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Purpose: Menopause is associated with a decrease in smell discrimination ability. This study assessed the impact of black cohosh on hippocampal (HC) and hypothalamic (HT) gene expression profiles in rats, to understand, if herbal treatment has an impact on neurologic changes due to menopause and whether this could address a decrease in smell discrimination. Methods: HC and HT tissues from female Sprague Dawley rats (total n = 19) were analyzed at three different life stages: intact tissues of the HC (n = 4) and the HT (n = 4), oophorectomized tissues 3 months after oophorectomy (OVX) of the HC (n = 4) and the HT (n = 3), and tissues after treatment with an isopropanolic extract (iCR) from the rhizomes of black cohosh (60 mg/kg) for 3 months after OVX of the HC (n = 2) and the HT (n = 2). Main outcome measures: To reveal underlying biological processes a gene set enrichment analysis (GSEA) was performed. Results: The GSEA revealed gene ontology terms that were significantly enriched, including several genes associated with the olfactory system, indicating biological processes regulated by treatment with iCR. Six olfactory receptor genes were further analyzed by another GSEA, demonstrating the possibility of iCR treatment to compensate for oophorectomy-induced changes. Conclusion: Findings suggest that herbal treatment, such as iCR, has an esteeming impact on HC and HT genes that are changed through menopause. Further studies are needed to suggest black cohosh as a treatment option for decreased smell discrimination. [ABSTRACT FROM AUTHOR]

Purpose: The loss of olfactory function is known to occur in patients suffering from (behavioral variant) frontotemporal dementia ((bv)FTD) and Alzheimer's disease (AD), although different pathophysiological mechanisms underpin this clinical symptom in both disorders. This study assessed whether brain metabolism of the olfactory circuit as assessed by positron emission tomography (PET) imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose ([18F]-FDG) can distinguish these entities in different subsets of patients. Methods: Patients presenting with cognitive decline were included from a prospectively kept database: (1) bvFTD patients, (2) AD patients and (3) patients with logopenic primary progressive aphasia (PPA). Metabolic rates were calculated for different regions of the olfactory circuit for each subgroup and compared with a cohort of subjects with normal brain metabolism. Additionally, in patients with a logopenic PPA pattern on PET-imaging, statistical parametric mapping (SPM) analysis was performed. Results: The metabolism of subdivisions of the olfactory circuit as assessed by [18F]-FDG PET brain imaging to bvFTD and AD from control subjects resulted in sensitivity/specificity rates of 95/87.5% and 80/83.3%, respectively. A sensitivity/specificity rate of 100/87.5% was achieved when used to differentiate AD from bvFTD. In patients with the PPA pattern on imaging, the underlying cause (either FTD or AD) could be determined with a sensitivity/specificity rate of 88/82%. SPM analysis concurred that different regions of the olfactory circuit were affected in patients suffering from AD PPA or bvFTD PPA. Conclusion: Metabolic dysfunction in the olfactory circuit is different in various neurodegenerative disorders. Further investigation of the correlations between the cerebral metabolism and the mechanisms which drive olfactory dysfunction is needed. [ABSTRACT FROM AUTHOR]

ABSTRACT The mammalian olfactory system is one of the most precocious sensory systems during development and is innately endowed with versatile functions distinct from other sensory systems. Perception of time‐locked olfaction‐related stimuli quickly from the external environment and encoding them accurately via the olfactory system is paramount for the survival and reproduction in the animal kingdom. The olfactory system of mammals encompasses the main and accessory parts. As one key component of the ventral striatum, the olfactory tubercle (OT), is also an important as well as indispensable sub‐region of the main olfactory system and plays a crucial role in the central processing of odours. The OT also serves as a hub linking the olfactory system with the reward system in the brain. Although extensive research has underscored the involvement of the ventral striatum in the reward and punishment process as well as motivational behaviour, the encoding mechanism of neural circuits engaged in odour detection and recognition by the OT is still largely unknown. Herein, we make a brief overview of the olfactory system and underscore the crucial role of olfactory receptors in odour detection. We also emphasize the structural and functional characterisations of the OT and corresponding neural circuits involved in odour processing. [ABSTRACT FROM AUTHOR]

Since zinc oxide (ZnO) nanoparticles (NPs) have been widely applied, the nano community and the general public have paid great attention to the toxicity of ZnO NPs. We detected 20-nm ZnO NPs biotoxicity following nasal exposure utilizing the non-invasive and real-time magnetic resonance imaging (MRI) technique. MR images were scanned in the rat olfactory epithelium (OE) and olfactory bulb (OB) on a 4.7 T scanner following the treatment (as early as 1 day and up to 21 days after), and the histological changes were evaluated. The influence of the size of the ZnO NPs and chemical components was also investigated. Our study revealed that 20-nm ZnO NPs induced obvious structural disruption and inflammation in the OE and OB at the acute stage. The results suggest that the real-time and non-invasive advantages of MRI allow it to observe and assess, directly and dynamically, the potential toxicity of long-term exposure to ZnO NPs in the olfactory system. These findings indicate the size-dependent toxicity of ZnO NPs with respect to the olfactory bulb. Further study is needed to reveal the mechanism behind ZnO NPs' toxicity. [ABSTRACT FROM AUTHOR]

Voluntary behaviors such as sniffing, moving, and eating require decision-making accompanied by intentional respiration. Based on the study of respirationcoherent activity of rodent olfactory networks, we infer that during the inhalation phase of respiration, olfactory cortical areas process environmental odor information and transmit it to the higher multisensory cognitive areas via feedforward pathways to comprehensively evaluate the surrounding situation. We also infer that during the exhalation phase, the higher multisensory areas generate cognitive-signals and transmit them not only to the behavioral output system but also back to the olfactory cortical areas. We presume that the cortical mechanism couples the intentional respiration with the voluntary behaviors. Thus, in one respiratory cycle, the mammalian brain may transmit and process sensory information to cognize and evaluate the multisensory image of the external world, leading to one behavioral decision and one emotional expression. In this perspective article, we propose that one respiratory cycle provides a minimum time unit for decision making during wakefulness. [ABSTRACT FROM AUTHOR]

Cellular communication network factor 2 (CCN2) is a matricellular protein that plays important roles in connective tissue. CCN2 is also expressed in the nervous system; however, its role is still unclear. To explore CCN2 function in the brain, we generated forebrain‐specific Ccn2 knockout (FbCcn2 KO) mice. In this study, we examined the behavioral phenotypes of FbCcn2KO mice. Male mice lacking CCN2 in the forebrain exhibited normal locomotion, sensorimotor gating, and social behaviors but signs of anxiety and elevated reactive aggression. We checked the c‐fos expression in aggression‐related brain regions following the resident‐intruder task (RIT), an aggression test. RIT‐induced c‐fos levels in the medial amygdala (MeA) were higher in FbCcn2−/− mice as compared to controls. However, in the prefrontal cortex, RIT‐induced c‐fos levels in FbCcn2−/− mice were lower than controls. Our results suggested in male mice lacking CCN2 in the olfaction‐related regions, olfactory social cues elicit greater signals in the MeA, resulting in greater reactive aggression in the RIT. Further, lacking CCN2 in the prefrontal cortex, the major area related to inhibitory control and emotion regulation, may lead to signs of anxiety and the failure to suppress aggressive behaviors. Our model is useful in elaborating the mechanism underlying reactive aggression and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract Purpose The loss of olfactory function is known to occur in patients suffering from (behavioral variant) frontotemporal dementia ((bv)FTD) and Alzheimer’s disease (AD), although different pathophysiological mechanisms underpin this clinical symptom in both disorders. This study assessed whether brain metabolism of the olfactory circuit as assessed by positron emission tomography (PET) imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose ([18F]-FDG) can distinguish these entities in different subsets of patients. Methods Patients presenting with cognitive decline were included from a prospectively kept database: (1) bvFTD patients, (2) AD patients and (3) patients with logopenic primary progressive aphasia (PPA). Metabolic rates were calculated for different regions of the olfactory circuit for each subgroup and compared with a cohort of subjects with normal brain metabolism. Additionally, in patients with a logopenic PPA pattern on PET-imaging, statistical parametric mapping (SPM) analysis was performed. Results The metabolism of subdivisions of the olfactory circuit as assessed by [18F]-FDG PET brain imaging to bvFTD and AD from control subjects resulted in sensitivity/specificity rates of 95/87.5% and 80/83.3%, respectively. A sensitivity/specificity rate of 100/87.5% was achieved when used to differentiate AD from bvFTD. In patients with the PPA pattern on imaging, the underlying cause (either FTD or AD) could be determined with a sensitivity/specificity rate of 88/82%. SPM analysis concurred that different regions of the olfactory circuit were affected in patients suffering from AD PPA or bvFTD PPA. Conclusion Metabolic dysfunction in the olfactory circuit is different in various neurodegenerative disorders. Further investigation of the correlations between the cerebral metabolism and the mechanisms which drive olfactory dysfunction is needed.

AbstractIn recent times, the nasal region has emerged as a distinctive and dynamic environment where a myriad of microbial communities establish residence from infancy, persisting as both commensal and opportunistic pathogens throughout the lifespan. Understanding the coexistence of microorganisms in respiratory mucosal layers, their potential for infections, and the underlying molecular mechanisms shaping these interactions is crucial for developing efficient diagnostic and therapeutic interventions against respiratory and neurodegenerative diseases. Despite significant strides in understanding the olfactory system’s nexus with nasal microbiota, comprehensive correlations with neurological diseases still need to be discovered. The nasal microbiome, a sentinel in immune defense, orchestrates a delicate equilibrium that, when disrupted, can precipitate severe respiratory infections, including Chronic Rhinosinusitis, Chronic obstructive pulmonary disorder (COPD), and Asthma, and instigate a cascade effect on central nervous system diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple sclerosis (MS). This review aims to redress this imbalance by meticulously exploring the anatomical and microbiological nuances of the nasal mucosal surface in health and disease. By delineating the molecular intricacies of these interactions, this review unravels the molecular mechanisms that govern the intricate nexus between nasal microbiota dysbiosis, olfactory dysfunction, and the progression of respiratory and neurological diseases. [ABSTRACT FROM AUTHOR]

Humans naturally integrate signals from the olfactory and intranasal trigeminal systems. A tight interplay has been demonstrated between these two systems, and yet the neural circuitry mediating olfactory–trigeminal (OT) integration remains poorly understood. Using functional magnetic resonance imaging (fMRI), combined with psychophysics, this study investigated the neural mechanisms underlying OT integration. Fifteen participants with normal olfactory function performed a localization task with air‐puff stimuli, phenylethyl alcohol (PEA; rose odor), or a combination thereof while being scanned. The ability to localize PEA to either nostril was at chance. Yet, its presence significantly improved the localization accuracy of weak, but not strong, air‐puffs, when both stimuli were delivered concurrently to the same nostril, but not when different nostrils received the two stimuli. This enhancement in localization accuracy, exemplifying the principles of spatial coincidence and inverse effectiveness in multisensory integration, was associated with multisensory integrative activity in the primary olfactory (POC), orbitofrontal (OFC), superior temporal (STC), inferior parietal (IPC) and cingulate cortices, and in the cerebellum. Multisensory enhancement in most of these regions correlated with behavioral multisensory enhancement, as did increases in connectivity between some of these regions. We interpret these findings as indicating that the POC is part of a distributed brain network mediating integration between the olfactory and trigeminal systems. Practitioner Points: Psychophysical and neuroimaging study of olfactory–trigeminal (OT) integration.Behavior, cortical activity, and network connectivity show OT integration.OT integration obeys principles of inverse effectiveness and spatial coincidence.Behavioral and neural measures of OT integration are correlated. [ABSTRACT FROM AUTHOR]

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood–brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted. [ABSTRACT FROM AUTHOR]

Abstract The phenomenon of contagious itch, observed in both humans and rodents, remains a topic of ongoing debate concerning its modulators and underlying pathways. This study delves into the relationship between contagious itch and familiar olfactory cues, a non-visual factor contributing to this intriguing behavior. Our findings showed that contagious itch in observer mice occurs during physical interaction with the cagemate itch-demonstrator but not with a stranger demonstrator or in a non-physical encounter condition. Notably, itch-experienced observer mice displayed an increased contagious itch behavior, highlighting the relevance of itch-associated memory in this phenomenon. Furthermore, anosmic observer mice, whether itch-naïve or itch-experienced, displayed no contagious itch behavior. These results demonstrate that the familiar olfactory cues, specifically cagemate body odors, are required for contagious itch behaviors in mice. In line with these behavioral findings, our study reveals increased activity in brain regions associated with olfaction, emotion, and memory during contagious itch, including the olfactory bulb, the amygdala, the hypothalamus, and the hippocampus, with this activity diminished in anosmic mice. In conclusion, our study unveils the critical role of familiar olfactory cues in driving contagious itch in mice, shedding light on the interplay between social factors, sensory perception, and memory in this phenomenon.

Fetal Alcohol Spectrum Disorders (FASD), resulting from maternal alcohol consumption during pregnancy, are a prominent non-genetic cause of physical disabilities and brain damage in children. Alongside common symptoms like distinct facial features and neurocognitive deficits, sensory anomalies, including olfactory dysfunction, are frequently noted in FASD-afflicted children. However, the precise mechanisms underpinning the olfactory abnormalities induced by prenatal alcohol exposure (PAE) remain elusive. Utilizing rodents as a model organism with varying timing, duration, dosage, and administration routes of alcohol exposure, prior studies have documented impairments in olfactory system development caused by PAE. Many reported a reduction in the olfactory bulb (OB) volume accompanied by reduced OB neuron counts, suggesting the OB is a brain region vulnerable to PAE. In contrast, no significant olfactory system defects were observed in some studies, though subtle alterations might exist. These findings suggest that the timing, duration, and extent of fetal alcohol exposure can yield diverse effects on olfactory system development. To enhance comprehension of PAE-induced olfactory dysfunctions, this review summarizes key findings from previous research on the olfactory systems of offspring prenatally exposed to alcohol. [ABSTRACT FROM AUTHOR]

The phenomenon of contagious itch, observed in both humans and rodents, remains a topic of ongoing debate concerning its modulators and underlying pathways. This study delves into the relationship between contagious itch and familiar olfactory cues, a non-visual factor contributing to this intriguing behavior. Our findings showed that contagious itch in observer mice occurs during physical interaction with the cagemate itch-demonstrator but not with a stranger demonstrator or in a non-physical encounter condition. Notably, itch-experienced observer mice displayed an increased contagious itch behavior, highlighting the relevance of itch-associated memory in this phenomenon. Furthermore, anosmic observer mice, whether itch-naïve or itch-experienced, displayed no contagious itch behavior. These results demonstrate that the familiar olfactory cues, specifically cagemate body odors, are required for contagious itch behaviors in mice. In line with these behavioral findings, our study reveals increased activity in brain regions associated with olfaction, emotion, and memory during contagious itch, including the olfactory bulb, the amygdala, the hypothalamus, and the hippocampus, with this activity diminished in anosmic mice. In conclusion, our study unveils the critical role of familiar olfactory cues in driving contagious itch in mice, shedding light on the interplay between social factors, sensory perception, and memory in this phenomenon. [ABSTRACT FROM AUTHOR]

Maintenance and regeneration of the zebrafish olfactory epithelium (OE) are supported by two distinct progenitor cell populations that occupy spatially discrete stem cell niches and respond to different tissue conditions. Globose basal cells (GBCs) reside at the inner and peripheral margins of the sensory OE and are constitutively active to replace sporadically dying olfactory sensory neurons (OSNs). In contrast, horizontal basal cells (HBCs) are uniformly distributed across the sensory tissue and are selectively activated by acute injury conditions. Here we show that expression of the heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is strongly and transiently upregulated in response to OE injury and signals through the EGF receptor (EGFR), which is expressed by HBCs. Exogenous stimulation of the OE with recombinant HB‐EGF promotes HBC expansion and OSN neurogenesis in a pattern that resembles the tissue response to injury. In contrast, pharmacological inhibition of HB‐EGF membrane shedding, HB‐EGF availability, and EGFR signaling strongly attenuate or delay injury‐induced HBC activity and OSN restoration without affecting maintenance neurogenesis by GBCs. Thus, HB‐EGF/EGFR signaling appears to be a critical component of the signaling network that controls HBC activity and, consequently, repair neurogenesis in the zebrafish OE. [ABSTRACT FROM AUTHOR]

The excitatory neurotransmitter glutamate has a role in neuronal migration and process elongation in the central nervous system (CNS). The effects of chronic glutamate hyperactivity on vesicular and protein transport within CNS neurons, that is, processes necessary for neurite growth, have not been examined previously. In this study, we measured the effects of lifelong hyperactivity of glutamate neurotransmission on axoplasmic transport in CNS neurons. We compared wild-type (wt) to transgenic (Tg) mice over-expressing the glutamate dehydrogenase gene Glud1 in CNS neurons and exhibiting increases in glutamate transmitter formation, release, and synaptic activation in brain throughout the lifespan. We found that Glud1 Tg as compared with wt mice exhibited increases in the rate of anterograde axoplasmic transport in neurons of the hippocampus measured in brain slices ex vivo, and in olfactory neurons measured in vivo. We also showed that the in vitro pharmacologic activation of glutamate synapses in wt mice led to moderate increases in axoplasmic transport, while exposure to selective inhibitors of ion channel forming glutamate receptors very significantly suppressed anterograde transport, suggesting a link between synaptic glutamate receptor activation and axoplasmic transport. Finally, axoplasmic transport in olfactory neurons of Tg mice in vivo was partially inhibited following 14-day intake of ethanol, a known suppressor of axoplasmic transport and of glutamate neurotransmission. The same was true for transport in hippocampal neurons in slices from Glud1 Tg mice exposed to ethanol for 2 h ex vivo. In conclusion, endogenous activity at glutamate synapses regulates and glutamate synaptic hyperactivity increases intraneuronal transport rates in CNS neurons. [ABSTRACT FROM AUTHOR]

Dysfunctional sensory systems, including altered olfactory function, have recently been reported in patients with autism spectrum disorder (ASD). Disturbances in olfactory processing can potentially result from gamma-aminobutyric acid (GABA)ergic synaptic abnormalities. The specific molecular mechanism by which GABAergic transmission affects the olfactory system in ASD remains unclear. Therefore, the present study aimed to evaluate selected components of the GABAergic system in olfactory brain regions and primary olfactory neurons isolated from Shank3-deficient (−/−) mice, which are known for their autism-like behavioral phenotype. Shank3 deficiency led to a significant reduction in GEPHYRIN/GABAAR colocalization in the piriform cortex and in primary neurons isolated from the olfactory bulb, while no change of cell morphology was observed. Gene expression analysis revealed a significant reduction in the mRNA levels of GABA transporter 1 in the olfactory bulb and Collybistin in the frontal cortex of the Shank3−/− mice compared to WT mice. A similar trend of reduction was observed in the expression of Somatostatin in the frontal cortex of Shank3−/− mice. The analysis of the expression of other GABAergic neurotransmission markers did not yield statistically significant results. Overall, it appears that Shank3 deficiency leads to changes in GABAergic synapses in the brain regions that are important for olfactory information processing, which may represent basis for understanding functional impairments in autism. [ABSTRACT FROM AUTHOR]

Parallel processing is a fundamental strategy of sensory coding. Through this processing, unique and distinct features of sensations are computed and projected to the central targets. This review proposes that mitral and tufted cells, which are the second-order projection neurons in the olfactory bulb, contribute to parallel processing within the olfactory system. Based on anatomical and functional evidence, I discuss potential features that could be conveyed through the unique channel formed by these neurons. [ABSTRACT FROM AUTHOR]

When we are asleep, we lose the ability to promptly respond to external stimuli, and yet we spend many hours every day in this inherently risky behavioral state. This simple fact strongly suggests that sleep must serve essential functions that rely on the brain going offline, on a daily basis, and for long periods of time. If these functions did not require partial sensory disconnection, it would be difficult to explain why they are not performed during waking. Paradoxically, despite its central role in defining sleep and what sleep does, sensory disconnection during sleep remains a mystery. We have a limited understanding of how it is implemented along the sensory pathways; we do not know whether the same mechanisms apply to all sensory modalities, nor do we know to what extent these mechanisms are shared between non-rapid eye movement (NREM) sleep and REM sleep. The main goal of this contribution is to review some knowns and unknowns about sensory disconnection during sleep as a first step to fill this gap. [ABSTRACT FROM AUTHOR]

Abstract Background Alzheimer’s disease (AD) and Parkinson’s disease (PD), two common irreversible neurodegenerative diseases, share similar early stage syndromes, such as olfaction dysfunction. Yet, the potential comorbidity mechanism of AD and PD was not fully elucidated. Methods The gene expression profiles of GSE5281 and GSE8397 were downloaded from the Gene Expression Omnibus (GEO) database. We utilized a series of bioinformatics analyses to screen the overlapped differentially expressed genes (DEGs). The hub genes were further identified by the plugin CytoHubba of Cytoscape and validated in the hippocampus (HIP) samples of APP/PS-1 transgenic mice and the substantial nigra (SN) samples of A53T transgenic mice by real-time quantitative polymerase chain reaction (RT-qPCR). Meanwhile, the expression of the target genes in the olfactory epithelium/bulb was detected by RT-qPCR. Finally, molecular docking was used to screen potential compounds for the target gene. Results One hundred seventy-four overlapped DEGs were identified in AD and PD. Five of the top ten enrichment pathways mainly focused on the synapse. Five hub genes were identified and further validated. As a common factor in AD and PD, the changes of synaptosomal-associated protein 25 (SNAP25) mRNA in olfactory epithelium/bulb were significantly decreased and had a strong association with those in the HIP and SN samples. Pazopanib was the optimal compound targeting SNAP25, with a binding energy of − 9.2 kcal/mol. Conclusions Our results provided a theoretical basis for understanding the comorbidity mechanism of AD and PD and highlighted that SNAP25 in the olfactory epithelium may serve as a potential target for early detection and intervention in both AD and PD.

Since zinc oxide (ZnO) nanoparticles (NPs) have been widely applied, the nano community and the general public have paid great attention to the toxicity of ZnO NPs. We detected 20-nm ZnO NPs biotoxicity following nasal exposure utilizing the non-invasive and real-time magnetic resonance imaging (MRI) technique. MR images were scanned in the rat olfactory epithelium (OE) and olfactory bulb (OB) on a 4.7 T scanner following the treatment (as early as 1 day and up to 21 days after), and the histological changes were evaluated. The influence of the size of the ZnO NPs and chemical components was also investigated. Our study revealed that 20-nm ZnO NPs induced obvious structural disruption and inflammation in the OE and OB at the acute stage. The results suggest that the real-time and non-invasive advantages of MRI allow it to observe and assess, directly and dynamically, the potential toxicity of long-term exposure to ZnO NPs in the olfactory system. These findings indicate the size-dependent toxicity of ZnO NPs with respect to the olfactory bulb. Further study is needed to reveal the mechanism behind ZnO NPs’ toxicity.

Plants and insects are engaged in a tight relationship, with phytophagous insects often utilizing volatile organic substances released by host plants to find food and egg-laying sites. Using plant volatiles as attractants for integrated pest management is vital due to its high efficacy and low environmental toxicity. Using naturally occurring plant volatiles combined with insect olfactory mechanisms to select volatile molecules for screening has proved an effective method for developing plant volatile-based attractant technologies. However, the widespread adoption of this technique is still limited by the lack of a complete understanding of molecular insect olfactory pathways. This paper first describes the nature of plant volatiles and the mechanisms of plant volatile perception by insects. Then, the attraction mechanism of plant volatiles to insects is introduced with the example of Cnaphalocrocis medinalis. Next, the progress of the development and utilization of plant volatiles to manage pests is presented. Finally, the functions played by the olfactory system of insects in recognizing plant volatiles and the application prospects of utilizing volatiles for green pest control are discussed. Understanding the sensing mechanism of insects to plant volatiles and its utilization will be critical for pest management in agriculture. [ABSTRACT FROM AUTHOR]

Many organisms communicate using signals in different sensory modalities (multicomponent or multimodal). When one signal or component is lost over evolutionary time, it may be indicative of changes in other characteristics of the signalling system, including the sensory organs used to perceive and process signals. Sceloporus lizards predominantly use chemical and visual signals to communicate, yet some species have lost the ancestral ventral colour patch used in male–male agonistic interactions and exhibit increased chemosensory behaviour. Here, we asked whether evolutionary loss of this sexual signal is associated with larger vomeronasal organ (VNO) volumes (an organ that detects chemical scents) compared with species that have retained the colour patch. We measured VNO coronal section areas of 7–8 adult males from each of 11 Sceloporus species (4 that lost and 7 that retained the colour patch), estimated sensory and total epithelium volume, and compared volumes using phylogenetic analysis of covariance, controlling for body size. Contrary to expectations, we found that species retaining the ventral patch had similar relative VNO volumes as did species that had lost the ancestral patch, and that body size explains VNO epithelium volume. Visual signal loss may be sufficiently compensated for by increased chemosensory behaviour, and the allometric pattern may indicate sensory system trade-offs for large-bodied species. [ABSTRACT FROM AUTHOR]

Chemosensory proteins (CSPs) are highly efficient carry tools to bind and deliver hydrophobic compounds, which play an important role in the chemosensory process in insects. The diamondback moth, Plutella xylostella L. (Lepidoptera: Plutellidae), is a cosmopolitan pest that attacks cruciferous crops. However, the detailed physiological functions of CSPs in P. xylostella remain limited to date. Here, we identified a typical CSP, named Pxyl CSP18, in P. xylostella and investigated its expression patterns and binding properties of volatiles. PxylCSP18 was highly expressed in antennae and head (without antennae), and the expression level in the male antennae of P. xylostella was obviously higher than that in the female antennae. Moreover, Pxyl CSP18 has a relatively broad binding spectrum. Fluorescence competitive binding assays showed that Pxyl CSP18 had strong binding abilities with 14 plant volatiles (Ki < 10 μM) that were repellent or attractive to P. xylostella. Notably, Pxyl CSP18 had no significant binding affinity to (Z)-11-hexadecenal, (Z)-11-hexadecenyl acetate, and (Z)-11-hexadecenyl alcolol, which are the pheromone components of P. xylostella. The attractive effects of trans-2-hexen-1-ol and isopropyl isothiocyanate to male adults and the attractive effects of isopropyl isothiocyanate and the repellent effects of linalool to female adults were significantly decreased after knocked down the expression of PxylCSP18. Our results revealed that Pxyl CSP18 might play an important role in host plant detection, avoidance of unsuitable hosts, and selection of oviposition sites; however, it does not participate in mating behavior. Overall, these results extended our knowledge on the CSP-related functions, which provided insightful information about CSP-targeted insecticides. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Parkinson's disease (PD), two common irreversible neurodegenerative diseases, share similar early stage syndromes, such as olfaction dysfunction. Yet, the potential comorbidity mechanism of AD and PD was not fully elucidated. Methods: The gene expression profiles of GSE5281 and GSE8397 were downloaded from the Gene Expression Omnibus (GEO) database. We utilized a series of bioinformatics analyses to screen the overlapped differentially expressed genes (DEGs). The hub genes were further identified by the plugin CytoHubba of Cytoscape and validated in the hippocampus (HIP) samples of APP/PS-1 transgenic mice and the substantial nigra (SN) samples of A53T transgenic mice by real-time quantitative polymerase chain reaction (RT-qPCR). Meanwhile, the expression of the target genes in the olfactory epithelium/bulb was detected by RT-qPCR. Finally, molecular docking was used to screen potential compounds for the target gene. Results: One hundred seventy-four overlapped DEGs were identified in AD and PD. Five of the top ten enrichment pathways mainly focused on the synapse. Five hub genes were identified and further validated. As a common factor in AD and PD, the changes of synaptosomal-associated protein 25 (SNAP25) mRNA in olfactory epithelium/bulb were significantly decreased and had a strong association with those in the HIP and SN samples. Pazopanib was the optimal compound targeting SNAP25, with a binding energy of − 9.2 kcal/mol. Conclusions: Our results provided a theoretical basis for understanding the comorbidity mechanism of AD and PD and highlighted that SNAP25 in the olfactory epithelium may serve as a potential target for early detection and intervention in both AD and PD. [ABSTRACT FROM AUTHOR]

In evolutionary terms, life is about reproduction. Yet, in some species, individuals forgo their own reproduction to support the reproductive efforts of others. Social insect colonies for example, can contain up to a million workers that actively cooperate in tasks such as foraging, brood care and nest defence, but do not produce offspring. In such societies the division of labour is pronounced, and reproduction is restricted to just one or a few individuals, most notably the queen(s). This extreme eusocial organisation exists in only a few mammals, crustaceans and insects, but strikingly, it evolved independently up to nine times in the order Hymenoptera (including ants, bees and wasps). Transitions from a solitary lifestyle to an organised society can occur through natural selection when helpers obtain a fitness benefit from cooperating with kin, owing to the indirect transmission of genes through siblings. However, this process, called kin selection, is vulnerable to parasitism and opportunistic behaviours from unrelated individuals. An ability to distinguish kin from non‐kin, and to respond accordingly, could therefore critically facilitate the evolution of eusociality and the maintenance of non‐reproductive workers. The question of how the hymenopteran brain has adapted to support this function is therefore a fundamental issue in evolutionary neuroethology. Early neuroanatomical investigations proposed that social Hymenoptera have expanded integrative brain areas due to selection for increased cognitive capabilities in the context of processing social information. Later studies challenged this assumption and instead pointed to an intimate link between higher social organisation and the existence of developed sensory structures involved in recognition and communication. In particular, chemical signalling of social identity, known to be mediated through cuticular hydrocarbons (CHCs), may have evolved hand in hand with a specialised chemosensory system in Hymenoptera. Here, we compile the current knowledge on this recognition system, from emitted identity signals, to the molecular and neuronal basis of chemical detection, with particular emphasis on its evolutionary history. Finally, we ask whether the evolution of social behaviour in Hymenoptera could have driven the expansion of their complex olfactory system, or whether the early origin and conservation of an olfactory subsystem dedicated to social recognition could explain the abundance of eusocial species in this insect order. Answering this question will require further comparative studies to provide a comprehensive view on lineage‐specific adaptations in the olfactory pathway of Hymenoptera. [ABSTRACT FROM AUTHOR]

Simple Summary: In order to sense the numerous chemical signals from their surroundings, insects have developed complex olfactory systems and olfactory mechanisms involving a wide range of chemosensory genes. Olfaction therefore plays an integral role in directing and regulating all insect behaviors and activities. Termites possess significant ecological significance due to their eusocial nature; that is, they use intricate chemical communication mechanisms to coordinate colony organization and regulate social behavior. In this study, a transcriptomic analysis of Odontotermes formosanus workers was performed to uncover candidate chemosensory genes. Forty-two candidate chemosensory genes were identified, and the relative expression profiles of these candidate genes were investigated. This study reveals new directions for the study of chemosensory genes and uncovers the molecular underpinnings of the functional olfactory system in termites, which will lead to the green pest management of termites in the future. Termites are eusocial insects. Chemical signals between colony members are crucial to the smooth running of colony operations, but little is known about their olfactory system and the roles played by various chemosensory genes in this process. Chemosensory genes are involved in basic olfactory perception in insects. Odontotermes formosanus (Shiraki) is one of the most damaging pests to agricultural crops, forests, and human-made structures. To better understand the olfactory system and the genes involved in olfactory processing in O. formosanus, we produced a transcriptome of worker termites. In this study, we identified 13 OforOBPs, 1 OforCSP, 15 OforORs, 9 OforGRs, and 4 OforSNMPs. Multiple sequence alignments were used in the phylogenetic study, which included data from other termite species and a wide variety of insect species. Moreover, we also investigated the mRNA expression levels using qRT-PCR. The significantly high expression levels of OforCSP1, OforOBP2, OforOR1, and OforSNMP1 suggest that these genes may play important roles in olfactory processing in termite social behavior, including caste differentiation, nestmate and non-nestmate discrimination, and the performance of colony operations among members. Our research establishes a foundation for future molecular-level functional studies of chemosensory genes in O. formosanus, which might lead to the identification of novel targets for termite integrated pest management. [ABSTRACT FROM AUTHOR]

Olfaction is fundamental in many species of mammals. In rodents, the integrity of this system is required for the expression of parental and sexual behavior, mate recognition, identification of predators, and finding food. Different anatomical and physiological evidence initially indicated the existence of two anatomically distinct chemosensory systems: The main olfactory system (MOS) and the accessory olfactory system (AOS). It was originally conceived that the MOS detected volatile odorants related to food, giving the animal information about the environment. The AOS, on the other hand, detected non-volatile sexually relevant olfactory cues that influence reproductive behaviors and neuroendocrine functions such as intermale aggression, sexual preference, maternal aggression, pregnancy block (Bruce effect), puberty acceleration (Vandenbergh effect), induction of estrous (Whitten effect) and sexual behavior. Over the last decade, several lines of evidence have demonstrated that although these systems could be anatomically separated, there are neuronal areas in which they are interconnected. Moreover, it is now clear that both the MOS and the AOS process both volatile and no-volatile odorants, indicating that they are also functionally interconnected. In the first part of the review, we will describe the behavioral evidence. In the second part, we will summarize data from our laboratory and other research groups demonstrating that sexual behavior in male and female rodents induces the formation of new neurons that reach the main and accessory olfactory bulbs from the subventricular zone. Three factors are essential for the neurons to reach the AOS and the MOS: The stimulation frequency, the stimulus's temporal presentation, and the release of opioids induced by sexual behavior. We propose that the AOS and the MOS are part of a large olfactory system with a high plastic capability, which favors the adaptation of species to different environmental signals. [ABSTRACT FROM AUTHOR]

In deep neural networks, representational learning in the middle layer is essential for achieving efficient learning. However, the currently prevailing backpropagation learning rules (BP) are not necessarily biologically plausible and cannot be implemented in the brain in their current form. Therefore, to elucidate the learning rules used by the brain, it is critical to establish biologically plausible learning rules for practical memory tasks. For example, learning rules that result in a learning performance worse than that of animals observed in experimental studies may not be computations used in real brains and should be ruled out. Using numerical simulations, we developed biologically plausible learning rules to solve a task that replicates a laboratory experiment where mice learned to predict the correct reward amount. Although the extreme learning machine (ELM) and weight perturbation (WP) learning rules performed worse than the mice, the feedback alignment (FA) rule achieved a performance equal to that of BP To obtain a more biologically plausible model, we developed a variant of FA, FA_Ex-100%, which implements direct dopamine inputs that provide error signals locally in the layer of focus, as found in the mouse entorhinal cortex. The performance of FA_Ex-100% was comparable to that of conventional BP Finally, we tested whether FA_Ex-100% was robust against rule perturbations and biologically inevitable noise. FA_Ex-100% worked even when subjected to perturbations, presumably because it could calibrate the correct prediction error (e.g., dopaminergic signals) in the next step as a teaching signal if the perturbation created a deviation. These results suggest that simplified and biologically plausible learning rules, such as FA_Ex-100%, can robustly facilitate deep supervised learning when the error signal, possibly conveyed by dopaminergic neurons, is accurate. [ABSTRACT FROM AUTHOR]

Purpose: Intermittent hypoxia (IH) results in low-grade inflammation, sympathetic overactivity, and oxidative stress. However, the specific effects of IH on olfaction have not yet been directly assessed and remain unclear. Therefore, the purpose of this study was to investigate the cytotoxic effects of IH exposure on the mouse olfactory epithelium and the relationship between the concentration of hypoxia and the degree of destruction of the olfactory system. Methods: Thirty mice were randomly divided into six groups: control (room air for 4 weeks), recovery control (room air for 5 weeks), IH 5% oxygen concentration, IH 7% oxygen concentration, recovery 5% hypoxia, and recovery 7% hypoxia groups. Mice in the two hypoxia groups were exposed to 5% and 7% oxygen for 4 weeks. Mice in the two recovery groups were exposed to room air for 1 week after 4 weeks of hypoxia period. Results: Based on, the olfactory marker protein (OMP), Olfr1507, ADCY3, and GNAL were lower, whereas S100b and NGFRAP1 messenger RNA (mRNA) levels were higher in the 5% hypoxia group than those in the control group in the olfactory neuroepithelium. In the brain tissue, the changes in RNA analysis for Olfr 1507, OMP, ADCY, and GNAL mRNA were not typical. However, NeuN and GFAP levels were decreased under 5% hypoxia in the brain tissue. In the recovery state, CNPase, S100b and NeuN levels were increased significantly in both the olfactory neuroepithelium and brain tissue in the 5% hypoxia group. The change in RNA activity in PCR was much higher in the 5% hypoxia group than in the 7% hypoxia group. Conclusions: Our findings suggest that IH damages the olfactory neuroepithelium and brain tissue in mouse model. The activity of olfactory marker genes and neurogenesis in the olfactory neuroepithelium were decreased. The levels of oxygen may be affect changes in the olfactory neuroepithelium. The olfactory ensheathing cell may be a major factor in the recovery of the olfactory neuroepithelium. [ABSTRACT FROM AUTHOR]

Olfaction is fundamental in many species of mammals. In rodents, the integrity of this system is required for the expression of parental and sexual behavior, mate recognition, identification of predators, and finding food. Different anatomical and physiological evidence initially indicated the existence of two anatomically distinct chemosensory systems: The main olfactory system (MOS) and the accessory olfactory system (AOS). It was originally conceived that the MOS detected volatile odorants related to food, giving the animal information about the environment. The AOS, on the other hand, detected non-volatile sexually relevant olfactory cues that influence reproductive behaviors and neuroendocrine functions such as intermale aggression, sexual preference, maternal aggression, pregnancy block (Bruce effect), puberty acceleration (Vandenbergh effect), induction of estrous (Whitten effect) and sexual behavior. Over the last decade, several lines of evidence have demonstrated that although these systems could be anatomically separated, there are neuronal areas in which they are interconnected. Moreover, it is now clear that both the MOS and the AOS process both volatile and no-volatile odorants, indicating that they are also functionally interconnected. In the first part of the review, we will describe the behavioral evidence. In the second part, we will summarize data from our laboratory and other research groups demonstrating that sexual behavior in male and female rodents induces the formation of new neurons that reach the main and accessory olfactory bulbs from the subventricular zone. Three factors are essential for the neurons to reach the AOS and the MOS: The stimulation frequency, the stimulus’s temporal presentation, and the release of opioids induced by sexual behavior. We propose that the AOS and the MOS are part of a large olfactory system with a high plastic capability, which favors the adaptation of species to different environmental signals.

Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPRCas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems' performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID. [ABSTRACT FROM AUTHOR]

In mandibulate arthropods, the primary olfactory centers, termed olfactory lobes in crustaceans, are typically organized in distinct fields of dense synaptic neuropils called olfactory glomeruli. In addition to olfactory sensory neuron terminals and their postsynaptic efferents, the glomeruli are innervated by diverse neurochemically distinctive interneurons. The functional morphology of the olfactory glomeruli is understudied in crustaceans compared with insects and even less well understood and described in a particular crustacean subgroup, the Peracarida, which embrace, for example, Amphipoda and Isopoda. Using immunohistochemistry combined with confocal laser scanning microscopy, we analyzed the neurochemistry of the olfactory pathway in the amphipod Parhyale hawaiensis. We localized the biogenic amines serotonin and histamine as well as the neuropeptides RFamide, allatostatin, orcokinin, and SIFamide. As for other classical neurotransmitters, we stained for γ‐aminobutyric acid and glutamate decarboxylase and used choline acetyltransferase as indicator for acetylcholine. Our study is another step in understanding principles of olfactory processing in crustaceans and can serve as a basis for understanding evolutionary transformations of crustacean olfactory systems. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) represents the cause of the second highest number of cancer-related deaths worldwide, and its clinical presentation can range from slow-growing to rapidly spreading metastatic disease. As the characteristics of most cases of PCa remains incompletely understood, it is crucial to identify new biomarkers that can aid in early detection. Despite the prostate-specific antigen serum (PSA) levels, prostate biopsy, and imaging representing the actual gold-standard for diagnosing PCa, analyzing volatile organic compounds (VOCs) has emerged as a promising new frontier. We and other authors have reported that highly trained dogs can recognize specific VOCs associated with PCa with high accuracy. However, using dogs in clinical practice has several limitations. To exploit the potential of VOCs, an electronic nose (eNose) that mimics the dog olfactory system and can potentially be used in clinical practice was designed. To explore the eNose as an alternative to dogs in diagnosing PCa, we conducted a systematic literature review and meta-analysis of available studies. PRISMA guidelines were used for the identification, screening, eligibility, and selection process. We included six studies that employed trained dogs and found that the pooled diagnostic sensitivity was 0.87 (95% CI 0.86–0.89; I2, 98.6%), the diagnostic specificity was 0.83 (95% CI 0.80–0.85; I2, 98.1%), and the area under the summary receiver operating characteristic curve (sROC) was 0.64 (standard error, 0.25). We also analyzed five studies that used an eNose to diagnose PCa and found that the pooled diagnostic sensitivity was 0.84 (95% CI, 0.80–0.88; I2, 57.1%), the diagnostic specificity was 0.88 (95% CI, 0.84–0.91; I2, 66%), and the area under the sROC was 0.93 (standard error, 0.03). These pooled results suggest that while highly trained dogs have the potentiality to diagnose PCa, the ability is primarily related to olfactory physiology and training methodology. The adoption of advanced analytical techniques, such as eNose, poses a significant challenge in the field of clinical practice due to their growing effectiveness. Nevertheless, the presence of limitations and the requirement for meticulous study design continue to present challenges when employing eNoses for the diagnosis of PCa. [ABSTRACT FROM AUTHOR]

Electronic Nose (E-Nose) technology unlocks the fascinating world of electronic detection, identification, and analysis of scents and odors, paving the way for innovative research and promising applications. ENose mimics the human sense of smell and has gained significant attention and is applied in various fields, including the food, health and drug industries, safety and crime, and the environmental and agricultural sectors. This technology has the potential to improve quality control, medical diagnostics, and hazardous material detection processes. The ENose consists of a combination of gas sensors that mimic the olfactory receptors of the human nose. These sensors detect and respond to different scent molecules, resulting in unique response patterns that can be interpreted and analyzed. E-Nose has found application in the food industry to assess food quality, detect contamination, and monitor fermentation processes. In the health field, it has been used for disease diagnosis, monitoring patient health, and detecting cancerous tissue. In addition, E-Nose has been used for security purposes, such as detection of explosives and prohibited substances, as well as identification of counterfeit products. In addition, it has been used in environmental monitoring for air quality assessment and agriculture for disease detection in crops. Despite its promising potential, widespread adoption of E-Nose faces challenges related to sensor sensitivity, data analysis algorithms (complex data interpretation), response diversity, regulatory considerations, implementation complexity, and cost. This article reviews the latest developments in E-Nose technology, explores its applications and future potential, and highlights challenges that need to be addressed. This is considered important because E-Nose opens up a world of electronic scent identification and analysis with the potential to improve quality control, diagnosis, and detection. [ABSTRACT FROM AUTHOR]

Nowadays, the electronic nose (e-nose) has gained a huge amount of attention due to its ability to detect and differentiate mixtures of various gases and odors using a limited number of sensors. Its applications in the environmental fields include analysis of the parameters for environmental control, process control, and confirming the efficiency of the odor-control systems. The e-nose has been developed by mimicking the olfactory system of mammals. This paper investigates e-noses and their sensors for the detection of environmental contaminants. Among different types of gas chemical sensors, metal oxide semiconductor sensors (MOXs) can be used for the detection of volatile compounds in air at ppm and sub-ppm levels. In this regard, the advantages and disadvantages of MOX sensors and the solutions to solve the problems arising upon these sensors' applications are addressed, and the research works in the field of environmental contamination monitoring are overviewed. These studies have revealed the suitability of e-noses for most of the reported applications, especially when the tools were specifically developed for that application, e.g., in the facilities of water and wastewater management systems. As a general rule, the literature review discusses the aspects related to various applications as well as the development of effective solutions. However, the main limitation in the expansion of the use of e-noses as an environmental monitoring tool is their complexity and lack of specific standards, which can be corrected through appropriate data processing methods applications. [ABSTRACT FROM AUTHOR]

• Fos expression in response to two chemicals of rat alarm pheromone was examined. • Each chemical activated the MeApv through separate olfactory systems. • The mixture further activated the MeApv. • The MeApv is suggested to integrate information from the two olfactory systems. In rats, a mixture of hexanal and 4-methylpentanal is a main component of the alarm pheromone. When detected by the main olfactory system (MOS) and the vomeronasal system, respectively, they activate the anterior part of the bed nucleus of the stria terminalis (BNSTa). Therefore, the information from the two olfactory systems is expected to be integrated before being transmitted to the BNSTa. To specify the integration site, we examined Fos expression in 16 brain regions in response to water (n = 10), hexanal (n = 9), 4-methylpentanal (n = 9), the mixture (n = 9), or the alarm pheromone (n = 9) in male rats. The posteroventral part of the medial amygdala showed increased Fos expression to hexanal and 4-methylpentanal. The expression was further increased by the mixture. Therefore, this region is suggested as the integration site. In addition, the BNSTa, paraventricular nucleus of the hypothalamus, and anteroventral, anterodorsal, and posterodorsal parts of the medial amygdala were suggested to be located downstream of the integrated site because only the mixture increased Fos expression. We suggest that the posterolateral part of the cortical amygdala is upstream of the integration site in the MOS because all stimuli increased Fos expression. The posterior part of the bed nucleus of the stria terminalis and posteromedial part of the cortical amygdala were suggested as being located upstream in the vomeronasal system because 4-methylpentanal and the mixture increased Fos expression. These results provide information about the neural pathway underlying the alarm pheromone effects. [ABSTRACT FROM AUTHOR]

Social experience and pheromone signaling in olfactory neurons affect neuronal responses and male courtship behaviors in Drosophila. We previously showed that social experience and pheromone signaling modulate chromatin around behavioral switch gene fruitless, which encodes a transcription factor necessary and sufficient for male sexual behaviors. Fruitless drives social experience-dependent modulation of courtship behaviors and physiological sensory neuron responses to pheromone; however, the molecular mechanisms underlying this modulation of neural responses remain less clear. To identify the molecular mechanisms driving social experience-dependent changes in neuronal responses, we performed RNA-seq from antennal samples of mutants in pheromone receptors and fruitless, as well as grouped or isolated wild-type males. Genes affecting neuronal physiology and function, such as neurotransmitter receptors, ion channels, ion and membrane transporters, and odorant binding proteins are differentially regulated by social context and pheromone signaling. While we found that loss of pheromone detection only has small effects on differential promoter and exon usage within fruitless gene, many of the differentially regulated genes have Fruitless-binding sites or are bound by Fruitless in the nervous system. Recent studies showed that social experience and juvenile hormone signaling co-regulate fruitless chromatin to modify pheromone responses in olfactory neurons. Interestingly, genes involved in juvenile hormone metabolism are also misregulated in different social contexts and mutant backgrounds. Our results suggest that modulation of neuronal activity and behaviors in response to social experience and pheromone signaling likely arise due to large-scale changes in transcriptional programs for neuronal function downstream of behavioral switch gene function. [ABSTRACT FROM AUTHOR]

Neural networks are constructed through the development of robust axonal projections from individual neurons, which ultimately establish connections with their targets. In most animals, developing axons assemble in bundles to navigate collectively across various areas within the central nervous system or the periphery, before they separate from these bundles in order to find their specific targets. These processes, called fasciculation and defasciculation respectively, were thought for many years to be controlled chemically: while guidance cues may attract or repulse axonal growth cones, adhesion molecules expressed at the surface of axons mediate their fasciculation. Recently, an additional non-chemical parameter, the mechanical longitudinal tension of axons, turned out to play a role in axon fasciculation and defasciculation, through zippering and unzippering of axon shafts. In this review, we present an integrated view of the currently known chemical and mechanical control of axon:axon dynamic interactions. We highlight the facts that the decision to cross or not to cross another axon depends on a combination of chemical, mechanical and geometrical parameters, and that the decision to fasciculate/defasciculate through zippering/unzippering relies on the balance between axon:axon adhesion and their mechanical tension. Finally, we speculate about possible functional implications of zippering-dependent axon shaft fasciculation, in the collective migration of axons, and in the sorting of subpopulations of axons. • Axon fasciculation/defasciculation is controlled by chemical and mechanical cues. • Zippering-dependent axon fasciculation is the result of a competition between axon:axon adhesion and their mechanical tension. • Decision to cross or not to cross another axon depends on a combination of chemical, mechanical and geometrical parameters. • Zippering and unzippering of axon shafts may play important roles in the collective migration of axons and in the sorting out of axons. [ABSTRACT FROM AUTHOR]

Ionotropic receptors (IRs) play a central role in detecting chemosensory information from the environment and guiding insect behaviors and are potential target genes for pest control. Empoasca onukii Matsuda is a major pest of the tea plant Camellia sinensis (L.) O. Ktze, and seriously influences tea yields and quality. In this study, the ionotropic receptor gene EonuIR25a in E. onukii was cloned, and the expression pattern of EonuIR25a was detected in various tissues. Behavioral responses of E. onukii to volatile compounds emitted by tea plants were determined using olfactometer bioassay and field trials. To further explore the function of EonuIR25a in olfactory recognition of compounds, RNA interference (RNAi) of EonuIR25a was carried out by ingestion of in vitro synthesized dsRNAs. The coding sequence (CDS) length of EonuIR25a was 1266 bp and it encoded a 48.87 kD protein. EonuIR25a was enriched in the antennae of E. onukii. E. onukii was more significantly attracted by 1-phenylethanol at a concentration of 100 µL/mL. Feeding with dsEonuIR25a significantly downregulated the expression level of EonuIR25a, after 3 h of treatment, which disturbed the behavioral responses of E. onukii to 1-phenylethanol at a concentration of 100 µL/mL. The response rate of E. onukii to 1-phenylethanol was significantly decreased after dsEonuIR25a treatment for 12 h. In summary, the ionotropic receptor gene EonuIR25a was highly expressed in the antennae of E. onukii and was involved in olfactory recognition of the tea plant volatile 1-phenylethanol. The present study may help us to use the ionotropic receptor gene as a target for the behavioral manipulation of E. onukii in the future. [ABSTRACT FROM AUTHOR]

A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer's Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1β and IL-6 mRNA in the brain's prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APPNL-G-F/NL-G-F Alzheimer's mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1β mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer's disease. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNSrelated diseases. [ABSTRACT FROM AUTHOR]

The Olfactory Bulb is a component of the Olfactory System, in which it plays an essential role as an interface between the peripheral components and the cerebral cortex responsible for olfactory interpretation and discrimination. It is in this element that the first selective integration of olfactory stimuli occurs through a complex cell interaction that forwards the received olfactory information to higher cortical centers. Considering its position in the organizational hierarchy of the olfactory system, it is now known that changes in the Olfactory Bulb can lead to olfactory abnormalities. Through imaging techniques, it was possible to establish relationships between the occurrence of changes secondary to brain aging and senility, neurodegenerative diseases, head trauma, and infectious diseases with a decrease in the size of the Olfactory Bulb and in olfactory acuity. In companion animals, this relationship has also been identified, with observations of relations between the cranial conformation, the disposition, size, and shape of the Olfactory Bulb, and the occurrence of structural alterations associated with diseases with different etiologies. However, greater difficulty in quantitatively assessing olfactory acuity in animals and a manifestly smaller number of studies dedicated to this topic maintain a lack of concrete and unequivocal results in this field of veterinary sciences. The aim of this work is to revisit the Olfactory Bulb in companion animals in all its dimensions, review its anatomy and histological characteristics, physiological integration in the olfactory system, importance as a potential early indicator of the establishment of specific pathologies, as well as techniques of imaging evaluation for its in vivo clinical exploration. [ABSTRACT FROM AUTHOR]

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Olfactory dysfunction and neuropsychiatric symptoms are commonly reported by patients of coronavirus disease 2019 (COVID-19), a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence from recent research suggests linkages between altered or loss of smell and neuropsychiatric symptoms after infection with the coronavirus. Systemic inflammation and ischemic injury are believed to be the major cause of COVID-19-related CNS manifestation. Yet, some evidence suggest a neurotropic property of SARS-CoV-2. This mini-review article summarizes the neural correlates of olfaction and discusses the potential of trans-neuronal transmission of SARSCoV-2 or its particles within the olfactory connections in the brain. The impact of the dysfunction in the olfactory network on the neuropsychiatric symptoms associated with COVID-19 will also be discussed. [ABSTRACT FROM AUTHOR]

Background and objective: Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system's morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. Methods: 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. Results: COVID-19 patients showed significantly lower left, right and total OB volumes than controls (p < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. Conclusions: Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology. [ABSTRACT FROM AUTHOR]

Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems’ performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.

When we are asleep, we lose the ability to promptly respond to external stimuli, and yet we spend many hours every day in this inherently risky behavioral state. This simple fact strongly suggests that sleep must serve essential functions that rely on the brain going offline, on a daily basis, and for long periods of time. If these functions did not require partial sensory disconnection, it would be difficult to explain why they are not performed during waking. Paradoxically, despite its central role in defining sleep and what sleep does, sensory disconnection during sleep remains a mystery. We have a limited understanding of how it is implemented along the sensory pathways; we do not know whether the same mechanisms apply to all sensory modalities, nor do we know to what extent these mechanisms are shared between non-rapid eye movement (NREM) sleep and REM sleep. The main goal of this contribution is to review some knowns and unknowns about sensory disconnection during sleep as a first step to fill this gap.