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Acta Pharmacologica Sinica Jun 2024Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of...
Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca influx evoked by high K solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.
PubMed: 38862816
DOI: 10.1038/s41401-024-01275-y -
Scientific Reports Jun 2024Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between...
Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis. Data of non-vaccinated COVID-19 convalescents recruited within the framework of the prospective Hamburg City Health Study COVID Program between March and December 2020 were analyzed. At baseline, 233 participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022, olfactory function was assessed at follow-up including quantitative olfactometric testing with Sniffin' Sticks. This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of self-reported olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute self-reported olfactory dysfunction had a significantly lower olfactory bulb volume at baseline than normally smelling individuals. Olfactory bulb volume at baseline predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume. Our work demonstrates an association of long-term self-reported smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19.
Topics: Humans; Olfactory Bulb; COVID-19; Male; Female; Middle Aged; Olfaction Disorders; Adult; Magnetic Resonance Imaging; SARS-CoV-2; Aged; Prospective Studies; Neuropsychological Tests; Smell
PubMed: 38862636
DOI: 10.1038/s41598-024-64367-z -
ORL; Journal For Oto-rhino-laryngology... Jun 2024The prevalence of post-viral olfactory dysfunction has increased significantly during the COVID-19 pandemic, posing a major challenge for patients and practitioners....
INTRODUCTION
The prevalence of post-viral olfactory dysfunction has increased significantly during the COVID-19 pandemic, posing a major challenge for patients and practitioners. While olfactory training (OT) is a common approach to therapy, there has been increasing interest in supplementing therapy with a combination of palmitoylethanolamide (PEA) and luteolin (LUT), which are known for their anti-inflammatory properties. In this study, their efficacy in the treatment of patients with olfactory loss following upper respiratory tract infections, mainly COVID-19, was investigated in an outpatient clinic.
METHODS
Fifty patients with persistent olfactory dysfunction were randomized to two groups: one receiving OT and PEA-LUT, the other OT alone. Olfactory function was evaluated before and after treatment.
RESULTS
The study group showed significant improvements in odor discrimination and overall olfactory function (TDI score) after treatment with PEA-LUT and OT, while the control group did not. However, when clinically meaningful improvements were considered, there was no significant difference between the groups.
CONCLUSION
The present study suggests that while PEA-LUT may have the potential to improve olfactory function in post-viral dysfunction, the additional benefit over OT alone may be limited. These results contrast with some previous studies.
PubMed: 38861957
DOI: 10.1159/000539651 -
Frontiers in Neural Circuits 2024The brain constructs spatially organized sensory maps to represent sensory information. The formation of sensory maps has traditionally been thought to depend on... (Review)
Review
The brain constructs spatially organized sensory maps to represent sensory information. The formation of sensory maps has traditionally been thought to depend on synchronous neuronal activity. However, recent evidence from the olfactory system suggests that cell type-specific temporal patterns of spontaneous activity play an instructive role in shaping the olfactory glomerular map. These findings challenge traditional views and highlight the importance of investigating the spatiotemporal dynamics of neural activity to understand the development of complex neural circuits. This review discusses the implications of new findings in the olfactory system and outlines future research directions.
Topics: Animals; Olfactory Pathways; Humans; Nerve Net; Neurons; Olfactory Bulb
PubMed: 38860141
DOI: 10.3389/fncir.2024.1409680 -
European Journal of Neurology Jun 2024Studies have found that up to 73% of COVID-19 patients experience hyposmia. It is unclear if the loss of smell in COVID-19 is due to damage to the peripheral or central...
BACKGROUND AND PURPOSE
Studies have found that up to 73% of COVID-19 patients experience hyposmia. It is unclear if the loss of smell in COVID-19 is due to damage to the peripheral or central mechanisms. This study aimed to explore the impacts of COVID-19-induced hyposmia on brain structure and cognitive functions.
METHODS
The study included 36 hyposmic (h-COV) and 21 normosmic (n-COV) participants who had recovered from mild COVID-19 infection, as well as 25 healthy controls (HCs). All participants underwent neurological examination, neuropsychiatric assessment and Sniffin' Sticks tests. High-resolution anatomical images were collected; olfactory bulb (OB) volume and cortical thickness were measured.
RESULTS
Addenbrooke's Cognitive Examination-Revised total and language sub-scores were slightly but significantly lower in the h-COV group compared to the HC group (p = 0.04 and p = 0.037). The h-COV group exhibited poorer performance in the Sniffin' Sticks test terms of discrimination score, identification score and the composite score compared to the n-COV and HC groups (p < 0.001, p = 0.001 and p = 0.002 respectively). A decrease in left and right OB volumes was observed in the h-COV group compared to the n-COV and HC groups (p = 0.003 and p = 0.006 respectively). The cortical thickness analysis revealed atrophy in the left lateral orbitofrontal cortex in the h-COV group compared to HCs. A significant low positive correlation of varying degrees was detected between discrimination and identification scores and both OB and left orbital sulci.
CONCLUSION
Temporary or permanent hyposmia after COVID-19 infection leads to atrophy in the OB and olfactory-related cortical structures and subtle cognitive problems in the long term.
PubMed: 38850121
DOI: 10.1111/ene.16378 -
Scientific Reports Jun 2024The enzyme dUTPase has an essential role in maintaining genomic integrity. In mouse, nuclear and mitochondrial isoforms of the enzyme have been described. Here we...
The enzyme dUTPase has an essential role in maintaining genomic integrity. In mouse, nuclear and mitochondrial isoforms of the enzyme have been described. Here we present the isoform-specific mRNA expression levels in different murine organs during development using RT-qPCR. In this study, we analyzed organs of 14.5-day embryos and of postnatal 2-, 4-, 10-week- and 13-month-old mice. We demonstrate organ-, sex- and developmental stage-specific differences in the mRNA expression levels of both isoforms. We found high mRNA expression level of the nuclear isoform in the embryo brain, and the expression level remained relatively high in the adult brain as well. This was surprising, since dUTPase is known to play an important role in proliferating cells, and mass production of neural cells is completed by adulthood. Thus, we investigated the pattern of the dUTPase protein expression specifically in the adult brain with immunostaining and found that dUTPase is present in the germinative zones, the subventricular and the subgranular zones, where neurogenesis occurs and in the rostral migratory stream where neuroblasts migrate to the olfactory bulb. These novel findings suggest that dUTPase may have a role in cell differentiation and indicate that accurate dTTP biosynthesis can be vital, especially in neurogenesis.
Topics: Animals; Neurogenesis; Pyrophosphatases; Mice; Female; Male; Brain; Gene Expression Regulation, Developmental; RNA, Messenger
PubMed: 38849394
DOI: 10.1038/s41598-024-63405-0 -
Journal of Medical Genetics Jun 2024Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by variations. Of the 41 patients reported, only 7 antenatal cases...
INTRODUCTION
Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by variations. Of the 41 patients reported, only 7 antenatal cases were described.
METHOD
After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.
RESULTS
We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in , outside of the two previously known mutational hotspots.
CONCLUSION
Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.
PubMed: 38849204
DOI: 10.1136/jmg-2024-109854 -
BMC Genomics Jun 2024Advances of spatial transcriptomics technologies enabled simultaneously profiling gene expression and spatial locations of cells from the same tissue. Computational...
BACKGROUND
Advances of spatial transcriptomics technologies enabled simultaneously profiling gene expression and spatial locations of cells from the same tissue. Computational tools and approaches for integration of transcriptomics data and spatial context information are urgently needed to comprehensively explore the underlying structure patterns. In this manuscript, we propose HyperGCN for the integrative analysis of gene expression and spatial information profiled from the same tissue. HyperGCN enables data visualization and clustering, and facilitates downstream analysis, including domain segmentation, the characterization of marker genes for the specific domain structure and GO enrichment analysis.
RESULTS
Extensive experiments are implemented on four real datasets from different tissues (including human dorsolateral prefrontal cortex, human positive breast tumors, mouse brain, mouse olfactory bulb tissue and Zabrafish melanoma) and technologies (including 10X visium, osmFISH, seqFISH+, 10X Xenium and Stereo-seq) with different spatial resolutions. The results show that HyperGCN achieves superior clustering performance and produces good domain segmentation effects while identifies biologically meaningful spatial expression patterns. This study provides a flexible framework to analyze spatial transcriptomics data with high geometric complexity.
CONCLUSIONS
HyperGCN is an unsupervised method based on hypergraph induced graph convolutional network, where it assumes that there existed disjoint tissues with high geometric complexity, and models the semantic relationship of cells through hypergraph, which better tackles the high-order interactions of cells and levels of noise in spatial transcriptomics data.
Topics: Humans; Animals; Mice; Gene Expression Profiling; Transcriptome; Deep Learning; Cluster Analysis; Computational Biology; Breast Neoplasms; Olfactory Bulb
PubMed: 38840049
DOI: 10.1186/s12864-024-10469-x -
EMBO Reports Jun 2024In developing olfactory bulb (OB), mitral cells (MCs) remodel their dendrites to establish the precise olfactory circuit, and these circuits are critical for individuals...
In developing olfactory bulb (OB), mitral cells (MCs) remodel their dendrites to establish the precise olfactory circuit, and these circuits are critical for individuals to sense odors and elicit behaviors for survival. However, how microtubules (MTs) participate in the process of dendritic remodeling remains elusive. Here, we reveal that calmodulin-regulated spectrin-associated proteins (CAMSAPs), a family of proteins that bind to the minus-end of the noncentrosomal MTs, play a crucial part in the development of MC dendrites. We observed that Camsap2 knockout (KO) males are infertile while the reproductive tract is normal. Further study showed that the infertility was due to the severe defects of mating behavior in male mice. Besides, mice with loss-of-function displayed defects in the sense of smell. Furthermore, we found that the deficiency of CAMSAP2 impairs the classical morphology of MCs, and the CAMSAP2-dependent dendritic remodeling process is responsible for this defect. Thus, our findings demonstrate that CAMSAP2 plays a vital role in regulating the development of MCs.
PubMed: 38839944
DOI: 10.1038/s44319-024-00166-x -
The Journal of Physiology Jun 2024In mammals, odour information within the olfactory bulb (OB) is processed by complex neural circuits before being ultimately represented in the action potential activity...
In mammals, odour information within the olfactory bulb (OB) is processed by complex neural circuits before being ultimately represented in the action potential activity of mitral/tufted cells (M/Ts). Cholecystokinin-expressing (CCK) superficial tufted cells (sTCs) are a subset of tufted cells that potentially contribute to olfactory processing in the OB by orchestrating M/T activity. However, the exact role of CCK sTCs in modulating odour processing and olfactory function in vivo is largely unknown. Here, we demonstrate that manipulating CCK sTCs can generate perception and induce place avoidance. Optogenetic activation/inactivation of CCK sTCs exerted strong but differing effects on spontaneous and odour-evoked M/T firing. Furthermore, inactivation of CCK sTCs disrupted M/T odour encoding and impaired olfactory detection and odour discrimination. These results establish the role of CCK sTCs in odour representation and olfactory behaviours. KEY POINTS: Mice could perceive the activity of CCK sTCs and show place avoidance to CCK sTC inactivation. Optical activation of CCK sTCs increased the percentage of cells with odour response but reduced the odour-evoked response in M/Ts in awake mice. Optical inactivation of CCK sTCs greatly decreased spontaneous firing and odour-evoked response in M/Ts. Inactivation of CCK sTCs impairs the odour decoding performance of M/Ts and disrupts odour detection and discrimination behaviours in mice. These results indicate that CCK sTCs participate in modulating the odour representation and maintaining normal olfactory-related behaviours.
PubMed: 38837412
DOI: 10.1113/JP285837