-
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 -
Inhalation Toxicology Apr 2024Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario...
OBJECTIVE
Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario can also be occupational, in areas such as the hard metal industry and specific nuclear facilities. Our study investigated the cerebral effects induced by the inhalation of tungsten particles.
METHODS
Inhalation exposure campaigns were carried out at two different concentrations (5 and 80 mg/m) in single and repeated modes (4 consecutive days) in adult rats within a nose-only inhalation chamber. Processes involved in brain toxicity were investigated 24 h after exposure.
RESULTS AND DISCUSSION
Site-specific effects in terms of neuroanatomy and concentration-dependent changes in specific cellular actors were observed. Results obtained in the olfactory bulb suggest a potential early effect on the survival of microglial cells. Depending on the mode of exposure, these cells showed a decrease in density accompanied by an increase in an apoptotic marker. An abnormal phenotype of the nuclei of mature neurons, suggesting neuronal suffering, was also observed in the frontal cortex, and can be linked to the involvement of oxidative stress. The differential effects observed according to exposure patterns could involve two components: local (brain-specific) and/or systemic. Indeed, tungsten, in addition to being found in the lungs and kidneys, was present in the brain of animals exposed to the high concentration.
CONCLUSION
Our data question the perceived innocuity of tungsten relative to other metals and raise hypotheses regarding possible adaptive or neurotoxic mechanisms that could ultimately alter neuronal integrity.
Topics: Animals; Tungsten; Male; Inhalation Exposure; Brain; Rats, Wistar; Rats; Biomarkers; Microglia; Neurons; Lung; Olfactory Bulb; Apoptosis; Oxidative Stress
PubMed: 38836331
DOI: 10.1080/08958378.2024.2349895 -
ENeuro Jun 2024Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity,...
Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity, the olfactory epithelium (OE) is particularly sensitive to infections which may lead to olfactory dysfunction. In patients suffering from coronavirus disease 2019, deficits in olfaction have been characterized as a distinctive symptom. Here, we used the K18hACE2 mice to study the spread of SARS-CoV-2 infection and inflammation in the olfactory system (OS) after 7 d of infection. In the OE, we found that SARS-CoV-2 selectively targeted the supporting/sustentacular cells (SCs) and macrophages from the lamina propria. In the brain, SARS-CoV-2 infected some microglial cells in the olfactory bulb (OB), and there was a widespread infection of projection neurons in the OB, piriform cortex (PC), and tubular striatum (TuS). Inflammation, indicated by both elevated numbers and morphologically activated IBA1 cells (monocyte/macrophage lineages), was preferentially increased in the OE septum, while it was homogeneously distributed throughout the layers of the OB, PC, and TuS. Myelinated OS axonal tracts, the lateral olfactory tract, and the anterior commissure, exhibited decreased levels of 2',3'-cyclic-nucleotide 3'-phosphodiesterase, indicative of myelin defects. Collectively, our work supports the hypothesis that SARS-CoV-2 infected SC and macrophages in the OE and, centrally, microglia and subpopulations of OS neurons. The observed inflammation throughout the OS areas and central myelin defects may account for the long-lasting olfactory deficit.
Topics: Animals; COVID-19; Mice; Olfactory Mucosa; Olfactory Bulb; SARS-CoV-2; Myelin Sheath; Microglia; Mice, Transgenic; Angiotensin-Converting Enzyme 2; Olfaction Disorders; Disease Models, Animal; Male; Inflammation; Macrophages; Female
PubMed: 38834299
DOI: 10.1523/ENEURO.0106-24.2024 -
Bioinformatics Advances 2024The recent spatial transcriptomics (ST) technologies have enabled characterization of gene expression patterns and spatial information, advancing our understanding of...
MOTIVATION
The recent spatial transcriptomics (ST) technologies have enabled characterization of gene expression patterns and spatial information, advancing our understanding of cell lineages within diseased tissues. Several analytical approaches have been proposed for ST data, but effectively utilizing spatial information to unveil the shared variation with gene expression remains a challenge.
RESULTS
We introduce STew, a Spatial Transcriptomic multi-viEW representation learning method, to jointly analyze spatial information and gene expression in a scalable manner, followed by a data-driven statistical framework to measure the goodness of model fit. Through benchmarking using human dorsolateral prefrontal cortex and mouse main olfactory bulb data with true manual annotations, STew achieved superior performance in both clustering accuracy and continuity of identified spatial domains compared with other methods. STew is also robust to generate consistent results insensitive to model parameters, including sparsity constraints. We next applied STew to various ST data acquired from 10× Visium, Slide-seqV2, and 10× Xenium, encompassing single-cell and multi-cellular resolution ST technologies, which revealed spatially informed cell type clusters and biologically meaningful axes. In particular, we identified a proinflammatory fibroblast spatial niche using ST data from psoriatic skins. Moreover, STew scales almost linearly with the number of spatial locations, guaranteeing its applicability to datasets with thousands of spatial locations to capture disease-relevant niches in complex tissues.
AVAILABILITY AND IMPLEMENTATION
Source code and the R software tool STew are available from github.com/fanzhanglab/STew.
PubMed: 38827413
DOI: 10.1093/bioadv/vbae064 -
Biopharmaceutics & Drug Disposition Jun 2024Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride...
Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood-brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC (2.4 μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.
Topics: Animals; Bumetanide; Brain; Male; Rats; Sodium Potassium Chloride Symporter Inhibitors; Rats, Sprague-Dawley; Tissue Distribution; Solute Carrier Family 12, Member 2; Blood-Brain Barrier
PubMed: 38823029
DOI: 10.1002/bdd.2390 -
Translational Stroke Research Jun 2024Timely relief of edema and clearance of waste products, as well as promotion of anti-inflammatory immune responses, reduce ischemic stroke pathology, and attenuate...
Timely relief of edema and clearance of waste products, as well as promotion of anti-inflammatory immune responses, reduce ischemic stroke pathology, and attenuate harmful long-term effects post-stroke. The discovery of an extensive and functional lymphatic vessel system in the outermost meningeal layer, dura mater, has opened up new possibilities to facilitate post-stroke recovery by inducing dural lymphatic vessel (dLV) growth via a single injection of a vector encoding vascular endothelial growth factor C (VEGF-C). In the present study, we aimed to improve post-stroke outcomes by inducing dLV growth in mice. We injected mice with a single intracerebroventricular dose of adeno-associated viral particles encoding VEGF-C before subjecting them to transient middle cerebral artery occlusion (tMCAo). Behavioral testing, Gadolinium (Gd) contrast agent-enhanced magnetic resonance imaging (MRI), and immunohistochemical analysis were performed to define the impact of VEGF-C on the post-stroke outcome. VEGF-C improved stroke-induced behavioral deficits, such as gait disturbances and neurological deficits, ameliorated post-stroke inflammation, and enhanced an alternative glial immune response. Importantly, VEGF-C treatment increased the drainage of brain interstitial fluid (ISF) and cerebrospinal fluid (CSF), as shown by Gd-enhanced MRI. These outcomes were closely associated with an increase in the growth of dLVs around the region where we observed increased vefgc mRNA expression within the brain, including the olfactory bulb, cortex, and cerebellum. Strikingly, VEGF-C-treated ischemic mice exhibited a faster and stronger Gd-signal accumulation in ischemic core area and an enhanced fluid outflow via the cribriform plate. In conclusion, the VEGF-C-induced dLV growth improved the overall outcome post-stroke, indicating that VEGF-C has potential to be included in the treatment strategies of post-ischemic stroke. However, to maximize the therapeutic potential of VEGF-C treatment, further studies on the impact of an enhanced dural lymphatic system at clinically relevant time points are essential.
PubMed: 38822994
DOI: 10.1007/s12975-024-01262-9 -
Frontiers in Neural Circuits 2024Fetal Alcohol Spectrum Disorders (FASD), resulting from maternal alcohol consumption during pregnancy, are a prominent non-genetic cause of physical disabilities and... (Review)
Review
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.
Topics: Pregnancy; Animals; Prenatal Exposure Delayed Effects; Female; Fetal Alcohol Spectrum Disorders; Humans; Ethanol; Olfactory Bulb; Olfactory Pathways
PubMed: 38818309
DOI: 10.3389/fncir.2024.1408187 -
Briefings in Bioinformatics May 2024The advancement of spatial transcriptomics (ST) technology contributes to a more profound comprehension of the spatial properties of gene expression within tissues....
The advancement of spatial transcriptomics (ST) technology contributes to a more profound comprehension of the spatial properties of gene expression within tissues. However, due to challenges of high dimensionality, pronounced noise and dynamic limitations in ST data, the integration of gene expression and spatial information to accurately identify spatial domains remains challenging. This paper proposes a SpaNCMG algorithm for the purpose of achieving precise spatial domain description and localization based on a neighborhood-complementary mixed-view graph convolutional network. The algorithm enables better adaptation to ST data at different resolutions by integrating the local information from KNN and the global structure from r-radius into a complementary neighborhood graph. It also introduces an attention mechanism to achieve adaptive fusion of different reconstructed expressions, and utilizes KPCA method for dimensionality reduction. The application of SpaNCMG on five datasets from four sequencing platforms demonstrates superior performance to eight existing advanced methods. Specifically, the algorithm achieved highest ARI accuracies of 0.63 and 0.52 on the datasets of the human dorsolateral prefrontal cortex and mouse somatosensory cortex, respectively. It accurately identified the spatial locations of marker genes in the mouse olfactory bulb tissue and inferred the biological functions of different regions. When handling larger datasets such as mouse embryos, the SpaNCMG not only identified the main tissue structures but also explored unlabeled domains. Overall, the good generalization ability and scalability of SpaNCMG make it an outstanding tool for understanding tissue structure and disease mechanisms. Our codes are available at https://github.com/ZhihaoSi/SpaNCMG.
Topics: Algorithms; Humans; Animals; Mice; Transcriptome; Gene Expression Profiling; Neural Networks, Computer; Computational Biology; Prefrontal Cortex
PubMed: 38811360
DOI: 10.1093/bib/bbae259 -
Scientific Reports May 2024Anxiety is among the most fundamental mammalian behaviors. Despite the physiological and pathological importance, its underlying neural mechanisms remain poorly...
Anxiety is among the most fundamental mammalian behaviors. Despite the physiological and pathological importance, its underlying neural mechanisms remain poorly understood. Here, we recorded the activity of olfactory bulb (OB) and medial prefrontal cortex (mPFC) of rats, which are critical structures to brain's emotional processing network, while exploring different anxiogenic environments. Our results show that presence in anxiogenic contexts increases the OB and mPFC regional theta activities. Also, these local activity changes are associated with enhanced OB-mPFC theta power- and phase-based functional connectivity as well as OB-to-mPFC information transfer. Interestingly, these effects are more prominent in the unsafe zones of the anxiogenic environments, compared to safer zones. This consistent trend of changes in diverse behavioral environments as well as local and long-range neural activity features suggest that the dynamics of OB-mPFC circuit theta oscillations might underlie different types of anxiety behaviors, with possible implications for anxiety disorders.
Topics: Prefrontal Cortex; Animals; Anxiety; Theta Rhythm; Olfactory Bulb; Male; Rats; Rats, Sprague-Dawley; Behavior, Animal
PubMed: 38802558
DOI: 10.1038/s41598-024-63101-z