-
Heliyon May 2024Chemosensation is important for the survival and reproduction of animals. The odorant binding proteins (OBPs) are thought to be involved in chemosensation together with...
Chemosensation is important for the survival and reproduction of animals. The odorant binding proteins (OBPs) are thought to be involved in chemosensation together with chemosensory receptors. While OBPs were initially considered to deliver hydrophobic odorants to olfactory receptors in the aqueous lymph solution, recent studies suggest more complex roles in various organs. Here, we use transgenes to systematically analyze the expression patterns of all 52 members of the gene family and 3 related chemosensory protein genes in adult , focusing on chemosensory organs such as the antenna, maxillary palp, pharynx, and labellum, and other organs such as the brain, ventral nerve cord, leg, wing, and intestine. The OBPs were observed to express in diverse organs and in multiple cell types, suggesting that these proteins can indeed carry out diverse functional roles. Also, we constructed 10 labellar-expressing mutants, and obtained behavioral evidence that these OBPs may be involved in bitter sensing. The resources we constructed should be useful for future OBP gene family research.
PubMed: 38694054
DOI: 10.1016/j.heliyon.2024.e29358 -
International Journal of Molecular... Apr 2024The primary entry point of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the nasal mucosa, where viral-induced inflammation occurs. When the immune...
The primary entry point of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the nasal mucosa, where viral-induced inflammation occurs. When the immune response fails against SARS-CoV-2, understanding the altered response becomes crucial. This study aimed to compare SARS-CoV-2 immunological responses in the olfactory and respiratory mucosa by focusing on epithelia and nerves. Between 2020 and 2022, we obtained post mortem tissues from the olfactory cleft from 10 patients with histologically intact olfactory epithelia (OE) who died with or from COVID-19, along with four age-matched controls. These tissues were subjected to immunohistochemical reactions using antibodies against T cell antigens CD3, CD8, CD68, and SARS spike protein for viral evidence. Deceased patients with COVID-19 exhibited peripheral lymphopenia accompanied by a local decrease in CD3 cells in the OE. However, SARS-CoV-2 spike protein was sparsely detectable in the OE. With regard to the involvement of nerve fibers, the present analysis suggested that SARS-CoV-2 did not significantly alter the immune response in olfactory or trigeminal fibers. On the other hand, SARS spike protein was detectable in both nerves. In summary, the post mortem investigation demonstrated a decreased T cell response in patients with COVID-19 and signs of SARS-CoV-2 presence in olfactory and trigeminal fibers.
Topics: Humans; COVID-19; Male; Female; SARS-CoV-2; Aged; Middle Aged; Nasal Mucosa; T-Lymphocytes; Aged, 80 and over; Spike Glycoprotein, Coronavirus; Olfactory Mucosa; Adult; Autopsy
PubMed: 38674011
DOI: 10.3390/ijms25084427 -
BMC Medicine Apr 2024ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown...
ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.
Topics: Humans; Animals; Mice; Abnormalities, Multiple; Intellectual Disability; Tooth Abnormalities; Bone Diseases, Developmental; Facies; Olfactory Bulb; Disease Models, Animal
PubMed: 38616269
DOI: 10.1186/s12916-024-03363-6 -
International Journal of Molecular... Mar 2024There is very little knowledge regarding the terminal nerve, from its implications in the involvement and pathogenesis of certain conditions, to its embryological... (Review)
Review
There is very little knowledge regarding the terminal nerve, from its implications in the involvement and pathogenesis of certain conditions, to its embryological origin. With this review, we try to summarize the most important evidence on the terminal nerve, aiming to clarify its anatomy and the various functions attributed to it, to better interpret its potential involvement in pathological processes. Recent studies have also suggested its potential role in the control of human reproductive functions and behaviors. It has been hypothesized that it plays a role in the unconscious perception of specific odors that influence autonomic and reproductive hormonal systems through the hypothalamic-pituitary-gonadal axis. We used the PubMed database and found different articles which were then selected independently by three authors. We found 166 articles, of which, after careful selection, only 21 were analyzed. The terminal nerve was always thought to be unimportant in our body. It was well studied in different types of animals, but few studies have been completed in humans. For this reason, its function remains unknown. Studies suggest a possible implication in olfaction due to the anatomical proximity with the olfactive nerve. Others suggest a more important role in reproduction and sexual behaviors. New emerging information suggests a possible role in Kallmann syndrome and COVID-19.
Topics: Animals; Humans; Smell; Kallmann Syndrome; Nerve Endings; Autonomic Nervous System; COVID-19
PubMed: 38612730
DOI: 10.3390/ijms25073920 -
Alzheimer's & Dementia (New York, N. Y.) 2024Nose-to-brain (N2B) insulin delivery has potential for Alzheimer's disease (AD) therapy. However, clinical implementation has been challenging without methods to follow...
INTRODUCTION
Nose-to-brain (N2B) insulin delivery has potential for Alzheimer's disease (AD) therapy. However, clinical implementation has been challenging without methods to follow N2B delivery non-invasively. Positron emission tomography (PET) was applied to measure F-18-labeled insulin ([F]FB-insulin) from intranasal dosing to brain uptake in non-human primates following N2B delivery.
METHODS
[F]FB-insulin was prepared by reacting A,B-di(tert-butyloxycarbonyl)insulin with [F]--succinimidyl-4-fluorobenzoate. Three methods of N2B delivery for [F]FB-insulin were compared - delivery as aerosol via tubing (rhesus macaque, = 2), as aerosol via preplaced catheter (rhesus macaque, = 3), and as solution via preplaced catheter (cynomolgus macaque, = 3). Following dosing, dynamic PET imaging (120 min) quantified delivery efficiency to the nasal cavity and whole brain. Area under the time-activity curve was calculated for 46 regions of the cynomolgus macaque brain to determine regional [F]FB-insulin levels.
RESULTS
Liquid instillation of [F]FB-insulin by catheter outperformed aerosol methods for delivery to the subject (39.89% injected dose vs 10.03% for aerosol via tubing, 0.17% for aerosol by catheter) and subsequently to brain (0.34% injected dose vs 0.00020% for aerosol via tubing, 0.05% for aerosol by catheter). [F]FB-insulin was rapidly transferred across the cribriform plate to limbic and frontotemporal areas responsible for emotional and memory processing. [F]FB-insulin half-life was longer in olfactory nerve projection sites with high insulin receptor density compared to the whole brain.
DISCUSSION
The catheter-based liquid delivery approach combined with PET imaging successfully tracked the fate of N2B [F]FB-insulin and is thought to be broadly applicable for assessments of other therapeutic agents. This method can be rapidly applied in humans to advance clinical evaluation of N2B insulin as an AD therapeutic.
HIGHLIGHTS FOR
[F]FB-insulin passage across the cribriform plate was detected by PET.Intranasal [F]FB-insulin reached the brain within 13 min.[F]FB-insulin activity was highest in emotional and memory processing regions.Aerosol delivery was less efficient than liquid instillation by preplaced catheter.Insulin delivery to the cribriform plate was critical for arrival in the brain.
PubMed: 38469552
DOI: 10.1002/trc2.12459 -
MedComm Mar 2024Neuro-COVID, a condition marked by persistent symptoms post-COVID-19 infection, notably affects various organs, with a particular focus on the central nervous system...
Neuro-COVID, a condition marked by persistent symptoms post-COVID-19 infection, notably affects various organs, with a particular focus on the central nervous system (CNS). Despite scant evidence of SARS-CoV-2 invasion in the CNS, the increasing incidence of Neuro-COVID cases indicates the onset of acute neurological symptoms early in infection. The Omicron variant, distinguished by heightened neurotropism, penetrates the CNS via the olfactory bulb. This direct invasion induces inflammation and neuronal damage, emphasizing the need for vigilance regarding potential neurological complications. Our multicenter study represents a groundbreaking revelation, documenting the definite presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of a significant proportion of Neuro-COVID patients. Furthermore, notable differences emerged between RNA-CSF-positive and negative patients, encompassing aspects such as blood-brain barrier integrity, extent of neuronal damage, and the activation status of inflammation. Despite inherent limitations, this research provides pivotal insights into the intricate interplay between SARS-CoV-2 and the CNS, underscoring the necessity for ongoing research to fully comprehend the virus's enduring effects on the CNS. The findings underscore the urgency of continuous investigation Neuro-COVID to unravel the complexities of this relationship, and pivotal in addressing the long-term consequences of COVID-19 on neurological health.
PubMed: 38463395
DOI: 10.1002/mco2.508 -
International Journal of Nanomedicine 2024Addressing disorders related to the central nervous system (CNS) remains a complex challenge because of the presence of the blood-brain barrier (BBB), which restricts...
Addressing disorders related to the central nervous system (CNS) remains a complex challenge because of the presence of the blood-brain barrier (BBB), which restricts the entry of external substances into the brain tissue. Consequently, finding ways to overcome the limited therapeutic effect imposed by the BBB has become a central goal in advancing delivery systems targeted to the brain. In this context, the intranasal route has emerged as a promising solution for delivering treatments directly from the nose to the brain through the olfactory and trigeminal nerve pathways and thus, bypassing the BBB. The use of lipid-based nanoparticles, including nano/microemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, has shown promise in enhancing the efficiency of nose-to-brain delivery. These nanoparticles facilitate drug absorption from the nasal membrane. Additionally, the in situ gel (ISG) system has gained attention owing to its ability to extend the retention time of administered formulations within the nasal cavity. When combined with lipid-based nanoparticles, the ISG system creates a synergistic effect, further enhancing the overall effectiveness of brain-targeted delivery strategies. This comprehensive review provides a thorough investigation of intranasal administration. It delves into the strengths and limitations of this specific delivery route by considering the anatomical complexities and influential factors that play a role during dosing. Furthermore, this study introduces strategic approaches for incorporating nanoparticles and ISG delivery within the framework of intranasal applications. Finally, the review provides recent information on approved products and the clinical trial status of products related to intranasal administration, along with the inclusion of quality-by-design-related insights.
Topics: Administration, Intranasal; Blood-Brain Barrier; Brain; Drug Delivery Systems; Lipids; Liposomes; Nanoparticles; Nasal Mucosa
PubMed: 38414526
DOI: 10.2147/IJN.S439181 -
International Journal of Molecular... Feb 2024Kinase D-interacting substrate of 220 kDa (Kidins220) is a transmembrane protein that participates in neural cell survival, maturation, and plasticity. Mutations in the...
Kinase D-interacting substrate of 220 kDa (Kidins220) is a transmembrane protein that participates in neural cell survival, maturation, and plasticity. Mutations in the human gene are associated with a neurodevelopmental disorder ('SINO' syndrome) characterized by spastic paraplegia, intellectual disability, and in some cases, autism spectrum disorder. To better understand the pathophysiology of KIDINS220-linked pathologies, in this study, we assessed the sensory processing and social behavior of transgenic mouse lines with reduced Kidins220 expression: the CaMKII-driven conditional knockout (cKO) line, lacking Kidins220 in adult forebrain excitatory neurons, and the Kidins220floxed line, expressing constitutively lower protein levels. We show that alterations in Kidins220 expression levels and its splicing pattern cause impaired response to both auditory and olfactory stimuli. Both transgenic lines show impaired startle response to high intensity sounds, with preserved pre-pulsed inhibition, and strongly reduced social odor recognition. In the Kidins220floxed line, olfactory alterations are associated with deficits in social memory and increased aggressive behavior. Our results broaden our knowledge of the SINO syndrome; understanding sensory information processing and its deviations under neuropathological conditions is crucial for devising future therapeutic strategies to enhance the quality of life of affected individuals.
Topics: Adult; Animals; Humans; Mice; Autism Spectrum Disorder; Membrane Proteins; Mice, Transgenic; Nerve Tissue Proteins; Perception; Quality of Life; Social Behavior; Sensation
PubMed: 38397009
DOI: 10.3390/ijms25042334 -
ENeuro Mar 2024Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions and even causes mental...
Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions and even causes mental dysfunctions such as depression and anxiety disorders. In this article, we conducted a multimodal study cross-sectionally and longitudinally, to evaluate how neuropathic pain affects the brain. Using the spared nerve injury (SNI) model which promotes long-lasting mechanical allodynia, results showed that neuropathic pain deeply modified the intrinsic organization of the brain functional network 2 weeks after injury. There are significant changes in the activity of the left thalamus (Th_L) and left olfactory bulb (OB_L) brain regions after SNI, as evidenced by both the blood oxygen level-dependent (BOLD) signal and c-Fos expression. Importantly, these changes were closely related to mechanical pain behavior of rats. However, it is worth noting that after morphine administration for analgesia, only the increased activity in the TH region is reversed, while the decreased activity in the OB region becomes more prominent. Functional connectivity (FC) and c-Fos correlation analysis further showed these two regions of interest (ROIs) exhibit different FC patterns with other brain regions. Our study comprehensively revealed the adaptive changes of brain neural networks induced by nerve injury in both cross-sectional and longitudinal dimensions and emphasized the abnormal activity and FC of Th_L and OB_L in the pathological condition. It provides reliable assistance in exploring the intricate mechanisms of diseases.
Topics: Humans; Rats; Animals; Rats, Sprague-Dawley; Cross-Sectional Studies; Neuralgia; Brain; Hyperalgesia; Disease Models, Animal
PubMed: 38346901
DOI: 10.1523/ENEURO.0272-23.2024 -
PloS One 2024Many soft-bodied animals have extensive peripheral nervous systems (PNS) with significant sensory roles. One such, the sea slug Pleurobranchaea californica, uses PNS...
Many soft-bodied animals have extensive peripheral nervous systems (PNS) with significant sensory roles. One such, the sea slug Pleurobranchaea californica, uses PNS computations in its chemotactile oral veil (OV) in prey tracking, averaging olfactory stimuli across the OV to target likely source direction, or "stimulus place". This suggests a peripheral subepithelial network (SeN) interconnecting sensory sites to compute the directional average. We pursued anatomy and connectivity of previously described ciliated putative sensory cells on OV papillae. Scanning electron microscopy (SEM) confirmed paddle-shaped cilia in clusters. Anti-tubulin and phalloidin staining showed connections to branching nervelets and muscle fibers for contraction and expansion of papillae. Ciliary cell processes could not be traced into nerves, consistent with sensory transmission to CNS via secondary afferents. Anti-tyrosine hydroxylase-stained ciliated cells in clusters and revealed an at least partially dopaminergic subepithelial network interconnecting clusters near and distant, connections consistent with PNS averaging of multiple stimulated loci. Other, unidentified, SeN neurotransmitters are likely. Confirming chemotactile functions, perfusible suction electrodes recorded ciliary spiking excited by both mechanical and appetitive chemical stimuli. Stimuli induced sensory nerve spiking like that encoding stimulus place. Sensory nerve spikes and cilia cluster spikes were not identifiable as generated by the same neurons. Ciliary clusters likely drive the sensory nerve spikes via SeN, mediating appetitive and stimulus place codes to CNS. These observations may facilitate future analyses of the PNS in odor discrimination and memory, and also suggest such SeNs as potential evolutionary precursors of CNS place-coding circuitry in the segmented, skeletonized protostomes and deuterostomes.
Topics: Animals; Pleurobranchaea; Peripheral Nervous System; Neurons; Aplysia; Predatory Behavior
PubMed: 38329975
DOI: 10.1371/journal.pone.0296872