the IVO odor selectively activated the OB region in which the axons of class I OSNs converged, whereas the T&T odors broadly activated the OB region in which axons of class I and class II OSNs converged. A response to T&T odors, but not IVO odor, in PVOD suggests that class I OSNs are injured preferentially, and that OSN damage in PVOD may occur heterogeneously in a neuron-type-dependent manner.

An Empirical Cross-Sectional Study to Identify the Olfactory and Gustatory Effects of SARS-CoV-2 – A Social Analysis

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a glycan-coated coronavirus with an exposed receptor-binding domain (RBD), capable of binding to the angiotensin-converting enzyme-2 (ACE2) receptors and entering the cell through the cleavage of the spike proteins by the extracellular host enzyme Transmembrane serine protease 2 (TMPRSS2). The severity of the infection is directly associated with loss of taste (ageusia) and loss of smell, varying from hyposmia (reduced perception of smell) to anosmia (complete loss of smell). The mechanisms underlying the independent symptoms remain inconclusive; however, have been linked to sustentacular cell infection, changes in the olfactory bulb and subcortical regions of the brain, defects in the respiratory centres of the central nervous system and cerebral glucose abnormalities. The survey for this cross-sectional study was conducted in 2021 and involved 126 individuals who were exposed to or tested positive for COVID-19, through the Reverse transcription polymerase chain reaction (RT-PCR). 6.3% of covid-negative and 34.9% covid-positive individuals exposed to COVID-19, experienced anosmia and ageusia. This study aims to identify patterns in symptoms presented when an individual is infected with COVID-19; focusing on the correlation between anosmia and ageusia and associated visual impairments or cognitive difficulties. The understanding of varied symptom combinations observed amongst individuals differing in age, sex, comorbidities or vaccination status could aid doctors and healthcare practitioners to provide a prognosis specific to the subset to which the patients belong, depending on their symptom combinations and severity for the same.

Progressive Spread of Beta-amyloid Pathology in an Olfactory-driven Amyloid Precursor Protein Mouse Model.

Years before Alzheimer's disease (AD) is diagnosed, patients experience an impaired sense of smell, and β-amyloid plaques accumulate within the olfactory mucosa and olfactory bulb (OB). The olfactory vector hypothesis proposes that external agents cause β-amyloid to aggregate and spread from the OB to connected downstream brain regions. To reproduce the slow accumulation of β-amyloid that occurs in human AD, we investigated the progressive accumulation of β-amyloid across the brain using a conditional mouse model that overexpresses a humanized mutant form of the amyloid precursor protein (hAPP) in olfactory sensory neurons. Using design-based stereology, we show the progressive accumulation of β-amyloid plaques within the OB and cortical olfactory regions with age. We also observe reduced OB volumes in these mice when hAPP expression begins prior-to but not post-weaning which we tracked using manganese-enhanced MRI. We therefore conclude that the reduced OB volume does not represent progressive degeneration but rather disrupted OB development. Overall, our data demonstrate that hAPP expression in the olfactory epithelium can lead to the accumulation and spread of β-amyloid through the olfactory system into the hippocampus, consistent with an olfactory system role in the early stages of β-amyloid-related AD progression.

Brain distribution and metabolic profiling of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats investigated by UHPLC-HRMS/MS following peripheral administration

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is known to be a tobacco-specific N-nitrosamine and has peripheral carcinogenic properties. It can also induce oxidative stress, glial cell activation, and neuronal damage in the brain. However, the distribution and metabolic characteristics of NNK in the central nervous system are still unclear. Here, a sensitive and effective UHPLC-HRMS/MS method was established to identify and investigate the metabolites of NNK and their distribution in the rat brain. In addition, the pharmacokinetic profiles were simultaneously investigated via blood-brain synchronous microdialysis. NNK and its seven metabolites were well quantified in the hippocampus, cortex, striatum, olfactory bulb, brain stem, cerebellum, and other regions of rat brain after peripheral exposure (5mg/kg, i.p.). The average content of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in all brain regions was at least threefold higher than that of NNK, indicating a rapid carbonyl reduction of NNK in the brain. Lower concentrations of pyridine N-oxidation products in the cortex, olfactory bulb, hippocampus, and striatum might be related to the poor detoxification ability in these regions. Compared to α-methyl hydroxylation, NNK and NNAL were more inclined to the α-methylene hydroxylation pathway. Synchronous pharmacokinetic results indicated that the metabolic activity of NNK in the brain was different from that in the blood. The mean α-hydroxylation ratio in the brain and blood was 0.037 and 0.161, respectively, which indicated poor metabolic activity of NNK in the central nervous system.

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis

Synucleinopathies are neurodegenerative diseases characterized by pathological inclusions called “Lewy pathology” (LP) that consist of aggregated alpha-synuclein predominantly phosphorylated at serine 129 (PSER129). Despite the importance for understanding disease, little is known about the endogenous function of PSER129 or why it accumulates in the diseased brain. Here we conducted several observational studies using a sensitive tyramide signal amplification (TSA) technique to determine PSER129 distribution and function in the non-diseased mammalian brain. In wild-type non-diseased mice, PSER129 was detected in the olfactory bulb (OB) and several brain regions across the neuroaxis (i.e., OB to brainstem). In contrast, PSER129 immunoreactivity was not observed in any brain region of alpha-synuclein knockout mice. We found evidence of PSER129 positive structures in OB mitral cells of non-diseased mice, rats, non-human primates, and healthy humans. Using TSA multiplex fluorescent labeling, we showed that PSER129 positive punctate structures occur within inactive (i.e., c-fos negative) T-box transcription factor 21 (TBX21) positive mitral cells and PSER129 within these cells was spatially associated with PK-resistant alpha-synuclein. Ubiquitin was found in PSER129 mitral cells but was not closely associated with PSER129. Biotinylation by antibody recognition (BAR) identified 125 PSER129-interacting proteins in the OB of healthy mice, which were significantly enriched for presynaptic vesicle trafficking/recycling, SNARE, fatty acid oxidation, oxidative phosphorylation, and RNA binding. TSA multiplex labeling confirmed the physical association of BAR-identified protein Ywhag with PSER129 in the OB and in other regions across the neuroaxis. We conclude that PSER129 accumulates in the mitral cells of the healthy OB as part of alpha-synuclein normal cellular functions. Incidental LP has been reported in the OB, and therefore we speculate that for synucleinopathies, either the disease processes begin locally in OB mitral cells or a systemic disease process is most apparent in the OB because of the natural tendency to accumulate PSER129.

Wide-ranging migration and destination of early olfactory placode-derived neurons in chick embryos.

Cell migration from the olfactory placode (OP) is a well-known phenomenon wherein various cell types, such as gonadotropin-releasing hormone (GnRH)-producing neurons, migrate toward the telencephalon (TEL) during early embryonic development. However, the spatial relationship between early migratory cells and the forebrain is unclear. We examined the early development of whole-mount chick embryos to observe the three-dimensional spatial relationship among OP-derived migratory neurons, olfactory nerve (ON), and TEL. Migratory neurons that express highly polysialylated neural cell adhesion molecule (PSA-NCAM) emerge from the OP and spread over a relatively wide TEL area at the Hamburger and Hamilton (HH) stage 17. Most migratory neurons form a cellular cord between the olfactory pit and rostral TEL within HH18-20. The earliest axons from the olfactory epithelium (OE) were detected along this neuronal cord using DiI-labeling at HH21. Furthermore, a few PSA-NCAM-positive neurons were dispersed around the cellular cord and over the lateral TEL at HH18. A long cellular cord branch extending to the lateral TEL was transiently observed within HH18-24. These results suggest a novel migratory route of OP-derived neurons during the early developmental stages. Following GFP vector introduction into the OP of HH13-15 embryos, labeled neurons were detected around and within the lateral TEL at HH23 and HH27. At HH36, labeled cells were observed in the rostral-lateral TEL, including the olfactory bulb (OB) region. GFP-labeled and calretinin-positive neurons were detected in the OB, suggesting that early OP-derived neurons enter the forebrain and function as interneurons in the OB.

Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes.

Therapeutic gene silencing in the brain is usually achieved using highly invasive intracranial administration methods and/or comparatively toxic vectors. In this work, we use a relatively biocompatible vector: poly(ethylene glycol) star-shaped polymer capped with amine groups (4APPA) via the nose to brain route. 4APPA complexes anti- itchy E3 ubiquitin protein ligase (anti-ITCH) siRNA to form positively charged (zeta potential +15 ± 5 mV) 150 nm nanoparticles. The siRNA-4APPA polyplexes demonstrated low cellular toxicity (IC50 = 13.92 ± 6 mg mL−1) in the A431 cell line and were three orders of magnitude less toxic than Lipofectamine 2000 (IC50 = 0.033 ± 0.04 mg mL−1) in this cell line. Cell association and uptake of fluorescently labelled siRNA bound to siRNA-4APPA nanoparticles was demonstrated using fluorescent activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), respectively. Gene silencing of the ITCH gene was observed in vitro in the A431 cell line (65% down regulation when compared to the use of anti-ITCH siRNA alone). On intranasal dosing with fluorescently labelled siRNA-4APPA polyplexes, fluorescence was seen in the cells of the olfactory bulb, cerebral cortex and mid-brain regions. Finally, down regulation of ITCH was seen in the brain cells (54 ± 13% ITCH remaining compared to untreated controls) in a healthy rat model, following intranasal dosing of siRNA-4APPA nanoparticles (0.15 mg kg−1 siRNA twice daily for 3 days). Gene silencing in the brain may be achieved by intranasal administration of siRNA- poly(ethylene glycol) based polyplexes.

MODL-11. The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice

Abstract CREBBP (cAMP response element-binding protein binding protein) and MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog), two essential proteins in central nervous system development that are described to be genetically altered in the same brain tumor entities, such as high grade glioma or medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. In order to investigate molecular mechanisms and potential tumor formation, we established a novel mouse model combining a deletion of Crebbp with an overexpression of MYCN in neural stem cells (hGFAP-cre::CrebbpFl/Fl::lsl-MYCN). The animals developed highly aggressive forebrain tumors with 75 % penetrance already detectable in seven-day old mice, leading to tumor-related death within eight months. Although tumors mostly developed in the olfactory bulb region, we hypothesized that these tumors develop from subventricular stem cells that migrate into the olfactory bulb, where they settle and establish large solid tumors. In order to test this hypothesis, we analyzed neural stem cells (NSCs) derived from our mouse model. Compared to control cells, NSCs from transgenic mice have a significantly increased cell viability and proliferation in vitro and did not undergo full glial differentiation. In order to gain further insights into the cellular origin and biology of the tumors, we finally employed single cell RNA sequencing. Apart from a high intratumoral heterogeneity within the tumor cell population, data comparison with non-neoplastic CNS cell populations revealed a high similarity with transit-amplifying NSCs of the subventricular zone. Together, we were able to show the oncogenic potential of a combined loss of Crebbp and aberrant expression of MYCN in neural stem cells. This novel mouse model will be an important tool for understanding tumor-driving mechanisms and a valuable model for preclinical testing and will thereby help to improve patient care.

Trace Amine-Associated Receptor 2 Is Expressed in the Limbic Brain Areas and Is Involved in Dopamine Regulation and Adult Neurogenesis.

Trace amines are a group of biogenic amines that are structurally and functionally close to classical monoamine neurotransmitters. Trace amine-associated receptors (TAARs) are emerging as promising targets for treating neuropsychiatric disorders. It has been documented that all TAARs, apart from TAAR1, function as olfactory receptors involved in sensing innate odors encoded by volatile amines. However, recently, brain expression and function of TAAR5 were also demonstrated. In this study, we assessed the behavior, brain neurochemistry, and electrophysiology changes in knock-out mice lacking Trace amine-associated receptor 2 (TAAR2) but expressing beta-Galactosidase mapping expression of TAAR2 receptors. As expected, we detected beta-Galactosidase staining in the glomerular layer of the olfactory bulb. However, we also found staining in the deeper layers of the olfactory bulb and several brain regions, including the hippocampus, cerebellum, cortex, raphe nuclei, hypothalamus, and habenula, indicating that TAAR2 receptors are not only expressed in the olfactory system but are also present in the limbic brain areas that receive olfactory input. In behavioral experiments, TAAR2 knock-out (TAAR2-KO) mice showed increased locomotor activity and less immobility in the forced swim test, with no changes in anxiety level. Furthermore, TAAR2-KO mice showed alterations in brain electrophysiological activity—particularly, decreased spectral power of the cortex and striatum in the 0, 9–20 Hz range. TAAR2-KO mice also had elevated tissue dopamine levels in the striatum and an increased dopaminergic neuron number in the Substantia Nigra. In addition, an increased brain-derived neurotrophic factor (BDNF) mRNA level in the striatum and Monoamine Oxidase B (MAO-B) mRNA level in the striatum and midbrain was found in TAAR2-KO mice. Importantly, TAAR2-KO mice demonstrated an increased neuroblast-like and proliferating cell number in the subventricular and subgranular zone, indicating increased adult neurogenesis. These data indicate that in addition to its role in the innate olfaction of volatile amines, TAAR2 is expressed in limbic brain areas and regulates the brain dopamine system, neuronal electrophysiological activity, and adult neurogenesis. These findings further corroborated observations in TAAR1-KO and TAAR5-KO mice, indicating common for TAAR family pattern of expression in limbic brain areas and role in regulating monoamine levels and adult neurogenesis, but with variable involvement of each subtype of TAAR receptors in these functions.

Evaluation of three methods for delineation and attenuation estimation of the sinus region in MR-based attenuation correction for brain PET-MR imaging

BackgroundAttenuation correction is crucial in quantitative positron emission tomography-magnetic resonance (PET-MRI) imaging. We evaluated three methods to improve the segmentation and modelling of the attenuation coefficients in the nasal sinus region. Two methods (cuboid and template method) included a MRI-CT conversion model for assigning the attenuation coefficients in the nasal sinus region, whereas one used fixed attenuation coefficient assignment (bulk method).MethodsThe study population consisted of data of 10 subjects which had undergone PET-CT and PET-MRI. PET images were reconstructed with and without time-of-flight (TOF) using CT-based attenuation correction (CTAC) as reference. Comparison was done visually, using DICE coefficients, correlation, analyzing attenuation coefficients, and quantitative analysis of PET and bias atlas images.ResultsThe median DICE coefficients were 0.824, 0.853, 0.849 for the bulk, cuboid and template method, respectively. The median attenuation coefficients were 0.0841 cm−1, 0.0876 cm−1, 0.0861 cm−1 and 0.0852 cm−1, for CTAC, bulk, cuboid and template method, respectively. The cuboid and template methods showed error of less than 2.5% in attenuation coefficients. An increased correlation to CTAC was shown with the cuboid and template methods. In the regional analysis, improvement in at least 49% and 80% of VOI was seen with non-TOF and TOF imaging. All methods showed errors less than 2.5% in non-TOF and less than 2% in TOF reconstructions.ConclusionsWe evaluated two proof-of-concept methods for improving quantitative accuracy in PET/MRI imaging and showed that bias can be further reduced by inclusion of TOF. Largest improvements were seen in the regions of olfactory bulb, Heschl's gyri, lingual gyrus and cerebellar vermis. However, the overall effect of inclusion of the sinus region as separate class in MRAC to PET quantification in the brain was considered modest.

Functional Activities Detected in the Olfactory Bulb and Associated Olfactory Regions in the Human Brain Using T2-Prepared BOLD Functional MRI at 7T.

Olfaction is a fundamental sense that plays a vital role in daily life in humans, and can be altered in neuropsychiatric and neurodegenerative diseases. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) using conventional echo-planar-imaging (EPI) based sequences can be challenging in brain regions important for olfactory processing, such as the olfactory bulb (OB) and orbitofrontal cortex, mainly due to the signal dropout and distortion artifacts caused by large susceptibility effects from the sinonasal cavity and temporal bone. To date, few studies have demonstrated successful fMRI in the OB in humans. T2-prepared (T2prep) BOLD fMRI is an alternative approach developed especially for performing fMRI in regions affected by large susceptibility artifacts. The purpose of this technical study is to evaluate T2prep BOLD fMRI for olfactory functional experiments in humans. Olfactory fMRI scans were performed on 7T in 14 healthy participants. T2prep BOLD showed greater sensitivity than GRE EPI BOLD in the OB, orbitofrontal cortex and the temporal pole. Functional activation was detected using T2prep BOLD in the OB and associated olfactory regions. Habituation effects and a bi-phasic pattern of fMRI signal changes during olfactory stimulation were observed in all regions. Both positively and negatively activated regions were observed during olfactory stimulation. These signal characteristics are generally consistent with literature and showed a good intra-subject reproducibility comparable to previous human BOLD fMRI studies. In conclusion, the methodology demonstrated in this study holds promise for future olfactory fMRI studies in the OB and other brain regions that suffer from large susceptibility artifacts.

Peripheric smell regions in patients with temporal and frontal lobe epilepsies: An MRI evaluation

ObjectivesWe investigated peripheric smell regions of olfactory bulb (OB) volume and olfactory sulcus (OS) depth in temporal and frontal lobe epilepsy patients by cranial magnetic resonance imaging (MRI). MethodsIn this retrospective study, cranial MRI images of 150 adult patients were included. Group 1 was consisted of 50 adult patients with temporal lobe epilepsy (TLE). Group 2 was consisted of 50 adult patients with frontal lobe epilepsy (FLE). The control group (Group 3) was consisted of 50 healthy subjects without epilepsy. OB volume and OS depth were measured in all groups. ResultsOB volumes of the temporal and frontal epilepsy groups were significantly lower than those of the control group (padjusted < 0.0175). However, OS depths were not different between groups 1–3 (p > 0.05). In the temporal and frontal epilepsy groups, there were positive correlations between OB volumes; OS depths; left OB volume and bilateral OS depths p < 0.05). There were no significant correlations between OB volume and OS depth; and age and gender of the epilepsy group (p > 0.05). ConclusionWe concluded that temporal and frontal epilepsy maybe related to decrease in OB volume and may cause olfactory impairment. Olfactory deficit maybe related to central epileptic focus. Therefore, early diagnosis and appropriate treatment of epilepsy are important to prevent olfactory impairment.

Olfactory subsystems associated with the necklace glomeruli in rodents.

The necklace glomeruli are a loosely defined group of glomeruli encircling the caudal main olfactory bulb in rodents. Initially defined by the expression of various immunohistochemical markers, they are now better understood in the context of the specialized chemosensory neurons of the main olfactory epithelium and Grueneberg ganglion that innervate them. It has become clear that the necklace region of the rodent main olfactory bulb is composed of multiple distinct groups of glomeruli, defined at least in part by their afferent inputs. In this review, we will explore the necklace glomeruli and the chemosensory neurons that innervate them.

COVID-19 and olfactory dysfunction: A possible associative approach towards neurodegenerative diseases.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the agent of novel coronavirus 2019 (COVID‐19), has kept the globe in disquiets due to its severe life‐threatening conditions. The most common symptoms of COVID‐19 are fever, sore throat, and shortness of breath. According to the anecdotal reports from the health care workers, it has been suggested that the virus could reach the brain and can cause anosmia, hyposmia, hypogeusia, and hypopsia. Once the SARS‐CoV‐2 has entered the central nervous system (CNS), it can either exit in an inactive form in the tissues or may lead to neuroinflammation. Here, we aim to discuss the chronic infection of the olfactory bulb region of the brain by SARS‐CoV‐2 and how this could affect the nearby residing neurons in the host. We further review the probable cellular mechanism and activation of the microglia 1 phenotype possibly leading to various neurodegenerative disorders. In conclusion, SARS‐CoV‐2 might probably infect the olfactory bulb neuron enervating the nasal epithelium accessing the CNS and might cause neurodegenerative diseases in the future.

Computational Model of Parkinson's Disease Pathology in Olfactory Bulb Predicts Localization of Neural Activity and Disruption to Oscillatory Behavior

One of the earliest symptoms of Parkinson's Disease (PD) is the loss of olfaction. This may be due to the damage PD causes in the olfactory bulb (OB), as evidenced by findings that in many PD patients, the OB contains large amounts of the alpha-synuclein protein, even in early stages of the disease. The olfactory bulb receives and processes olfactory input before relaying activity to higher areas of the brain. This olfactory information appears to be encoded in part by patterns of high frequency oscillations in neural firing rates in the OB. An early computational model by Z. Li and J. Hopfield simulated these high frequency oscillations. The model consisted of two groups of neurons, mitral cells (excitatory) and granule cells (inhibitory). These formed a collection of coupled nonlinear oscillators arranged on a one dimensional ring. In the present work, this model was extended to larger sizes and a two dimensional network structure. The model network was subjected to synaptic damage representative of PD pathology, and the ensuing responses to simulated odor input were characterized and compared to the baseline response. Results show increased localization of model network activity in response to odors, as well as disruption to network oscillations. The severity of the effects depends on the size and structure of the network. Future work aims to implement recent models that incorporate other OB features likely affected by PD, such as dopaminergic input. By computationally investigating the OB under conditions caused by PD, this work attempts to better understand OB function and the mechanisms by which PD impairs the OB and other regions of the brain.

Using of ¹⁸F-FDG to evaluate the effect of traumatic olfactory nerve injury on drug delivery through the nasal-brain pathway: a PET-MRI pilot study

Objective:This study evaluated the effect of traumatic olfactory nerve injury on drug delivery through the nasal-brain pathway via the instillation of ¹⁸F-FDG at the olfactory cleft. Method:Seven healthy volunteers and 5 patients with traumatic dysosmia were enrolled in the study. Subjects were all instilled with ¹⁸F-FDG on each side of the olfactory cleft under endoscopy. After 12 hours, a PET/MR scan was performed to track the metabolism pathway of ¹⁸F-FDG. Then, we compared the diameter of the olfactory bulb and the olfactory bulb intake between normal volunteers and patients with traumatic olfactory disorders. Result:In healthy volunteers, there was a significant difference in ¹⁸F-FDG uptake between the regions of interest in which ¹⁸F-FDG was or was not in contact with the cribriform plate（P=0.012 7）; this difference also existed in patients with traumatic olfactory disorders（P=0.038 1）. Patients with traumatic olfactory disorders did not exhibit significant differences in ¹⁸F-FDG uptake in the region of interest compared with healthy volunteers（P=0.937 2）. Conclusion:The olfactory bulb is obviously atrophied in patients with traumatic olfactory dysfunction, and the uptake of ¹⁸F-FDG in the olfactory bulb region of interest is also reduced. The administration of ¹⁸F-FDG via olfactory fissure area can enter olfactory bulb and parafrontal tissues through the nasal brain pathway,¹⁸F-FDG can enter the central nervous system through the nasal-brain pathway, which is not affected by olfactory nerve transection injury.

Systemic Exosomal Delivery of shRNA Minicircles Prevents Parkinsonian Pathology.

The development of new therapies to slow down or halt the progression of Parkinson's disease is a health care priority. A key pathological feature is the presence of alpha-synuclein aggregates, and there is increasing evidence that alpha-synuclein propagation plays a central role in disease progression. Consequently, the downregulation of alpha-synuclein is a potential therapeutic target. As a chronic disease, the ideal treatment will be minimally invasive and effective in the long-term. Knockdown of gene expression has clear potential, and siRNAs specific to alpha-synuclein have been designed; however, the efficacy of siRNA treatment is limited by its short-term efficacy. To combat this, we designed shRNA minicircles (shRNA-MCs), with the potential for prolonged effectiveness, and used RVG-exosomes as the vehicle for specific delivery into the brain. We optimized this system using transgenic mice expressing GFP and demonstrated its ability to downregulate GFP protein expression in the brain for up to 6weeks. RVG-exosomes were used to deliver anti-alpha-synuclein shRNA-MC therapy to the alpha-synuclein preformed-fibril-induced model of parkinsonism. This therapy decreased alpha-synuclein aggregation, reduced the loss of dopaminergic neurons, and improved the clinical symptoms. Our results confirm the therapeutic potential of shRNA-MCs delivered by RVG-exosomes for long-term treatment of neurodegenerative diseases.