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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: 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 -
ACS Chemical Neuroscience Jun 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.
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 -
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 -
Acta Pharmacologica Sinica Jun 2024Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of...
Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca influx evoked by high K solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.
PubMed: 38862816
DOI: 10.1038/s41401-024-01275-y