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NPJ Microgravity Jun 2024Cognitive impairments have been reported in astronauts during spaceflights and documented in ground-based models of simulated microgravity (SMG) in animals. However, the...
Cognitive impairments have been reported in astronauts during spaceflights and documented in ground-based models of simulated microgravity (SMG) in animals. However, the neuronal causes of these behavioral effects remain largely unknown. We explored whether adult neurogenesis, known to be a crucial plasticity mechanism supporting memory processes, is altered by SMG. Adult male Long-Evans rats were submitted to the hindlimb unloading model of SMG. We studied the proliferation, survival and maturation of newborn cells in the following neurogenic niches: the subventricular zone (SVZ)/olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus, at different delays following various periods of SMG. SMG exposure for 7 days, but not shorter periods of 6 or 24 h, resulted in a decrease of newborn cell proliferation restricted to the DG. SMG also induced a decrease in short-term (7 days), but not long-term (21 days), survival of newborn cells in the SVZ/OB and DG. Physical exercise, used as a countermeasure, was able to reverse the decrease in newborn cell survival observed in the SVZ and DG. In addition, depending on the duration of SMG periods, transcriptomic analysis revealed modifications in gene expression involved in neurogenesis. These findings highlight the sensitivity of adult neurogenesis to gravitational environmental factors during a transient period, suggesting that there is a period of adaptation of physiological systems to this new environment.
PubMed: 38906877
DOI: 10.1038/s41526-024-00411-6 -
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 -
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: Humans; alpha-Synuclein; Disease Progression; Lewy Body Disease; Aged; Male; Female; Lewy Bodies; Aged, 80 and over; Alzheimer Disease; Brain; Brain Stem; Olfactory Bulb; Middle Aged
PubMed: 38879548
DOI: 10.1038/s41467-024-49402-x -
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 -
Scientific Data Jun 2024The development and aging of the brain constitute a lifelong dynamic process, marked by structural and functional changes that entail highly coordinated cellular...
The development and aging of the brain constitute a lifelong dynamic process, marked by structural and functional changes that entail highly coordinated cellular differentiation and epigenetic regulatory mechanisms. Chromatin accessibility serves as the foundational basis for genetic activity. However, the holistic and dynamic chromatin landscape that spans various brain regions throughout development and ageing remains predominantly unexplored. In this study, we employed single-nucleus ATAC-seq to generate comprehensive chromatin accessibility maps, incorporating data from 69,178 cells obtained from four distinct brain regions - namely, the olfactory bulb (OB), cerebellum (CB), prefrontal cortex (PFC), and hippocampus (HP) - across key developmental time points at 7 P, 3 M, 12 M, and 18 M. We delineated the distribution of cell types across different age stages and brain regions, providing insight into chromatin accessible regions and key transcription factors specific to different cell types. Our data contribute to understanding the epigenetic basis of the formation of different brain regions, providing a dynamic landscape and comprehensive resource for revealing gene regulatory programs during brain development and aging.
Topics: Animals; Chromatin; Mice; Aging; Brain; Epigenesis, Genetic; Hippocampus; Prefrontal Cortex
PubMed: 38866804
DOI: 10.1038/s41597-024-03382-1 -
EBioMedicine Jun 2024Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However,...
BACKGROUND
Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However, mechanisms by which SARS-CoV-2 disrupts brain function remain unclear and treatment strategies are lacking. We previously demonstrated neuroinflammation in the olfactory bulb of intranasally infected hamsters, followed by alpha-synuclein and tau accumulation in cortex, thus mirroring pathogenesis of neurodegenerative diseases such as Parkinson's or Alzheimer's disease.
METHODS
To uncover the sex-specific spatiotemporal profiles of neuroinflammation and neuronal dysfunction following intranasal SARS-CoV-2 infection, we quantified microglia cell density, alpha-synuclein immunoreactivity and inhibitory interneurons in cortical regions, limbic system and basal ganglia at acute and late post-recovery time points.
FINDINGS
Unexpectedly, microglia cell density and alpha-synuclein immunoreactivity decreased at 6 days post-infection, then rebounded to overt accumulation at 21 days post-infection. This biphasic response was most pronounced in amygdala and striatum, regions affected early in Parkinson's disease. Several brain regions showed altered densities of parvalbumin and calretinin interneurons which are involved in cognition and motor control. Of note, females appeared more affected.
INTERPRETATION
Our results demonstrate that SARS-CoV-2 profoundly disrupts brain homeostasis without neuroinvasion, via neuroinflammatory and protein regulation mechanisms that persist beyond viral clearance. The regional patterns and sex differences are in line with neurological deficits observed after SARS-CoV-2 infection.
FUNDING
Federal Ministry of Health, Germany (BMG; ZMV I 1-2520COR501 to G.G.), Federal Ministry of Education and Research, Germany (BMBF; 03COV06B to G.G.), Ministry of Science and Culture of Lower Saxony in Germany (14-76403-184, to G.G. and F.R.).
PubMed: 38865747
DOI: 10.1016/j.ebiom.2024.105191 -
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 -
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 -
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