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The Journal of Comparative Neurology Mar 2024During embryonic development, the olfactory placode (OP) generates migratory neurons, including olfactory pioneer neurons, cells of the terminal nerve (TN),...
During embryonic development, the olfactory placode (OP) generates migratory neurons, including olfactory pioneer neurons, cells of the terminal nerve (TN), gonadotropin-releasing hormone-1 (GnRH-1) neurons, and other uncharacterized neurons. Pioneer neurons from the OP induce olfactory bulb (OB) morphogenesis. In mice, GnRH-1 neurons appear in the olfactory system around mid-gestation and migrate via the TN axons to different brain regions. The GnRH-1 neurons are crucial in controlling the hypothalamic-pituitary-gonadal axis. Kallmann syndrome is characterized by impaired olfactory system development, defective OBs, secretion of GnRH-1, and infertility. The precise mechanistic link between the olfactory system and GnRH-1 development remains unclear. Studies in humans and mice highlight the importance of the prokineticin-2/prokineticin-receptor-2 (Prokr2) signaling pathway in OB morphogenesis and GnRH-1 neuronal migration. Prokr2 loss-of-function mutations can cause Kallmann syndrome (KS), and hence the Prokr2 signaling pathway represents a unique model to decipher the olfactory/GnRH-1 connection. We discovered that Prokr2 is expressed in the TN neurons during the critical period of GnRH-1 neuron formation, migration, and induction of OB morphogenesis. Single-cell RNA sequencing identified that the TN is formed by neurons distinct from the olfactory neurons. The TN neurons express multiple genes associated with KS. Our study suggests that the aberrant development of pioneer/TN neurons might cause the KS spectrum.
Topics: Humans; Animals; Mice; Kallmann Syndrome; Neurons; Gonadotropin-Releasing Hormone; Brain; Axons; Olfactory Bulb; Cell Movement
PubMed: 38488687
DOI: 10.1002/cne.25599 -
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 -
Otolaryngology--head and Neck Surgery :... Jul 2024
Topics: Humans; COVID-19; Stellate Ganglion; Autonomic Nerve Block; Olfaction Disorders; SARS-CoV-2
PubMed: 38415931
DOI: 10.1002/ohn.700 -
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 -
Integrative and Comparative Biology Feb 2024Pacific salmon (Oncorhynchus spp.) hatch and feed in freshwater habitats, migrate to sea to mature, and return to spawn at natal sites. The final, riverine stages of the...
Pacific salmon (Oncorhynchus spp.) hatch and feed in freshwater habitats, migrate to sea to mature, and return to spawn at natal sites. The final, riverine stages of the return migrations are mediated by chemical properties of the natal stream that they learned as juveniles. Like some other fishes, salmon growth is asymptotic; they grow continuously throughout life toward a maximum size. The continued growth of the nervous system may be plastic in response to environmental variables. Due to the ecological, cultural, and economic importance of Pacific salmon, individuals are often reared in hatcheries and released into the wild as juveniles to supplement natural populations. However, hatchery-reared individuals display lower survivorship and may also stray (i.e., spawn in a non-natal stream) at higher rates than their wild counterparts. Hatchery environments may lack stimuli needed to promote normal development of the nervous system, thus leading to behavioral deficits and a higher incidence of straying. This study compared the peripheral olfactory system and brain organization of hatchery-reared and wild-origin sockeye salmon fry (O. nerka). Surface area of the olfactory rosette, diameter of the olfactory nerve, total brain size, and size of major brain regions were measured from histological sections and compared between wild and hatchery-origin individuals. Hatchery-origin fish had significantly larger optic tecta, and marginally insignificant, yet noteworthy trends, existed in the valvula cerebelli (hatchery > wild) and olfactory bulbs (hatchery < wild). We also found a putative difference in olfactory nerve diameter (dmin) (hatchery > wild), but the validity of this finding needs further analyses with higher resolution methods Overall, these results provide insight into the potential effects of hatchery rearing on nervous system development in salmonids, and may explain behavioral deficits displayed by hatchery-origin individuals post-release.
PubMed: 38373826
DOI: 10.1093/icb/icae002 -
Nature Neuroscience Mar 2024Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later...
Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various stages of COVID-19. We detected an inflammatory type I interferon response in acute COVID-19 cases, which resolves in the late disease phase. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation, one neuronal with a direct focus on cranial nerve nuclei and a separate diffuse pattern affecting the whole brainstem. The latter reflects a bystander effect of the respiratory infection that spreads throughout the vascular unit and alters the transcriptional state of mainly oligodendrocytes, microglia and astrocytes, while alterations of the brainstem nuclei could reflect the connection of the immune system and the central nervous system via, for example, the vagus nerve. Our results indicate that even without persistence of severe acute respiratory syndrome coronavirus 2 in the central nervous system, local immune reactions are prevailing, potentially causing functional disturbances that contribute to neurological complications of COVID-19.
Topics: Humans; COVID-19; Proteomics; Brain Stem; Cerebellum; Gene Expression Profiling
PubMed: 38366144
DOI: 10.1038/s41593-024-01573-y -
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 -
ORL; Journal For Oto-rhino-laryngology... 2024The trigeminal nerve is a mixed cranial nerve responsible for the motor innervation of the masticatory muscles and the sensory innervation of the face, including the... (Review)
Review
BACKGROUND
The trigeminal nerve is a mixed cranial nerve responsible for the motor innervation of the masticatory muscles and the sensory innervation of the face, including the nasal cavities. Through its nasal innervation, we perceive sensations, such as cooling, tingling, and burning, while the trigeminal system mediates the perception of airflow. However, the intranasal trigeminal system has received little attention in the clinical evaluation of patients with nasal pathology.
SUMMARY
Testing methods that enable the clinical assessment of intranasal trigeminal function have recently been developed. This study aims to present the current clinical methods that can be utilised in everyday practice, as described in the literature. These methods include four assessment techniques: (1) the quick screening test of trigeminal sensitivity involves patients rating the intensity of ammonium vapour presented in a lipstick-like container. (2) The lateralisation test requires subjects to identify which nasal cavity is being stimulated by a trigeminal stimulus, such as eucalyptol or menthol, while the other side receives an odourless stimulus. (3) The trigeminal sticks test evaluates the trigeminal function similarly to the olfactory function using sticks filled with trigeminal stimulant liquids. (4) The automated CO2 stimulation device is used for measuring trigeminal pain thresholds, utilising intranasal CO2 stimuli to define the pain threshold.
KEY MESSAGES
Assessing intranasal trigeminal function clinically may prove useful in evaluating rhinology patients, particularly those who encounter nasal obstruction without anatomical blockage and those experiencing olfactory disorders with suspected trigeminal dysfunction. Despite their limitations, the presented methods may provide useful information about nasal patency, chemosensitivity, and pain sensation in the daily clinical practice of such patients, leading to better therapeutic decisions.
Topics: Humans; Trigeminal Nerve; Pain Threshold; Nasal Cavity
PubMed: 38330928
DOI: 10.1159/000536645