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BioRxiv : the Preprint Server For... Jun 2024Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological...
Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.
PubMed: 38895239
DOI: 10.1101/2024.06.02.596989 -
International Journal of Molecular... May 2024A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with...
A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of and its editing, however, are still largely undefined. In this study, we first demonstrated that editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant () exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" () counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors-both deficient () and mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of 's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity.
Topics: Animals; RNA Editing; Mice; Olfactory Perception; Adenosine Deaminase; Olfactory Bulb; RNA-Binding Proteins; Neurons; CRISPR-Cas Systems; Male; Mice, Inbred C57BL; Nerve Tissue Proteins
PubMed: 38892173
DOI: 10.3390/ijms25115985 -
Integrative and Comparative Biology Jun 2024Traits often do not evolve in isolation or vary independently of other traits. Instead, they can be affected by covariation, both within and across species. However, the...
Traits often do not evolve in isolation or vary independently of other traits. Instead, they can be affected by covariation, both within and across species. However, the importance of within species trait covariation and, critically, the degree to which it varies between species has yet to be thoroughly studied. Brain morphology is a trait of great ecological and behavioral importance, with regions that are hypothesized to vary in size based on behavioral and cognitive demands. Sizes of brain regions have also been shown to covary with each other across various taxa. Here we test the degree to which covariation in brain region sizes within species has been conserved across ten teleost fish species. These ten species span five orders, allowing us to examine how phylogenetic proximity influences similarities in intraspecific trait covariation. Our results showed a trend that similar patterns of brain region size covariation occur in more closely related species. Interestingly, there were certain brain region pairs that showed similar levels of covariation across all species regardless of phylogenetic distance, such as the telencephalon and optic tectum, while others, such as the olfactory bulb and the hypothalamus, varied more independently. Ultimately, the patterns of brain region covariation shown here suggest that evolutionary mechanisms or constraints can act on specific brain regions independently, and that these constraints can change over evolutionary time.
PubMed: 38886128
DOI: 10.1093/icb/icae075 -
Methods in Cell Biology 2024The prevalence of central nervous system (CNS) dysfunction as a result of disease or trauma remains a clinically unsolved problem which is raising increased awareness in...
The prevalence of central nervous system (CNS) dysfunction as a result of disease or trauma remains a clinically unsolved problem which is raising increased awareness in our aging society. Human Dental Pulp Stem Cells (hDPSCs) are excellent candidates to be used in tissue engineering and regenerative therapies of the CNS due to their neural differentiation ability and lack of tumorigenicity. Accordingly, they have been successfully used in animal models of spinal cord injury, stroke and peripheral neuropathies. The ideal therapy in brain injury should combine strategies aiming to protect the damaged lesion and, at the same time, accelerate brain tissue regeneration, thus promoting fast recovery while minimizing side or long-term effects. The use of bioresorbable nanopatterned poly(lactide-co-ɛ-caprolactone) (PLCL) polymeric scaffolds as hDPCSs carriers can represent an advantage for tissue regeneration. In this chapter, we describe the surgical procedures to implant functionalized bioresorbable scaffolds loaded with hDPSCs to improve the brain lesion microenvironment in an intracranial stab wound injury model severing the rostral migratory stream (RMS) that connects the brain subventricular zone (SVZ) and the olfactory bulb in nude mice. Additionally, we also describe the technical steps after animal sacrifice for histological tissue observation and characterization.
Topics: Dental Pulp; Animals; Humans; Tissue Scaffolds; Mice; Stem Cells; Disease Models, Animal; Mice, Nude; Stem Cell Transplantation; Wounds, Stab; Absorbable Implants; Brain Injuries; Tissue Engineering
PubMed: 38880526
DOI: 10.1016/bs.mcb.2024.03.011 -
Nature Communications Jun 2024Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in...
Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; alpha-Synuclein; Alzheimer Disease; Brain; Brain Stem; Disease Progression; Lewy Bodies; Lewy Body Disease; Olfactory Bulb
PubMed: 38879548
DOI: 10.1038/s41467-024-49402-x -
ACS Chemical Neuroscience Jul 2024Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves...
Brain Glucose Metabolism as a Readout of the Central Nervous System Impact of Cigarette Smoke Exposure and Withdrawal and the Effects of NFL-101, as an Immune-Based Drug Candidate for Smoking Cessation Therapy.
Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves currently investigated as an immune-based smoking cessation therapy in humans. However, the immune response to NFL-101 and its ability to induce significant changes in brain function remain to be demonstrated. Brain glucose metabolism was investigated using [F]fluoro-deoxy-glucose ([F]FDG) PET imaging in a mouse model of cigarette smoke exposure (CSE, 4-week whole-body inhalation, twice daily). Compared with control animals, the relative uptake of [F]FDG in CSE mice was decreased in the thalamus and brain stem ( < 0.001, = 14 per group) and increased in the hippocampus, cortex, cerebellum, and olfactory bulb ( < 0.001). NFL-101 induced a humoral immune response (specific IgGs) in mice and activated human natural-killer lymphocytes in vitro. In CSE mice, but not in control mice, single-dose NFL-101 significantly increased [F]FDG uptake in the thalamus ( < 0.01), thus restoring normal brain glucose metabolism after 2-day withdrawal in this nicotinic receptor-rich region. In tobacco research, [F]FDG PET imaging provides a quantitative method to evaluate changes in the brain function associated with the withdrawal phase. This method also showed the CNS effects of NFL-101, with translational perspectives for future clinical evaluation in smokers.
Topics: Animals; Glucose; Brain; Mice; Positron-Emission Tomography; Smoking Cessation; Humans; Male; Plant Extracts; Mice, Inbred C57BL; Fluorodeoxyglucose F18; Nicotiana; Smoke; Substance Withdrawal Syndrome
PubMed: 38875216
DOI: 10.1021/acschemneuro.4c00204 -
Genesis (New York, N.Y. : 2000) Jun 2024The organization of the olfactory glomerular map involves the convergence of olfactory sensory neurons (OSNs) expressing the same odorant receptor (OR) into glomeruli in... (Review)
Review
The organization of the olfactory glomerular map involves the convergence of olfactory sensory neurons (OSNs) expressing the same odorant receptor (OR) into glomeruli in the olfactory bulb (OB). A remarkable feature of the olfactory glomerular map formation is that the identity of OR instructs the topography of the bulb, resulting in thousands of discrete glomeruli in mice. Several lines of evidence indicate that ORs control the expression levels of various kinds of transmembrane proteins to form glomeruli at appropriate regions of the OB. In this review, we will discuss how the OR identity is decoded by OSNs into gene expression through intracellular regulatory mechanisms.
Topics: Animals; Mice; Olfactory Bulb; Olfactory Receptor Neurons; Receptors, Odorant
PubMed: 38874301
DOI: 10.1002/dvg.23610 -
Brain and Behavior Jun 2024Traumatic brain injury (TBI) refers to damage to brain tissue by mechanical or blunt force via trauma. TBI is often associated with impaired cognitive abilities, like... (Review)
Review
INTRODUCTION
Traumatic brain injury (TBI) refers to damage to brain tissue by mechanical or blunt force via trauma. TBI is often associated with impaired cognitive abilities, like difficulties in memory, learning, attention, and other higher brain functions, that typically remain for years after the injury. Lithium is an elementary light metal that is only utilized in salt form due to its high intrinsic reactivity. This current review discusses the molecular mechanisms and therapeutic and neuroprotective effects of lithium in TBI.
METHOD
The "Boolean logic" was used to search for articles on the subject matter in PubMed and PubMed Central, as well as Google Scholar.
RESULTS
Lithium's therapeutic action is extremely complex, involving multiple effects on gene secretion, neurotransmitter or receptor-mediated signaling, signal transduction processes, circadian modulation, as well as ion transport. Lithium is able to normalize multiple short- as well as long-term modifications in neuronal circuits that ultimately result in disparity in cortical excitation and inhibition activated by TBI. Also, lithium levels are more distinct in the hippocampus, thalamus, neo-cortex, olfactory bulb, amygdala as well as the gray matter of the cerebellum following treatment of TBI.
CONCLUSION
Lithium attenuates neuroinflammation and neuronal toxicity as well as protects the brain from edema, hippocampal neurodegeneration, loss of hemispheric tissues, and enhanced memory as well as spatial learning after TBI.
Topics: Brain Injuries, Traumatic; Humans; Neuroprotective Agents; Animals; Lithium; Brain; Lithium Compounds
PubMed: 38874089
DOI: 10.1002/brb3.3595 -
AJNR. American Journal of Neuroradiology Jun 2024Parkinson disease is a prevalent disease, with olfactory dysfunction recognized as an early nonmotor manifestation. It is sometimes difficult to differentiate Parkinson...
BACKGROUND AND PURPOSE
Parkinson disease is a prevalent disease, with olfactory dysfunction recognized as an early nonmotor manifestation. It is sometimes difficult to differentiate Parkinson disease from atypical parkinsonism using conventional MR imaging and motor symptoms. It is also known that olfactory loss occurs to a lesser extent or is absent in atypical parkinsonism. To the best of our knowledge, no study has examined olfactory bulb changes to differentiate Parkinson disease from atypical parkinsonism, even in an early diagnosis, and its association with conventional MR imaging findings. Hence, we aimed to assess the utility of olfactory bulb measurements in differentiating Parkinson disease from atypical parkinsonism even in the early stage.
MATERIALS AND METHODS
In this retrospective study, we enrolled 108 patients with Parkinson disease, 13 with corticobasal syndrome, 15 with multiple system atrophy, and 17 with progressive supranuclear palsy who developed parkinsonism. Thirty-nine age-matched healthy subjects served as controls. All subjects underwent conventional MR imaging and 3D FIESTA for olfactory bulb measurements using manual ROI quantification of the cross-sectional olfactory bulb area using the coronal plane. Bilateral olfactory bulb measurements were averaged. For group comparisons, we used the Welch test, and we assessed diagnostic accuracy using receiver operating characteristic analysis.
RESULTS
Patients with Parkinson disease had a mean olfactory bulb area of 4.2 (SD, 1.0 mm), significantly smaller than in age-matched healthy subjects (6.6 [SD, 1.7 mm], < .001), and those with corticobasal syndrome (5.4 [SD, 1.2 mm], < .001), multiple system atrophy (6.5 [SD, 1.2 mm], < .001), and progressive supranuclear palsy (5.4 [SD, 1.2 mm], < .001). The receiver operating characteristic analysis for the olfactory bulb area measurements showed good diagnostic performance in differentiating Parkinson disease from atypical parkinsonism, with an area under the curve of 0.87, an optimal cutoff value of 5.1 mm, and a false-positive rate of 18%. When we compared within 2 years of symptom onset, the olfactory bulb in Parkinson disease (4.2 [SD, 1.1 mm]) remained significantly smaller than in atypical parkinsonism (versus corticobasal syndrome (6.1 [SD, 0.7 mm]), < .001; multiple system atrophy (6.3 [SD, 1.4 mm]), < .001; and progressive supranuclear palsy (5.2 [1.3 mm], = .003, respectively).
CONCLUSIONS
3D FIESTA-based olfactory bulb measurement holds promise for distinguishing Parkinson disease from atypical parkinsonism, especially in the early stage.
PubMed: 38871365
DOI: 10.3174/ajnr.A8275 -
Behavioural Brain Research Jun 2024The role of the gut-brain axis in mental health disorders has been extensively studied. As the oral cavity is the starting point of the digestive tract, the role that... (Review)
Review
The role of the gut-brain axis in mental health disorders has been extensively studied. As the oral cavity is the starting point of the digestive tract, the role that the oral microbiota plays in mental health disorders has gained recent attention. Oral microbiota can enter the bloodstream and trigger inflammatory responses or translocate to the brain through the trigeminal nerve or olfactory system. Hence, the concept of the oral microbiota-brain axis has emerged. Several hypotheses have been suggested that the oral microbiota can enter the gastrointestinal tract and affect the gut-brain axis; however, literature describing oral-brain communication remains limited. This review summarizes the characteristics of oral microbiota and its mechanisms associated with mental health disorders. Through a comprehensive examination of the relationship between oral microbiota and various neuropsychiatric diseases, such as anxiety, depression, schizophrenia, autism spectrum disorder, epilepsy, Parkinson's disease, and dementia, this review seeks to identify promising avenues of future research.
PubMed: 38871130
DOI: 10.1016/j.bbr.2024.115111