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Previous research has revealed that the insula, pallidum, thalamus, hippocampus, middle frontal gyrus, and supplementary motor area are activated during odor memory and that the performance of olfactory working memory is affected by the verbalization of odors. However, the neural mechanisms underlying olfactory working memory and the role of verbalization in olfactory working memory are not fully understood. Twenty-nine participants were enrolled in a study to complete olfactory and visual n-back tasks using high- and low-verbalizability stimuli while undergoing fMRI imaging. The behavioral results showed that the participants achieved greater accuracy in the visual rather than olfactory n-back task. We observed increased activation in the precentral gyrus, superior frontal gyrus, middle frontal gyrus, supplementary motor area, and inferior parietal gyrus during olfactory working memory. Interestingly, decreased activation was observed in the olfactory 2-back task versus the 0-back task. Moreover, the left angular gyrus and inferior parietal gyrus were more strongly activated during processing of olfactory working memory using high-verbalizability odors. In conclusion, olfactory working memory engages cross-modal regions to facilitate responses, is involved in the monitoring and manipulation of information during working memory, and boasts a unique activation pattern that is different from that of visual working memory. Semantic information supports the representation of odor information in the working memory system., Competing Interests: Declaration of competing interest We have nothing to declare., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

The fight against Glioblastoma multiforme (GBM) is ongoing and the long-term outlook for GBM remains challenging due to low prognosis but every breakthrough brings us closer to improving patient outcomes. Significant hurdles in GBM are heterogeneity, fortified tumor location, and blood-brain barrier (BBB), hindering adequate drug concentrations within functioning brain regions, thus leading to low survival rates. The nasal passageway has become an appealing location to commence the course of cancer therapy. Utilization of the nose-to-brain (N2B) route for drug delivery takes a sidestep from the BBB to allow therapeutics to directly access the central nervous system (CNS) and enhance drug localization in the vicinity of the tumor. This comprehensive review provides insights into pertinent anatomy and cellular organization of the nasal cavity, present-day diagnostic tools, intracranial invasive therapies, and advancements in intranasal (IN) therapies in GBM models for better clinical outcomes. Also, this review highlights groundbreaking carriers and delivery techniques that could revolutionize GBM management such as biomimetics, image guiding-drug delivery, and photodynamic and photothermal therapies for GBM management.

Objective: To investigate the effectiveness of platelet-rich plasma (PRP) injection into the olfactory clefts of coronavirus disease 2019 (COVID-19) patients with persistent anosmia, hyposmia, and parosmia., Study Design: Controlled study., Setting: Multicenter study., Methods: From March 2022 to July 2024, 514 COVID-19 patients undergoing PRP injection and olfactory training versus olfactory training (controls) for a persistent olfactory dysfunction (OD) were consecutively recruited from two medical centers. Subjects were evaluated from pre- to 3 months post-injection with the olfactory disorder questionnaire (ODQ) and the threshold, discrimination, and identification (TDI) test. Olfactory outcomes were compared between controls and patients considering the type of OD (anosmia, hyposmia, and parosmia)., Results: The PRP group was composed of 416 patients with anosmia (N = 111; 26.7%), hyposmia (N = 160; 38.5%), and parosmia (N = 145; 34.9%). The baseline ODQ of patients with parosmia was significantly higher than those of the other groups (P = .001). The increase in TDI subscores and total score was significantly higher in all PRP subgroups compared to controls (P = 0.001). The ODQ significantly reduced from pre- to post-PRP injection in hyposmia and parosmia groups (P = 0.001). Patients with parosmia showed a significantly greater reduction in ODQ scores compared to the control group. The 3-month TDI score was negatively influenced by the age of patients (r s  = -0.263; P = 0.001) and the duration of OD (r s  = -0.213; P = .001)., Conclusion: Patients with parosmia experienced a stronger impact of OD on quality of life (QoL), and showed greater QoL improvement following PRP injections compared to other groups., (© 2025 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Introduction: Odors with prominent trigeminal compounds are more easily localized than purely olfactory ones. However, it is still unclear whether adding a small amount of a trigeminal compound to an olfactory odor significantly improves lateralization performance., Methods: We included 81 healthy adults aged 25.4 ± 4.8 years to complete odor lateralization tasks using 12 odors: two "olfactory", two "trigeminal" odors, and eight odor mixtures at two low concentrations of "trigeminal" odors (4%, 8%). This task utilized a "Squeezer" delivering odor or air to either nostril, and participants indicated which nostril received the odor. Evaluations also included olfactory function, odor intensity ratings, and individual olfactory importance., Results: Degrees of trigeminal compounds significantly affected lateralization performance (F = 82.32, p < 0.001), with 100% irritants showing higher performance than 0%, 4%, and 8% irritants (p's < 0.001), while no significant differences were found between odors with 0%, 4%, and 8% irritants (p's > 0.05). Chi-square tests confirmed higher percentages of above-chance lateralization with 100% irritants than with 0%, 4%, and 8% irritants (χ2 = 30.89 to 47.33, p's < 0.001)., Conclusions: Adding a small amount of a trigeminal compound to a selective olfactory odor does not significantly improve lateralization performance. Trigeminal lateralization likely follows an "accumulative" pattern rather than an "all or none" rule. With only 20 trials, the task may lack sensitivity to detect low levels of trigeminal irritation in selective olfactory odors, though it does not rule out trigeminal activation. The odor lateralization task can screen for odors with prominent trigeminal compounds by comparing group-level performance with that of purely olfactory odors. Future studies should use more ideal stimuli (e.g., PEA for olfactory, CO2 for trigeminal) to test the replicability of the results., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests., (© 2024. The Author(s).)

The vomeronasal organ (VNO) detects signaling molecules that often prompt innate behaviors, such as aggression and reproduction. Vomeronasal sensory neurons, classified into apical and basal lineages based on receptor expression, have a limited lifespan and are continuously replaced from a common stem cell niche. Using a combination of single-cell RNA sequencing data, immunofluorescence staining and lineage tracing, we identified CXCR4 expression in proliferative stem cells and the basal neuronal lineage. Mice with a conditional knockout of Cxcr4 showed an increased number of SOX2-positive proliferative stem cells and enhanced basal neuronal lineage maturation. In addition, computational gene perturbation analysis revealed 87 transcription factors that might contribute to neurogenesis, among which was SOX2. Conditional knockout of Cxcr4 did not only disturb neuronal maturation, but also affected non-neuronal cell types, resulting in a decrease of basal lamina lining quiescent stem cells and an increase in sustentacular support cells. Together, these findings enhance our understanding how a common pool of stem cells can give rise to different cell types of the VNO, highlighting the distinct role of CXCR4 in this process., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2025. Published by The Company of Biologists.)

The olfactory sensory system plays vital roles in daily activities, such as locating mate partners, foraging, and risk avoidance. Natural enemies can locate their prey through characteristic volatiles. However, little is known about whether prey can recognize the volatiles of their predators and if this recognition can increase the efficiency of prey escaping from predators. Xylocoris flavipes is a predator of Tribolium castaneum (Herbst) and Oryzaephilus surinamensis (Linne) that has been widely used in stored pest control. Herein, we analyze the volatile components of Xylocoris flavipes and their impacts on the olfactory behavior of T. castaneum and O. surinamensis . We found that T. castaneum and O. surinamensis preferred blank air rather than odors of X. flavipes and X. flavipes emissions, which significantly decreased the orientation preference of T. castaneum and O. surinamensis to wheat. X. flavipes emits three major volatiles, including linalool, α-terpineol, and geraniol. Y-tube bioassays showed that T. castaneum and O. surinamensis can recognize linalool and geraniol at certain concentrations, especially at 200 μg/mL. EAG recordings verified that linalool and geraniol elicit higher olfactory responses in the two pests, but very small EAG responses were observed in the insects to α-terpineol. A further repellency evaluation also proved that linalool and geraniol are repellent to the two pests, and this repellency can be slightly enhanced by mixing them together. T. castaneum and O. surinamensis can recognize the predator X. flavipes by perceiving its volatiles and using them as signals for escaping. The two most potent volatiles, linalool and geraniol, may have potential values as repellents in controlling pests in these two stored products.

Despite recent progress, the complex roles played by the extracellular matrix in development and disease are still far from being fully understood. Here, we took advantage of the zebrafish sly mutation which affects Laminin γ1, a major component of basement membranes, to explore its role in the development of the olfactory system. Following a detailed characterisation of Laminin distribution in the developing olfactory circuit, we analysed basement membrane integrity, olfactory placode and brain morphogenesis, and olfactory axon development in sly mutants, using a combination of immunochemistry, electron microscopy and quantitative live imaging of cell movements and axon behaviours. Our results point to an original and dual contribution of Laminin γ1-dependent basement membranes in organising the border between the olfactory placode and the adjacent brain: they maintain placode shape and position in the face of major brain morphogenetic movements, they establish a robust physical barrier between the two tissues while at the same time allowing the local entry of the sensory axons into the brain and their navigation towards the olfactory bulb. This work thus identifies key roles of Laminin γ1-dependent basement membranes in neuronal tissue morphogenesis and axon development in vivo., Competing Interests: PT, KP, AG, MD, MC, CF, ML, JF, MR, SA, AT, MB No competing interests declared, FD Reviewing editor, eLife, (© 2023, Tignard et al.)

Aortic aneurysm, the pathological dilatation of the aorta at distinct locations, can be attributed to many different genetic and environmental factors. The resulting pathobiological disturbances generate a complex interplay of processes affecting cells and extracellular molecules of the tunica interna, media and externa. In short, aortic aneurysm can affect processes involving the extracellular matrix, lipid trafficking/atherosclerosis, vascular smooth muscle cells, inflammation, platelets and intraluminal thrombus formation, as well as various endothelial functions. Many of these processes are interconnected, potentiating one another. Newer discoveries, including the involvement of odorant olfactory receptors in these processes, have further shed light on disease initiation and pathology. Olfactory receptors are a varied group of G protein coupled-receptors responsible for the recognition of chemosensory information. Although they comprise many different subgroups, some of which are not well-characterized or identified in humans, odorant olfactory receptors, in particular, are most commonly associated with recognition of olfactory information. They can also be ectopically localized and thus carry out additional functions relevant to the tissue in which they are identified. It is thus the purpose of this narrative review to summarize and present pathobiological processes relevant to the initiation and propagation of aortic aneurysm, while also incorporating evidence associating these ectopically functioning odorant olfactory receptors with the overall pathology.

Introduction: This study aims to investigate the progressive impact of chronic iron overload on the olfactory bulb, a region significantly affected in early neurodegenerative diseases like Parkinson's and Alzheimer's. The focus is on understanding how iron accumulation leads to oxidative stress, mitochondrial dysfunction, and neuronal damage over time in middle-aged mice., Method: The mice were continuously administered FC for a duration of 16 weeks, and the olfactory behavior of the mice was observed at intervals of 4 weeks. Inductively coupled plasma mass spectrometry (ICP-MS) was employed to detect alterations in iron content within the olfactory bulb of the mice, while levels of lipid peroxidation and antioxidant indexes were assessed using biochemical kits. Additionally, western blotting and qPCR techniques were utilized to analyze transcriptional and expression changes in proteins and genes related to iron metabolism. Furthermore, microstructural modifications as well as mitochondrial observations were conducted through paraffin sectioning and transmission electron microscopy (TEM)., Result: A significant and progressive increase in iron accumulation in the olfactory bulb, starting from week 8 and peaking at week 16. This accumulation coincided with a decline in olfactory function observed at week 12. Key markers of oxidative stress, such as 4-HNE and MDA, were elevated in specific layers, and antioxidant defenses were reduced. Mitochondrial damage became evident from week 8, with caspase-3 activation indicating increased apoptosis, particularly in the granular layer. This study is to demonstrate the link between chronic iron overload and progressive olfactory dysfunction in the context of neurodegenerative diseases. It provides evidence that iron-induced oxidative stress and mitochondrial damage in the olfactory bulb contribute to early sensory deficits, suggesting that the olfactory bulb's selective vulnerability can serve as an early biomarker for neurodegenerative conditions., Conclusion: Chronic iron overload leads to progressive oxidative damage, mitochondrial dysfunction, and apoptosis in the olfactory bulb, causing sensory deficits. Targeting iron accumulation and oxidative damage may offer new strategies for early intervention in neurodegenerative diseases, highlighting the importance of addressing iron dysregulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Deng, Luo, Liu, Wang, Xiong, Wang, Zhao, Jia, Shi, Huang and Chen.)

In a real-world environment, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems. However, little is known about the neuronal circuits governing how odors influence and modulate sound processing. Here, we investigated the mechanisms underlying auditory-olfactory integration using anatomical, electrophysiological, and optogenetic approaches, focusing on the auditory cortex as a key locus for cross-modal integration. First, retrograde and anterograde viral tracing strategies revealed a direct projection from the piriform cortex to the auditory cortex. Next, using in vivo electrophysiological recordings of neuronal activity in the auditory cortex of awake male or female mice, we found that odors modulate auditory cortical responses to sound. Finally, we used in vivo optogenetic manipulations during electrophysiology to demonstrate that olfactory modulation in the auditory cortex, specifically, odor-driven enhancement of sound responses, depends on direct input from the piriform cortex. Together, our results identify a novel role of piriform-to-auditory cortical circuitry in shaping olfactory modulation in the auditory cortex, shedding new light on the neuronal mechanisms underlying auditory-olfactory integration., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Focal intranasal drug delivery to the olfactory cleft is a promising avenue for pharmaceuticals targeting the brain. However, traditional nasal sprays often fail to deliver enough medication to this specific area. We present a laminar fluid ejection (LFE) method for precise delivery of medications to the olfactory cleft. Using a 3D-printed model of the nasal passages, we determined the precise velocity and angle of insertion needed to deposit fluid at the olfactory cleft. Then, we conducted three proof-of-concept in-vivo imaging studies to confirm olfactory delivery in humans. First, we used Technetium-99 (a radiolabeled tracer) and methylene blue (a laboratory-made dye) to visualize olfactory deposition. Both tracers showed successful deposition. In a separate study, we used functional MRI (fMRI), to compare our LFE method with a conventional nasal spray while delivering insulin. From the fMRI results, we qualitatively observed focal decreases in brain activity in prefrontal cortex following insulin delivery. Overall, these preliminary results suggest that LFE offers a targeted approach to olfactory drug delivery, opening opportunities for access to the brain.Clinical and Translational Impact Statement - Focal deposition at the olfactory cleft is a promising target for delivering medication to the brain. We present in-human tests of a laminar fluid ejection method for intranasal drug delivery and demonstrate improvements over conventional nasal spray., (© 2024 The Authors.)

Herpes simplex virus type 1 (HSV-1) primarily targets the oral and nasal epithelia before establishing latency in the trigeminal ganglion (TG) and other peripheral ganglia. HSV-1 can also infect and become latent in the central nervous system (CNS) independent of latency in the TGs. Recent studies suggest entry to the CNS via two distinct routes: the TG-brainstem connection and olfactory nerve; however, to date, there is no characterization of brain regions targeted during HSV-1 primary infection. Furthermore, the immune response by microglia may also contribute to the heterogeneity between different brain regions. However, the response to HSV-1 by microglia has not been characterized in a region-specific manner. This study investigated the time course of HSV-1 spread within the olfactory epithelium (OE) and CNS following intranasal inoculation and the corresponding macrophage/microglial response in a C57BL/6 mouse model. We found an apical to basal spread of HSV-1 within the OE and underlying tissue accompanied by an inflammatory response of macrophages. OE infection was followed by infection of a small subset of brain regions targeted by the TG in the brainstem and other cranial nerve nuclei, including the vagus and hypoglossal nerve. Furthermore, other brain regions were positive for HSV-1 antigens, such as the locus coeruleus (LC), raphe nucleus (RaN), and hypothalamus while sparing the hippocampus and cortex. Within each brain region, microglia activation also varied widely. These findings provide critical insights into the region-specific dissemination of HSV-1 within the CNS, elucidating potential mechanisms linking viral infection to neurological and neurodegenerative diseases.IMPORTANCEThis study shows how herpes simplex virus type 1 (HSV-1) spreads within the brain after infecting the nasal passages. Our data reveal the distinct pattern of HSV-1 through the brain during a non-encephalitic infection. Furthermore, microglial activation was also temporally and spatially specific, with some regions of the brain having sustained microglial activation even in the absence of viral antigens. Previous reports have identified specific brain regions found to be positive for HSV-1 infection; however, to date, there has not been a concise investigation of the anatomical spread of HSV-1 and the brain regions consistently vulnerable to viral entry and spread. Understanding these region-specific differences in infection and immune response is crucial because it links HSV-1 infection to potential triggers for neurological and neurodegenerative diseases., Competing Interests: The authors declare no conflict of interest.

Conserved protein-coding sequences are critical for maintaining protein function across species. Odorant receptors (ORs), a large poorly understood multigene family responsible for odor detection, lack comprehensive classification methods that reflect their functional diversity. In this study, we propose a new approach called conserved motif-based classification (CMC) for classifying ORs based on amino acid sequence similarities within conserved motifs. Specifically, we focused on three well-conserved motifs: MAYDRYVAIC in TM3, KAFSTCASH in TM6, and PMLNPFIY in TM7. Using an unsupervised clustering technique, we classified human ORs (hORs) into two main clusters with six sub-clusters. CMC partly reflects previously identified subfamilies, revealing altered residue positions among the sub-clusters. These altered positions interacted with specific residues within or adjacent to the transmembrane domain, suggesting functional implications. Furthermore, we found that the CMC correlated with both ligand responses and ectopic expression patterns, highlighting its relevance to OR function. This conserved motif-based classification will help in understanding the functions and features that are not understood by classification based solely on entire amino acid sequence similarity., (© 2024. The Author(s).)

Objective: To investigate the platelet-rich plasma (PRP) effectiveness in patients with a long-lasting postviral olfactory dysfunction (LPOD)., Methods: Forty-three consecutive patients with a long-lasting postviral OD were prospectively recruited. The injection of 1 mL of PRP was carried out in both olfactory clefts. The pre- to 6-month post-PRP injection change in olfaction was assessed with the olfactory disorder questionnaire (ODQ) and the threshold, discrimination, and identification (TDI) tests., Results: Forty-three patients received bilateral PRP injections (24 females). The mean age of patients was 58.9 ± 16.8 years. The mean duration of LPOD was 8.7 years. The pre to 6-month post-injection mean TDI significantly improved from 10.3 ± 10.2 to 20.12 ± 12.07 (p = 0.001). The mean ODQ significantly decreased from 29.8 ± 13.0 to 23.4 ± 11.3 (p = 0.013). The average change of the TDI and the ODQ were 9.8 and 6.4, respectively. Age was inversely associated with the 6-month threshold score., Conclusion: PRP appears to be a promising therapeutic strategy for long-lasting postviral OD. Our findings support the conduction of controlled randomized trial in this population of patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Animals have evolved innate responses to cues including social, food, and predator odors. In the natural environment, animals are faced with choices that involve balancing risk and reward where innate significance may be at odds with internal need. The ability to update the value of a cue through learning is essential for navigating changing and uncertain environments. However, the mechanisms involved in this modulation are not well defined in mammals. We have established a new olfactory assay that challenges a thirsty mouse to choose an aversive odor over an attractive odor in foraging for water, thus overriding their innate behavioral response to odor. Innately, mice prefer the attractive odor port over the aversive odor port. However, decreasing the probability of water at the attractive port leads mice to prefer the aversive port, reflecting a learned override of the innate response to the odors. The orbitofrontal cortex (OFC) is a fourth-order olfactory brain area, involved in flexible value association, with behaviorally relevant outputs throughout the limbic system. We performed optogenetic and chemogenetic silencing experiments that demonstrate the OFC is necessary for this learned modulation of innate aversion to odor. Further, we characterized odor evoked c-fos expression in learned and control mice and found significant suppression of activity in the bed nucleus of the stria terminalis, lateral septum, and central and medial amygdala. These findings reveal that the OFC is necessary for the learned override of innate behavior and may signal to limbic structures to modulate innate response to odor., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Miyamoto et al.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

"An elephant never forgets" is a popular phrase that refers not only to the elephant's extraordinary ability to remember migration routes but also to its pronounced social long-term memory (SLTM). Previous studies have shown intra- and interspecies SLTM performance, but the ability of elephants to have memories of individual humans has not yet been investigated. We tested this interspecific SLTM using auditory, olfactory, and visual stimuli, each from familiar and unfamiliar persons, in two African savanna elephant (Loxodonta africana) cows living in a zoo. The two-choice object tests revealed a higher interest in sensory stimuli from familiar keepers they had not seen for 13 years than in unfamiliar people. Statistically significant differences were found for olfactory stimuli. In addition, there was significantly more interest in visual stimuli from current keepers than in stimuli from unfamiliar people. Contrary to the results of a previous study with elephants, this was not observed for olfactory stimuli. Due to the small sample size and magnitude of the influencing factors, that is, outdoor experiment, only spatial separation of the animals, these results only represent indications of the possible interspecific SLTM. Nevertheless, we were able to provide the first empirical evidence that L. africana stores information about specific people over a long period of time. Further studies with larger sample sizes, cross-modal testing, and people disliked by the elephants could provide more insights., (© 2024 The Author(s). Zoo Biology published by Wiley Periodicals LLC.)

Aim: Chemosensory anhedonia refers to the lack of hedonic ability to experience pleasure through the senses of smell and taste, which reduces the pleasure and comfort of food, and increases the risk of nutritional and immune deficiencies. However, there is no direct scientific evidence regarding chemosensory anhedonia in patients with late-life depression (LLD). The aim of this study was to investigate chemosensory anhedonia in patients with LLD, and its potential association with depressive symptoms and cognitive function., Methods: A total of 114 patients with LLD and 92 normal controls were included in this study. They experienced clinical assessment, Chemosensory Pleasure Scale assessment, 17-item Hamilton Depression Rating Scale assessment and cognitive assessments, which contain the Verbal Fluency Test. The associations between chemosensory pleasure and depressive symptoms or cognitive function in patients with LLD were explored using partial correlation analysis and mediation analysis., Results: The Chemosensory Pleasure Scale scores were lower in the LLD group than in the normal control group, and were negatively correlated with the total scores and factors' scores (retardation, cognitive bias and anxiety/somatization) of the 17-item Hamilton Depression Rating Scale, and positively correlated with the Verbal Fluency Test scores. The scores for the Food and Imagination dimensions of the Chemosensory Pleasure Scale showed partial mediating effects on the differences in Cognitive bias (a factor of the 17-item Hamilton Depression Rating Scale) between patients with LLD and normal controls., Conclusions: Patients with LLD showed significant chemosensory anhedonia, and both depressive symptoms and cognitive impairment were associated with the severity of chemosensory anhedonia. Enhancing chemosensory pleasure in patients with LLD could potentially ameliorate their depressive symptoms. Geriatr Gerontol Int 2024; 24: 1022-1029., (© 2024 Japan Geriatrics Society.)

Purpose: This pilot study aimed to determine whether the Henkin olfactory test discriminates between the olfactory function of patients with olfactory loss and healthy individuals, and whether the Henkin test is correlated with a validated psychophysical olfactory test., Methods: Participants underwent olfactory testing using the modified Henkin test (including detection [DT] and recognition [RT] thresholds, magnitude estimation [ME], and hedonic ratings [H], for four different odors) and the extended "Sniffin' Sticks" test battery (odor detection, discrimination, identification)., Results: Forty-four individuals (28 women, aged 19-81 years, mean: 39 years) were included. Twenty-three were healthy (mean age: 38 years) and 21 had olfactory dysfunction (OD) (mean age: 40 years). OD patients had worse mean DT, lower composite RT, and lower ME ratings. Mean and individual odor H ratings were not significantly different between the groups. Most individuals were classified as hyposmic when using the prescribed classification by Henkin, with only very few satisfying the stringent criteria of anosmia and normosmia. Modified Henkin subtests were all positively correlated with each other and with the "Sniffin' Sticks", except for Unpleasant Mean H which was only correlated with Pleasant Mean H; and Pleasant mean H which was not correlated with mean DT scores., Conclusion: The Henkin test is able to separate between OD patients and controls. However, modifications to the conduct of this test may be required. Studies that used this test should be carefully interpreted., (© 2024. The Author(s).)

In a real-world environment, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems. However, little is known about the neuronal circuits governing how odors influence and modulate sound processing. Here, we investigated the mechanisms underlying auditory-olfactory integration using anatomical, electrophysiological, and optogenetic approaches, focusing on the auditory cortex as a key locus for cross-modal integration. First, retrograde and anterograde viral tracing strategies revealed a direct projection from the piriform cortex to the auditory cortex. Next, using in vivo electrophysiological recordings of neuronal activity in the auditory cortex of awake male or female mice, we found that odors modulate auditory cortical responses to sound. Finally, we used in vivo optogenetic manipulations during electrophysiology to demonstrate that olfactory modulation in auditory cortex, specifically, odor-driven enhancement of sound responses, depends on direct input from the piriform cortex. Together, our results identify a novel role of piriform-to-auditory cortical circuitry in shaping olfactory modulation in the auditory cortex, shedding new light on the neuronal mechanisms underlying auditory-olfactory integration., Competing Interests: Conflict of Interest: The authors declare no competing financial interests.

Background: The litchi fruit borer Conopomorpha sinensis Bradley is a major destructive pest of litchi and longan plants in China, India and South East Asia. Given its strong olfactory-based oviposition behaviour, interfering with the chemical communication between this insect pest and its host plant may serve as a potential control strategy. However, the chemical compounds associated with its egg-laying behaviour remain poorly understood., Results: In this study, we investigated the olfactory preference of female C. sinensis for oviposition on intact mature fruits of the Feizixiao (FZX) and Guiwei (GW) varieties. Results showed that female C. sinensis preferred to lay eggs on FZX compared with GW fruits, and this preference was olfactory-induced. In addition, we identified differences in the chemical composition of the volatile blend and proportions between FZX and GW fruits, with terpenes being the main volatile components contributing to this divergence. Compounds that induced electrophysiological activity in female borers were subsequently screened from FZX. d-Limonene exhibited the strongest oviposition attraction among four candidates. Furthermore, this compound served as a volatile olfactory cue for recognition and orientation in female C. sinensis., Conclusion: The results of this study provide a deeper understanding of the olfactory preferences of female C. sinensis for oviposition on specific litchi varieties. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: Olfactory stimulation with mastic resin, derived from the Pistacia lentiscus tree, demonstrated a bona fide sialagogic effect in healthy volunteers [1]. Its main volatile compound, α-pinene, also showed this effect. The current study aimed to validate the effect of mastic resin volatiles in chronic dry mouth patients with confirmed decreased saliva secretion., Methods: 41 chronic dry mouth patients with decreased unstimulated saliva secretion (<0.25 mL/min) were exposed to mastic resin volatiles as part of the diagnostic routine at the Saliva Clinic of Academic Centre for Dentistry Amsterdam. During their visit, dry-mouth questionnaires were conducted and samples of unstimulated whole saliva, chew-stimulated saliva, acid-stimulated saliva and mastic resin stimulated saliva were collected. Saliva flow rate, spinnbarkeit, pH, ion composition, MUC5B and MUC7 levels in all samples were analyzed., Results: Salivary flow rates increased by all stimuli when compared to the baseline unstimulated saliva (P<0.001). During olfactory mastic resin stimulation, the salivary spinnbarkeit (P<0.001) and sodium concentration (P<0.01) were increased compared to unstimulated saliva. MUC5B and MUC7 levels were increased during olfactory mastic resin stimulation compared to chew-stimulated saliva (P=0.016 and P<0.001, respectively). Spinnbarkeit correlated positively with MUC5B (R=0.399, P=0.002) and MUC7 levels (R=0.375, P=0.004). Results of dry-mouth questionnaires indicated reduced posterior palate dryness shortly after olfactory mastic resin stimulation (P=0.04)., Conclusions: Olfactory mastic resin stimulation increased mucous saliva secretion and reduced posterior palate dryness in a group of chronic dry mouth patients. These findings, validated in patients, underscore mastic resin scent as a beneficial and non-invasive sialagogic treatment for clinical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Aedes albopictus is an important vector of arboviruses and prefers small containers of stagnant water as oviposition sites. One of the mechanisms mosquitoes use to search for suitable oviposition sites is relying on odor cues from prospective sites and their surroundings. The genetic and molecular bases of this behavior are not known for Ae. albopictus. Oviposition site-searching behavior can be separated into 2 stages: container location and water detection. We applied a glue compound to the antennae and the maxillary palps of adult females to mask their ability to detect molecules that may guide them to preferred oviposition sites. Treatment of the antennae significantly reduces the location index (P < 0.001), indicating a decreased ability to find oviposition sites, whereas no significant difference was observed in mosquitoes with maxillary palps treated with the same glue compound (P > 0.05). The detection time, measured as the duration from contact with the water surface to the deposition of the first egg, was extended in mosquitoes with treated antennae or maxillary palps, supporting the conclusion that olfaction is involved in the detection of oviposition site. Transcriptomic analysis identified differentially expressed olfactory-related genes, including obp67, obp56d-like, obp19d-like and obp67-like. RNA interference (RNAi)-mediated knockdown of obp67 and obp56d-like significantly affected the location index and detection time, respectively. Cas9/guide RNA-mediated knockout of obp56d-like resulted in a prolonged detection time, compared with the wild type (P < 0.05). These findings help to elucidate aspects of the olfactory mechanisms involved in Ae. albopictus oviposition site selection, and provide a basis for the development of mosquito surveillance and control strategies., (© 2024 Institute of Zoology, Chinese Academy of Sciences.)

Alzheimer's disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review.

Rationale: Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. Methods: We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Conclusions: Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The olfactory system plays crucial roles in perceiving and interacting with their surroundings. Previous studies have deciphered basic odor perceptions, but how information processing in the olfactory system is associated with learning and memory is poorly understood. In this review, we summarize recent studies on the anatomy and functional dynamics of the mouse olfactory learning pathway, focusing on how neuronal circuits in the olfactory bulb (OB) and olfactory cortical areas integrate odor information in learning. We also highlight in vivo evidence for the role of the lateral entorhinal cortex (LEC) in olfactory learning. Altogether, these studies demonstrate that brain regions throughout the olfactory system are critically involved in forming and representing learned knowledge. The role of olfactory areas in learning and memory, and their susceptibility to dysfunction in neurodegenerative diseases, necessitate further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Lee and Igarashi.)

In the human brain, the regions responsible for emotion processing, motivation, and memory are heavily influenced by olfaction, whose neural pathway is directly exposed to the outer world. In this study, we used fMRI to examine how different olfactory conditions might affect the functional connectivity circuit underlying working memory in the brain. To this end, 30 adults (aged 20-35), 13 males and 17 females, with high educational levels were chosen. Participants were screened for potential olfactory issues before undergoing the Sniffin' sticks test, which was part of the inclusion criteria. Before imaging, each participant was given the required level of training and was then asked to complete four olfactory tests involving pleasant and unpleasant odors, air, and null stimulation. The results of Seed-based analysis suggested a function connection between the inferior parietal region and the left frontal pole region upon olfactory stimulation with vanilla scent in contrast to null stimulation in this comparison, ROI-based analysis revealed an inverse synchronous among the entorhinal cortex, orbitofrontal cortex, and dorsolateral prefrontal cortex (dlPFC). Both dlPFC and hippocampus were involved in olfactory discrimination between two different stimulants. Our findings indicate the presence of inverse correlations between several regions associated with olfaction and working memory, with pleasant scents leaving a stronger impact on the working memory-related areas, particularly the inferior parietal region., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This is the largest study in North America investigating olfactory outcomes after pituitary surgery to date., Objective: Characterize factors associated with subjective olfactory dysfunction (OD) and worsened sinonasal quality-of-life (QOL) after endoscopic TSA., Methods: Patients undergoing primary TSA for secreting and non-secreting pituitary adenomas between 2017 and 2021 with pre- and post-operative SNOT-22 scores were included. Subjective OD was determined by the smell/taste dysfunction question on the SNOT-22 (smell-SNOT)., Results: 159 patients with pre- and post-operative SNOT-22 scores were included. Average total SNOT-22 scores worsened from pre-operative (16.91 ± 16.91) to POM1 (25.15 ± 20.83, P  < .001), with no difference from pre-operative (16.40 ± 15.88) to POM6 (16.27 ± 17.92, P  = .936) or pre-operative (13.63 ± 13.54) to POM12 (12.60 ± 16.45, P  = .651). Average smell-SNOT scores worsened from pre-operative (0.40 ± 1.27) to POM1 (2.09 ± 2.01, P  < .001), and pre-operative (0.46 ± 1.29) to POM6 (1.13 ± 2.45, P  = .002), with no difference from pre-operative (0.40 ± 1.07) to POM12 (0.71 ± 1.32, P  = .100). Female gender had a 0.9-point (95% CI 0.1 to 1.6) P  = .021, increase in smell-SNOT at POM1, resolving by POM6 (0.1 [-0.9 to 1.1], P  = .800) and POM12 (0.0 [-1.0 to 0.9], P  = .942). Septoplasty with tunnel approach had a 1.1 [0.2 to 2.0] out of 5-point ( P  = .023) increase in smell-SNOT at POM1, resolving by POM6 (0.2 [-1.1 to 1.6], P  = .764) and POM12 (0.4 [-0.9 to 1.6], P  = .567). Female gender had a 9.5 (4.0 to 15.1)-point ( P  = .001) increase in SNOT-22 scores at POM1, resolving by POM6 (3.4 [-3.0 to 9.8], P  = .292) and POM12 (6.4 [-5.4 to 18.2], P  = .276). Intra-operative CSF leak had an 8.6 [2.1 to 15.1]-point ( P  = .009) increase in SNOT-22 scores at POM1, resolving by POM6 (5.4 [-1.7 to 12.5], P  = .135), and POM12 (1.1 [-12.9 to 15.1], P  = .873)., Conclusion: Changes in subjective olfaction and sinonasal QOL after TSA may be associated with gender, operative approach, and intra-operative CSF leak, resolving 6-12 months post-operatively., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Fatigue poses risks to occupational health and safety, affecting individuals' work efficiency, physical health, and social security, as well as human wellbeing and quality of life. Olfactory interventions, due to their low interference, are considered promising strategies for mitigating fatigue and reducing occupational health hazards., Objective: The objective of this review is to bridge the current gaps in the literature by conducting a scoping review of olfactory interventions on human alertness. It aims to explore their application in various occupational settings and to provide comprehensive and practical guidance for the practical application of olfactory interventions in mitigating fatigue and reducing occupational risks., Methods: The literature research was conducted in English using electronic databases such as Web of Science. Keywords related to scent and fatigue and the review followed PRISMA Extension for Scoping Reviews and PICO framework., Results: 28 studies were included in this work. Participant characteristics, fatigue measurement methods, and scent intervention methods, such as types of scents, intervention strategies, and scent presentation systems, are thoroughly investigated and discussed. Additionally, the study places a specific emphasis on the applications and research within the field of scent interventions for fatigue driving. Olfactory interventions have been applied to populations in various occupational fields, demonstrating beneficial effects on both physiological and psychological fatigue., Conclusions: Olfactory intervention is effective and promising for enhancing alertness and improving the occupational environment. To provide detailed and practical guidance for the actual application of olfactory intervention in fatigue relief and reducing occupational health and safety hazards, further research into the potential mechanisms, applications, and efficacy assessment systems of fatigue-related olfactory interventions is necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Muthusamy and Fang.)

In the process of murder investigation, it is of great significance to find the discarded and buried human remains accurately. The main methods of searching for human remains include human visual search, aerial detection, geophysical technology, remote imaging technology and canine olfactory search technique. Canine olfactory search for human remains is a recognized time-effective and non-invasive search method, making dogs the most valuable search tool in forensic investigation. By systematically reviewing and summarizing relevant literature, and based on the theory of volatile organic compound produced by the decomposition of human remains, this paper explores the basic principle of the canine olfactory search technique for human remains. This paper also reviews the application of training canine search technique for human remains in forensic investigation by using human blood, tissue, cadaver putrefying fluid and odor substitutes as sniffing sources. The application prospect of canine olfactory search for human remains was prospected from the perspectives of detection of volatile organic compound during cadaver decay, development of odor substitutes and adsorption devices, and technology tactics used in canine training and use, to provide references for the relevant research of canine olfactory search for human remains in China.

Purpose: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH are characterized by low 18 F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (α-syn) in dermal sympathetic noradrenergic nerves by the α-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH., Methods: Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18 F-dopamine-derived radioactivity was 6000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased α-syn-TH colocalization index ≥ 1.57., Results: A total of 44 patients (31 LB, 13 non-LB nOH) had data for all three biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18 F-dopamine-derived radioactivity, low UPSIT scores, and high α-syn-TH colocalization indexes (p < 0.0001 each). Combining the three biomarkers completely separated the groups. Cluster analysis identified two distinct groups (p < 0.0001) independently of the clinical diagnosis, with one cluster corresponding exactly to LB nOH., Conclusion: LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased α-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Olfactory sensory neurons (OSNs) are one of a few neuron types that are generated continuously throughout life in mammals. The persistence of olfactory sensory neurogenesis beyond early development has long been thought to function simply to replace neurons that are lost or damaged through exposure to environmental insults. The possibility that olfactory sensory neurogenesis may also serve an adaptive function has received relatively little consideration, largely due to the assumption that the generation of new OSNs is stochastic with respect to OSN subtype, as defined by the single odorant receptor gene that each neural precursor stochastically chooses for expression out of hundreds of possibilities. Accordingly, the relative birthrates of different OSN subtypes are predicted to be constant and impervious to olfactory experience. This assumption has been called into question, however, by evidence that the birthrates of specific OSN subtypes can be selectively altered by manipulating olfactory experience through olfactory deprivation, enrichment, and conditioning paradigms. Moreover, studies of recovery of the OSN population following injury provide further evidence that olfactory sensory neurogenesis may not be strictly stochastic with respect to subtype. Here we review this evidence and consider mechanistic and functional implications of the prospect that specific olfactory experiences can regulate olfactory sensory neurogenesis rates in a subtype-selective manner., (© 2024 Wiley Periodicals LLC.)

In this paper, we described technique of platelet rich plasma injection into the olfactory cleft in a 22-year-old female with 24-month post-COVID-19 anosmia. The technique starts with the blood extraction and the isolation of PRP through a 10-min centrifugation. The supernatant was injected in nasal regions after a local anesthesia through a 0° rigid optic. Several points of .2-.5 mL were performed in the nasal septum in regard of the head of the middle turbine and in the head of the middle turbine in both sides. The baseline threshold, discrimination, and identification scores were 1, 8, and 0, and the Olfactory Disorder Questionnaire score was 51, respectively. The injection of PRP in olfactory cleft was done without complication and mild pain. The patient perception of recovery of smell sense occurred at 3-week post-injection. From this time, the smell sense progressively improved to the 2-month consultation. At 2-month post-injection, the TDI scores reached 16, 16, and 16 (48), while the Olfactory Disorder Questionnaire was 73. The injection of PRP into the olfactory cleft appears to be a safe and easiness new approach that may improve the recovery of smell sense. Future controlled studies are needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Emotions experienced within sleep mentation (dreaming) affect mental functioning in waking life. There have been attempts at enhancing dream emotions using olfactory stimulation. Odors readily acquire affective value, but to profoundly influence emotional processing, they should bear personal significance for the perceiver rather than be generally pleasant. The main objective of the present sleep laboratory study was to examine whether prolonged nocturnal exposure to self-selected, preferred ambient room odor while asleep influences emotional aspects of sleep mentation and valence of post-sleep core affect. We asked twenty healthy participants (12 males, mean age 25 ± 4 years) to pick a commercially available scented room diffuser cartridge that most readily evoked positively valenced mental associations. In weekly intervals, the participants attended three sessions. After the adaptation visit, they were administered the odor exposure and odorless control condition in a balanced order. Participants were awakened five minutes into the first rapid eye movement (REM) stage that took place after 2:30 a.m. and, if they had been dreaming, they were asked to rate their mental sleep experience for pleasantness, emotional charge, and magnitude of positive and negative emotions and also to evaluate their post-sleep core affect valence. With rs < 0.20, no practically or statistically significant differences existed between exposure and control in any outcome measures. We conclude that in young, healthy participants, the practical value of olfactory stimulation with self-selected preferred scents for enhancement of dream emotions and post-sleep core affect valence is very limited., (© 2024. The Author(s).)

Objective: To evaluate the olfactory acuity and quality of life in patients who have undergone total laryngectomy. The study also aims to identify any specific patient-related risk factors linked to worse olfactory outcomes., Methods: This is a prospective cross-sectional study conducted at the University Malaya Medical Centre. A total of 30 patients who have undergone total laryngectomy were assessed objectively using the Sniffin' Sticks test and compared against normal age-matched Malaysians. Subsequently, they also filled out the modified Questionnaire on Olfactory Disorders. Correlations of patient demographics, disease and treatment variables against olfactory outcomes were conducted., Results: All subjects suffered olfactory impairment, with 66.7% of them being anosmic after total laryngectomy. The Sniffin' Sticks test demonstrated a statistically significant difference between laryngectomees and the normal age-matched Malaysian population in all three subtests for odor threshold, discrimination and identification. 37% of patients developed olfactory adaptive methods, which resulted in higher olfactory scores and a better quality of life. There were no patient demographics, disease or treatment variables associated with a poorer olfactory outcome identified., Conclusion: Olfactory impairment should not be overlooked among patients after total laryngectomy. Although as many as a third of patients developed some sort of olfactory adaptive behavior, early rehabilitation should be integrated into the multidisciplinary rehabilitation program after total laryngectomy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Manganese (Mn) is an essential micronutrient as well as a well-established neurotoxicant. Occupational and environmental exposures may bypass homeostatic regulation and lead to increased systemic Mn levels. Translocation of ultrafine ambient airborne particles via nasal neuronal pathway to olfactory bulb and tract may be an important pathway by which Mn enters the central nervous system., Objective: To measure olfactory tract/bulb tissue metal concentrations in Mn-exposed and non-exposed mineworkers., Methods: Using inductively coupled plasma-mass spectrometry (ICP-MS), we measured and compared tissue metal concentrations in unilateral olfactory tracts/bulbs of 24 Mn-exposed and 17 non-exposed South African mineworkers. We used linear regression to investigate the association between cumulative Mn exposures and olfactory tract/bulb Mn concentration., Results: The difference in mean olfactory tract/bulb Mn concentrations between Mn-exposed and non-Mn exposed mineworkers was 0.16 µg/g (95% CI -0.11, 0.42); but decreased to 0.09 µg/g (95% CI 0.004, 0.18) after exclusion of one influential observation. Olfactory tract/bulb metal concentration and cumulative Mn exposure suggested there may be a positive association; for each mg Mn/m 3 -year there was a 0.05 µg/g (95% CI 0.01, 0.08) greater olfactory tract/bulb Mn concentration overall, but -0.003 (95% CI -0.02, 0.02) when excluding the three influential observations. Recency of Mn exposure was not associated with olfactory tract/bulb Mn concentration., Conclusions: Our findings suggest that Mn-exposed mineworkers might have higher olfactory tract/bulb tissue Mn concentrations than non-Mn exposed mineworkers, and that concentrations might depend more on cumulative dose than recency of exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cilia are fascinating organelles that act as cellular antennae, sensing the cellular environment. Cilia gained significant attention in the late 1990s after their dysfunction was linked to genetic diseases known as ciliopathies. Since then, several breakthrough discoveries have uncovered the mechanisms underlying cilia biogenesis and function. Like most cells in the animal kingdom, neurons also harbor cilia, which are enriched in neuromodulatory receptors. Yet, how neuronal cilia modulate neuronal physiology and animal behavior remains poorly understood. By comparing ciliary biology between the sensory and central nervous systems (CNS), we provide new perspectives on the functions of cilia in brain physiology., Competing Interests: Declaration of interests The authors declare no competing interests in relation to this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Among the numerous long COVID symptoms, olfactory dysfunction persists in ∼10 % of patients suffering from SARS-CoV-2 induced anosmia. Among the few potential therapies, corticoid treatment has been used for its anti-inflammatory effect with mixed success in patients. In this study, we explored its impact using hamster as an animal model. SARS-CoV-2 infected hamsters lose their smell abilities and this loss is correlated with damage of the olfactory epithelium and persistent presence of innate immunity cells. We started a dexamethasone treatment 2 days post infection, when olfaction was already impacted, until 11 days post infection when it started to recover. We observed an improvement of olfactory capacities in the animals treated with corticoid compared to those treated with vehicle. This recovery was not related to differences in the remaining damage to the olfactory epithelium, which was similar in both groups. This improvement was however correlated with a reduced inflammation in the olfactory epithelium with a local increase of the mature olfactory neuron population. Surprisingly, at 11 days post infection, we observed an increased and disorganized presence of immature olfactory neurons, especially in persistent inflammatory zones of the epithelium. This unusual population of immature olfactory neurons coincided with a strong increase of olfactory epithelium proliferation in both groups. Our results indicate that persistent inflammation of the olfactory epithelium following SARS-CoV-2 infection may alter the extent and speed of regeneration of the olfactory neuron population, and that corticoid treatment is effective to limit inflammation and improve olfaction recovery following SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical characteristics associated with measured gustatory dysfunction in patients with chemosensory (smell and taste) discomfort., Study Design: Retrospective study., Design: Hospital-based cohort., Setting: The clinical characteristics associated with the measured diagnosis of gustatory dysfunction were statistically analysed., Participants: Patients who underwent all the psychophysical olfactory and chemical gustatory function tests (YSK olfactory function test and chemical gustometry exam) and the subjective questionnaires between October 2021 and February 2023., Main Outcome Measures: YSK olfactory function test and chemical gustometry results, subjective questionnaire score about chemosensory (smell and taste) functions. The Medical records of patients who visited the smell and taste centre in a tertiary., Results: A total of 219 patients were enrolled; 180 were diagnosed as having normal gustatory function, and 39 were diagnosed as having gustatory dysfunction. Subjective recognition of gustatory function was not associated with the measured gustatory function. Age, sex, measured olfactory function and the threshold and discrimination scores for the olfactory function test were significant factors in the multivariate analysis. When the patients were further divided according to age, the threshold test scores rather than other subsets in the olfactory function test were significantly associated with measured gustatory dysfunction in patients 60 and older., Conclusion: In older adult male patients with olfactory dysfunction, gustatory function should be considered regardless of subjective gustatory dysfunction., (© 2024 John Wiley & Sons Ltd.)

The Sitophilus zeamais (maize weevil) and Sitophilus oryzae (rice weevil) are two insect pests that have caused huge economic losses to stored grains worldwide. It is urgent to develop an environmentally friendly strategy for the control of these destructive pests. Here, the olfactory-mediated selection preference of the two weevil species to three stored grains was analyzed, which should help establish a pull-push system in managing them. Bioassays showed that maize weevil adults prefer to select maize, followed by paddy and wheat, while rice weevil adults mainly migrate towards wheat. Volatile analyses revealed that 2-ethylhexanol, piperitone, and (+)-Δ-cadiene are the major components in volatiles from both maize and wheat, but the abundance of these chemicals is much lower in maize than that in wheat. The volatile limonene was only detected in paddy. Y-tube bioassays suggest that 2-ethylhexanol, piperitone, and (+)-Δ-cadiene were all attractive to both weevils, whereas limonene was attractive only to rice weevils. Overall, maize weevil appeared more sensitive to the tested volatiles based on having much lower effective concentrations of these volatiles needed to attract them. The differences in volatile profiles among the grains and the sensitivity of the two species towards these volatiles may explain the behavioral differences between maize and rice weevils in selecting host grains. The differences in sensitivity of maize and rice weevils towards host volatile components with abundance differences are likely determinants driving the two insect species to migrate towards different host grains., Competing Interests: The authors declare no conflicts of interest.

Aims: The aim of the study was to analyze objective and subjective olfactory/gustatory function in post-COVID-19 infection (PCI)., Materials and Methods: Patients with past PCR-confirmed COVID-19 infection and persistent olfactory/gustatory complaints were investigated. Olfactory threshold and identification, gustatory detection, identification, and magnitude scaling were tested., Results: A total of 42 PCI subjects were compared to 41 age- and gender-matched controls with no COVID-19 history. All PCI tested had mild COVID-19 disease. Mean interval between COVID-19 confirmations to testing was 7.4 ± 3.1 months. PCI subjects complained of combined dysfunction in 85.7%, isolated olfactory or gustatory dysfunction in 7.1% each. Combined complaints were significantly higher in PCI (p < 0.001). Objective testing showed significantly higher prevalence of dysfunction in PCI versus controls for hyposmia (73.8%, 12.2%), anosmia (11.9%, 0%), odor identification (68.5%, 83.0%), hypogeusia (23% and 2.4%, respectively), and impaired magnitude scaling, (p < 0.05). All PCI subjects with hypogeusia had abnormal gustatory magnitude scaling., Conclusions: While most PCI subjects complained of combined gustatory and olfactory dysfunction, objective testing showed in the majority an isolated single sense dysfunction, with a low level of agreement between subjective and objective findings. Abnormal objective results for all olfactory and gustatory functions tested may suggest a central rather than peripheral mechanism, although concomitant mechanisms cannot be excluded., (© 2023 Wiley Periodicals LLC.)

Introduction: The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products., Areas Covered: This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines., Expert Opinion: As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.

Introduction: Cumulative evidence suggests that sensory cortices interact with the basolateral amygdala (BLA) defense circuitry to mediate threat conditioning, memory retrieval, and extinction learning. The olfactory piriform cortex (PC) has been posited as a critical site for olfactory associative memory. Recently, we have shown that N-methyl-D-aspartate receptor (NMDAR)-dependent plasticity in the PC critically underpins olfactory threat extinction. Aging-associated impairment of olfactory threat extinction is related to the hypofunction of NMDARs in the PC., Methods: In this study, we investigated activation of neuronal cFos and epigenetic marks in the BLA and PC using immunohistochemistry, following olfactory threat conditioning and extinction learning in rats., Results: We found highly correlated cFos activation between the posterior PC (pPC) and BLA. cFos was correlated with the degree of behavioral freezing in the pPC in both adult and aged rats, and in the BLA only in adult rats. Markers of DNA methylation 5 mC and histone acetylation H3K9/K14ac, H3K27ac, and H4ac exhibited distinct training-, region-, and age-dependent patterns of activation. Strong correlations of epigenetic marks between the BLA and pPC in adult rats were found to be a general feature. Conversely, aged rats only exhibited correlations of H3 acetylations between the two structures. Histone acetylation varied as a function of aging, revealed by a reduction of H3K9/K14ac and an increase of H4ac in aged brains at basal condition and following threat conditioning., Discussion: These findings underscore the coordinated role of PC and BLA in olfactory associative memory storage and extinction, with implications for understanding aging related cognitive decline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qin, Xia, Nazari, Sepahvand and Yuan.)

The olfactory region of the nasal cavity directly links the brain to the external environment, presenting a potential direct route to the central nervous system (CNS). However, targeting drugs to the olfactory region is challenging and relies on a combination of drug formulation, delivery device, and administration technique to navigate human nasal anatomy. In addition, in vitro and in vivo models utilized to evaluate the performance of nasal formulations do not accurately reflect deposition and uptake in the human nasal cavity. The current study describes the development of a respirable poly(lactic- co -glycolic acid) nanoparticle (PLGA NP) formulation, delivered via a pressurized metered dose inhaler (pMDI), and a cell-containing three-dimensional (3D) human nasal cast model for deposition assessment of nasal formulations in the olfactory region. Fluorescent PLGA NPs (193 ± 3 nm by dynamic light scattering) were successfully formulated in an HFA134a-based pMDI and were collected intact following aerosolization. RPMI 2650 cells, widely employed as a nasal epithelial model, were grown at the air-liquid interface (ALI) for 14 days to develop a suitable barrier function prior to exposure to the aerosolized PLGA NPs in a glass deposition apparatus. Direct aerosol exposure was shown to have little effect on cell viability. Compared to an aqueous NP suspension, the transport rate of the aerosolized NPs across the RPMI 2650 barrier was higher at all time points indicating the potential advantages of delivery via aerosolization and the importance of employing ALI cellular models for testing respirable formulations. The PLGA NPs were then aerosolized into a 3D-printed human nasal cavity model with an insert of ALI RPMI 2650 cells positioned in the olfactory region. Cells remained highly viable, and there was significant deposition of the fluorescent NPs on the ALI cultures. This study is a proof of concept that pMDI delivery of NPs is a viable means of targeting the olfactory region for nose-to-brain drug delivery (NTBDD). The cell-based model allows not only maintenance under ALI culture conditions but also sampling from the basal chamber compartment; hence, this model could be adapted to assess drug deposition, uptake, and transport kinetics in parallel under real-life settings.

Purpose: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH entail low 18 F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (ɑ-syn) in dermal sympathetic noradrenergic nerves by the ɑ-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH., Methods: Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18 F-dopamine-derived radioactivity was 6,000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased ɑ-syn-TH colocalization index ≥ 1.57., Results: A total of 44 patients (31 LB, 13 non-LB nOH) had data for all 3 biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18 F-dopamine-derived radioactivity, low UPSIT scores, and high ɑ-syn-TH colocalization indexes (p<0.0001 each). Combining the 3 biomarkers completely separated the groups. Cluster analysis identified 2 distinct groups (p<0.0001) independently of the clinical diagnosis, 1 cluster corresponding exactly to LB nOH., Conclusion: LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased ɑ-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients., Competing Interests: CONFLICTS OF INTEREST: The authors have no conflicts of interest to disclose.

The blood-brain barrier presents a key limitation to the administration of therapeutic molecules for the treatment of brain disease. While drugs administered orally or intravenously must cross this barrier to reach brain targets, the unique anatomical structure of the olfactory system provides a route to deliver drugs directly to the brain. Entering the brain via receptor, carrier, and adsorption-mediated transcytosis in the nasal olfactory and trigeminal regions has the potential to increase drug delivery. In this review, we introduce the physiological and anatomical structures of the nasal cavity, and summarize the possible modes of transport and the relevant receptors and carriers in the nose-to-brain pathway. Additionally, we provide examples of nanotherapeutics developed for intranasal drug delivery to the brain. Further development of nanoparticles that can be applied to intranasal delivery systems promises to improve drug efficacy and reduce drug resistance and adverse effects by increasing molecular access to the brain. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease., (© 2024 Wiley Periodicals LLC.)

Hippocampal networks required for associative memory formation are involved in cue- and context-dependent threat conditioning. The hippocampus is functionally heterogeneous at its dorsal and ventral poles, and recent investigations have focused on the specific roles required from each sub-region for associative conditioning. Cumulative evidence suggests that contextual and emotional information is processed by the dorsal and ventral hippocampus, respectively. However, it is not well understood how these two divisions engage in threat conditioning with cues of different sensory modalities. Here, we compare the involvement of the dorsal and ventral hippocampus in two types of threat conditioning: olfactory and auditory. Our results suggest that the dorsal hippocampus encodes contextual information and is activated upon recall of an olfactory threat memory only if contextual cues are relevant to the threat. Overnight habituation to the context eliminates dorsal hippocampal activation, implying that this area does not directly support cue-dependent threat conditioning. The ventral hippocampus is activated upon recall of olfactory, but not auditory, threat memory regardless of habituation duration. Concurrent activation of the piriform cortex is consistent with its direct connection with the ventral hippocampus. Together, our study suggests a unique role of the ventral hippocampus in olfactory threat conditioning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sepahvand, Carew and Yuan.)

Sequential neural dynamics encoded by time cells play a crucial role in hippocampal function. However, the role of hippocampal sequential neural dynamics in associative learning is an open question. We used two-photon Ca 2+ imaging of dorsal CA1 (dCA1) neurons in the stratum pyramidale (SP) in head-fixed mice performing a go-no go associative learning task to investigate how odor valence is temporally encoded in this area of the brain. We found that SP cells responded differentially to the rewarded or unrewarded odor. The stimuli were decoded accurately from the activity of the neuronal ensemble, and accuracy increased substantially as the animal learned to differentiate the stimuli. Decoding the stimulus from individual SP cells responding differentially revealed that decision-making took place at discrete times after stimulus presentation. Lick prediction decoded from the ensemble activity of cells in dCA1 correlated linearly with lick behavior. Our findings indicate that sequential activity of SP cells in dCA1 constitutes a temporal memory map used for decision-making in associative learning. VIDEO ABSTRACT., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)