| 1. |
- Chotiwan, Nunya, et al.
(författare)
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Type I interferon shapes brain distribution and tropism of tick-borne flavivirus
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.
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| 2. |
- Estévez-Silva, Héctor M., et al.
(författare)
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Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis
- 2022
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Ingår i: European Journal of Neuroscience. - : John Wiley & Sons. - 0953-816X .- 1460-9568. ; 55:5, s. 1356-1372
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.
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| 3. |
- Estévez-Silva, Héctor M., et al.
(författare)
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Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer’s Disease APP/PS1 Mouse Model
- 2022
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Ingår i: Neurotherapeutics. - : Springer. - 1933-7213 .- 1878-7479. ; 19, s. 1566-1587
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Tidskriftsartikel (refereegranskat)abstract
- Sigma-1 receptor agonists have recently gained a great deal of interest due to their anti-amnesic, neuroprotective, and neurorestorative properties. Compounds such as PRE-084 or pridopidine (ACR16) are being studied as a potential treatment against cognitive decline associated with neurodegenerative disease, also to include Alzheimer’s disease. Here, we performed in vitro experiments using primary neuronal cell cultures from rats to evaluate the abilities of ACR16 and PRE-084 to induce new synapses and spines formation, analyzing the expression of the possible genes and proteins involved. We additionally examined their neuroprotective properties against neuronal death mediated by oxidative stress and excitotoxicity. Both ACR16 and PRE-084 exhibited a concentration-dependent neuroprotective effect against NMDA- and H2O2-related toxicity, in addition to promoting the formation of new synapses and dendritic spines. However, only ACR16 generated dendritic spines involved in new synapse establishment, maintaining a more expanded activation of MAPK/ERK and PI3K/Akt signaling cascades. Consequently, ACR16 was also evaluated in vivo, and a dose of 1.5 mg/kg/day was administered intraperitoneally in APP/PS1 mice before performing the Morris water maze. ACR16 diminished the spatial learning and memory deficits observed in APP/PS1 transgenic mice via PI3K/Akt pathway activation. These data point to ACR16 as a pharmacological tool to prevent synapse loss and memory deficits associated with Alzheimer’s disease, due to its neuroprotective properties against oxidative stress and excitotoxicity, as well as the promotion of new synapses and spines through a mechanism that involves AKT and ERK signaling pathways.
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| 4. |
- Fuxe, Kjell, et al.
(författare)
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From the Golgi-Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: wiring and volume transmission.
- 2007
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Ingår i: Brain research reviews. - : Elsevier BV. - 0165-0173. ; 55:1, s. 17-54
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Tidskriftsartikel (refereegranskat)abstract
- After Golgi-Cajal mapped neural circuits, the discovery and mapping of the central monoamine neurons opened up for a new understanding of interneuronal communication by indicating that another form of communication exists. For instance, it was found that dopamine may be released as a prolactin inhibitory factor from the median eminence, indicating an alternative mode of dopamine communication in the brain. Subsequently, the analysis of the locus coeruleus noradrenaline neurons demonstrated a novel type of lower brainstem neuron that monosynaptically and globally innervated the entire CNS. Furthermore, the ascending raphe serotonin neuron systems were found to globally innervate the forebrain with few synapses, and where deficits in serotonergic function appeared to play a major role in depression. We propose that serotonin reuptake inhibitors may produce antidepressant effects through increasing serotonergic neurotrophism in serotonin nerve cells and their targets by transactivation of receptor tyrosine kinases (RTK), involving direct or indirect receptor/RTK interactions. Early chemical neuroanatomical work on the monoamine neurons, involving primitive nervous systems and analysis of peptide neurons, indicated the existence of alternative modes of communication apart from synaptic transmission. In 1986, Agnati and Fuxe introduced the theory of two main types of intercellular communication in the brain: wiring and volume transmission (WT and VT). Synchronization of phasic activity in the monoamine cell clusters through electrotonic coupling and synaptic transmission (WT) enables optimal VT of monoamines in the target regions. Experimental work suggests an integration of WT and VT signals via receptor-receptor interactions, and a new theory of receptor-connexin interactions in electrical and mixed synapses is introduced. Consequently, a new model of brain function must be built, in which communication includes both WT and VT and receptor-receptor interactions in the integration of signals. This will lead to the unified execution of information handling and trophism for optimal brain function and survival.
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| 5. |
- Giacobbo, B., et al.
(författare)
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Metabolic changes in an animal model of Amyotrophic Lateral Sclerosis by [F-18]-Fluorodeoxyglucose
- 2020
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 47:Suppl. 1, s. S638-S638
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Aim/Introduction: Amyotrophic Lateral Sclerosis (ALS) isa fatal neurodegenerative disorder that affects motorneurons, leading to muscle atrophy, paralysis, and eventuallyrespiratory failure. As with many other neurodegenerativedisorders, neuronal apoptosis is often associated with aloss of neuronal function and metabolic changes. [18F]-FDG is a well-validated biomarker to observe metabolicchanges in several brain disorders in humans, but its usein preclinical ALS research is not yet widespread. We aim tocompare [18F]-FDG uptake in SOD1G93A and wild-type beforethe development of terminal ALS symptoms.Materials and Methods: animals (6 SOD1WT, 7 SOD1G93A) were previouslygenotyped for mutant SOD1 using qPCR. When SOD1G93Aanimals started to develop ALS-like symptoms, animals werefasted for 4 hours and then injected intravenously with [18F]-FDG (injected dose of 10.8±2 MBq). One hour after injection,animals were placed in a microPET-CT scanner (MedisonanoPET-CT) and scanned (5 minutes for CT, 10 minutesfor PET). CT data was used for attenuation correction. Afterreconstruction, data were coregistered to an MRI templateand brain VOIs were created for several regions and dividedbetween left and right hemispheres using the Allen mousebrain atlas as a VOI template and the uptake of each ROIwas calculated to the whole-brain (SUVR) with T-test.P<0.05 was used for statistical significance.Results: OurSUVR data suggest a significant metabolic deregulationin SOD1G93A animals when analyzing [18F]-FDG in the brain.There was significant hypometabolism in anterior cingulatecortex (9% decrease in SOD1G93A vs. SOD1WT for both left and right hemispheres), in left entorhinal cortex (14%decrease), left hippocampus (12% decrease), right noseassociated primary somatosensory cortex (6% decrease),left supplementary somatosensory cortex (8% decrease),thalamus (11% and 8% for left and right, respectively),and right vermal region of the cerebellum (9% decrease).Hypermetabolism was, on the other hand, found in pallidum(12% increase in SOD1G93A vs. SOD1WT), lateral amygdala (41%and 64% increase in left and right, respectively), and corticalamygdala (98% increase for both left and right).Conclusion:These preliminary findings suggest a significant metabolicderegulation in animals with mutant SOD1 that developALS disease. Since animals were scanned after developingALS symptoms, further studies aimed to study brainmetabolism with [18F]-FDG in prodromal stages of diseaseare warranted. This would provide us better insight intothe usefulness of metabolic radiotracers for the detectionof disease onset and progression, as well as the efficacy oftherapeutic treatment strategies.References: None
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| 6. |
- Giacobbo, B., et al.
(författare)
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The Aged Striatum : Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP ND ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP ND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.
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| 7. |
- Kolan, Shrikant S, 1983-, et al.
(författare)
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Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.
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| 8. |
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| 9. |
- Luis-Ravelo, Diego, et al.
(författare)
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Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington's disease
- 2018
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 299, s. 137-147
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal expansion of the polyglutamine tract in the huntingtin protein (HTT). The toxicity of mutant HTT (mHTT) is associated with intermediate mHTT soluble oligomers that subsequently form intranuclear inclusions. Thus, interventions promoting the clearance of soluble mHTT are regarded as neuroprotective. Striatal neurons are particularly vulnerable in HD. Their degeneration underlies motor symptoms and striatal atrophy, the anatomical hallmark of HD. Recent studies indicate that autophagy may be activated by dopamine D-2 and D-3 receptor (D2R/D3R) agonists. Since autophagy plays a central role in the degradation of misfolded proteins, and striatal neurons express D2R and D3R, D2R/D3R agonists may promote the clearance of mHTT in striatal neurons. Here, this hypothesis was tested by treating 8 week old R6/1 mice with the D2R/D3R agonist pramipexole for 4 weeks. Pramipexole reduced striatal levels of soluble mHTT and increased the size of intranuclear inclusions in R6/1 mice. Furthermore, striatal DARPP-32 levels and motor functions were recovered. These effects were accompanied by an increase in LC3-II and a decrease in p62 in the striatum. Tollip, a selective adaptor of ubiquitinated polyQ proteins to LC3, was also reduced in the striata of R6/lmice but not in their wild-type littermates. No changes were detected in the cerebral cortex where D3R expression is very low, and behavioral and biochemical effects in the striatum were prevented by a D3R antagonist. The findings indicate that PPX protects striatal neurons by promoting the clearance of soluble mHTT through a D3R-mediated mechanism. The evidence of autophagy markers suggests that autophagy is activated, although it is not efficient at removing all mHTT recruited by the autophagic machinery as indicated by the increase in the size of intranuclear inclusions.
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| 10. |
- Mao, Haian, et al.
(författare)
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Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning
- 2022
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Ingår i: Brain Research. - : Elsevier. - 0006-8993 .- 1872-6240. ; 1782
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Tidskriftsartikel (refereegranskat)abstract
- Motor learning induces plasticity in multiple brain regions involving the cerebellum as a crucial player. Synaptic plasticity in the excitatory collaterals to the cerebellar output, the deep cerebellar nuclei (DCN), have recently been shown to be an important part of motor learning. These synapses are composed of climbing fiber (CF) and mossy fiber synapses, with the former conveying unconditioned and the latter conditioned responses in classical conditioning paradigms. The CF synapse on to the cerebellar cortex and the DCN express vesicular transporter 2 (vGluT2), whereas mossy fibers express vGluT1 and /or vGluT2 in their terminals. However, the underlying regulatory mechanism of vGluT expression in the DCN remains unknown. Here we confirm the increase of vGluT2 in a specific part of the DCN during the acquisition of a skilled reaching task in mice. Furthermore, our findings show that this is due to an increase in co-expression of vGluT2 in vGluT1 presynapses instead of the formation of new vGluT2 synapses. Our data indicate that remodeling of synapses – in contrast to synaptogenesis - also plays an important role in motor learning and may explain the presence of both vGluT's in some mossy fiber synapses.
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| 11. |
- Mediavilla, Tomás, et al.
(författare)
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Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination.
- 2022
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Ingår i: eLife. - : eLife Sciences Publications. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- From observations in rodents, it has been suggested that the cellular basis of learning-dependent changes, detected using structural MRI, may be increased dendritic spine density, alterations in astrocyte volume, and adaptations within intracortical myelin. Myelin plasticity is crucial for neurological function, and active myelination is required for learning and memory. However, the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown. We used a motor skill learning paradigm in male mice to evaluate experience-dependent brain plasticity by voxel-based morphometry (VBM) in longitudinal MRI, combined with a cross-sectional immunohistochemical investigation. Whole-brain VBM revealed nonlinear decreases in gray matter volume (GMV) juxtaposed to nonlinear increases in white matter volume (WMV) within GM that were best modeled by an asymptotic time course. Using an atlas-based cortical mask, we found nonlinear changes with learning in primary and secondary motor areas and in somatosensory cortex. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed an increase in myelin immunoreactivity followed by a return towards baseline levels. Further investigations using quantitative confocal microscopy confirmed these changes specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that nonlinear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity. Together, these observations indicate a nonlinear increase of intracortical myelin during learning and support the hypothesis that myelin is a component of structural changes observed by VBM during learning.
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| 12. |
- Mediavilla, Tomás, 1991-
(författare)
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Temporal dynamics of brain plasticity : characterizing brain structural changes during skill acquisition
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Traditionally, structural plasticity in the human brain has been considered to follow a linear or asymptotic increase over the course of training. However, recent studies using structural MRI revealed transient increases in grey matter volume (GMV) with learning. Furthermore, significant increases in white matter microstructure have been observed in white matter underlying motor cortex in animals at the last training day. Nevertheless, the involvement of activity-dependent myelination has received little attention and the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown.In this thesis, to characterize the dynamics of learning-related structural changes in the mouse brain, we have combined a motor skilled learning paradigm with longitudinal in vivo magnetic resonance imaging and immunohistochemical investigation. Wholebrain voxel-based morphometry (VBM) analysis revealed non-linear decreases in GMV juxtaposed with non-linear increases in white matter volume (WMV) in both cortical and subcortical areas of the brain. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed a transient increase in myelin immunoreactivity. Further investigation using confocal microscopy confirmed these changes, specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that nonlinear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity.Whole-brain VBM revealed non-linear decreases in GMV with learning in primary motor cortex (MOp), secondary motor cortex (MOs) and posterior parietal cortex (PTLp). These areas of the brain are known to be involved in sensory discrimination and motor selection. Using cross-sectional correlational tractography we found an increase in fractional anisotropy (FA) values with learning between MOs and MOp, PTLp and MOs and PTLp and MOp. Increases in FA values suggest an increase in connectivity, which can be attributed to an increase in axon density or myelination. Based on existent literature and our non-linear VBM changes with learning in the deep cerebellar nuclei we investigated synaptic plasticity using immunohistochemical examination of glutamate transporters. We found an increase of vesicular glutamate transporter 2 in pre-existing vesicular glutamate 1 synapses. Our data indicate that remodeling of synapses - in contrast to synaptogenesis – plays an important role in motor learning.Altogether, these results highlight the importance of non-linear structural plasticity in the acquisition of dexterous motor skill and stress the relevance of adaptive myelination in learning.
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| 13. |
- Olmedo-Díaz, Sonia, et al.
(författare)
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An altered blood–brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease
- 2017
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Ingår i: Neuroscience. - : Elsevier. - 0306-4522 .- 1873-7544. ; 362, s. 141-151
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Tidskriftsartikel (refereegranskat)abstract
- Brain iron accumulation is a common feature shared by several neurodegenerative disorders including Parkinson's disease. However, what produces this accumulation of iron is still unknown. In this study, the 6-hydroxydopamine (6-OHDA) hemi-parkinsonian rat model was used to investigate abnormal iron accumulation in substantia nigra. We investigated three possible causes of iron accumulation; a compromised blood-brain barrier (BBB), abnormal expression of ferritin, and neuroinflammation. We identified alterations in the BBB subsequent to the injection of 6-OHDA using gadolinium-enhanced magnetic resonance imaging (MRI). Moreover, detection of extravasated IgG suggested that peripheral components are able to enter the brain through a leaky BBB. Presence of iron following dopamine cell degeneration was studied by MRI, which revealed hypointense signals in the substantia nigra. The presence of iron deposits was further validated in histological evaluations. Furthermore, iron inclusions were closely associated with active microglia and with increased levels of L-ferritin indicating a putative role for microglia and L-ferritin in brain iron accumulation and dopamine neurodegeneration.
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| 14. |
- Piltti, Juha, 1982-, et al.
(författare)
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Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and change the S100 protein profile in human chondrosarcoma cells
- 2017
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Articular chondrocytes are slowly dividing cells that tend to lose their cell type-specific phenotype and ability to produce structurally and functionally correct cartilage tissue when cultured. Thus, culture conditions, which enhance the maintenance of chondrocyte phenotype would be very useful for cartilage research. Here we show that Rho-kinase inhibition by Y-27632 under hypoxic conditions efficiently maintains and even enhances chondrocyte-specific extracellular matrix production by chondrocytic cells. The effects of long-term Y-27632 exposure to human chondrosarcoma 2/8 cell phenotype maintenance and extracellular matrix production were studied at normoxia and at a 5% low oxygen atmosphere. Y-27632 treatment at normoxia induced ACAN and COL2A1 gene up-regulation and a minor increase of sulfated glycosaminoglycans (sGAGs), while type II collagen expression was not significantly up-regulated. A further increase in expression of ACAN and COL2A1 was achieved with Y-27632 treatment and hypoxia. The production of sGAGs increased by 65.8%, and ELISA analysis revealed a 6-fold up-regulation of type II collagen. Y-27632 also induced the up-regulation of S100-A1 and S100-B proteins and modified the expression of several other S100 protein family members, such as S100-A4, S100-A6, S100-A13 and S100-A16. The up-regulation of S100-A1 and S100-B proteins is suggested to enhance the chondrocytic phenotype of these cells.
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| 15. |
- Piltti, Juha, et al.
(författare)
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Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and modify S100 protein profiles in human chondrosarcoma cells
- 2017
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Ingår i: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Articular chondrocytes are slowly dividing cells that tend to lose their cell type-specific phenotype and ability to produce structurally and functionally correct cartilage tissue when cultured. Thus, culture conditions, which enhance the maintenance of chondrocyte phenotype would be very useful for cartilage research. Here we show that Rho-kinase inhibition by Y-27632 under hypoxic conditions efficiently maintains and even enhances chondrocyte-specific extracellular matrix production by chondrocytic cells. The effects of long-term Y-27632 exposure to human chondrosarcoma 2/8 cell phenotype maintenance and extracellular matrix production were studied at normoxia and at a 5% low oxygen atmosphere. Y-27632 treatment at normoxia induced ACAN and COL2A1 gene up-regulation and a minor increase of sulfated glycosaminoglycans (sGAGs), while type II collagen expression was not significantly up-regulated. A further increase in expression of ACAN and COL2A1 was achieved with Y-27632 treatment and hypoxia. The production of sGAGs increased by 65.8%, and ELISA analysis revealed a 6-fold up-regulation of type II collagen. Y-27632 also induced the up-regulation of S100-A1 and S100-B proteins and modified the expression of several other S100 protein family members, such as S100-A4, S100-A6, S100-A13 and S100-A16. The up-regulation of S100-A1 and S100-B proteins is suggested to enhance the chondrocytic phenotype of these cells.
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| 16. |
- Willekens, Stefanie M. A., et al.
(författare)
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An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy in neuroscience
- 2024
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Optical Projection Tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high resolution optical imaging techniques, ideally suited for ex vivo 3D whole mouse brain imaging. Although they exhibit high specificity for their targets, the anatomical detail provided by tissue autofluorescence remains limited.Methods: T1-weighted images were acquired from 19 BABB or DBE cleared brains to create an MR template using serial longitudinal registration. Afterwards, fluorescent OPT and LSFM images were coregistered/normalized to the MR template to create fusion images.Results: Volumetric calculations revealed a significant difference between BABB and DBE cleared brains, leading to develop two optimized templates, with associated tissue priors and brain atlas, for BABB (OCUM) and DBE (iOCUM). By creating fusion images, we identified virus infected brain regions, mapped dopamine transporter and translocator protein expression, and traced innervation from the eye along the optic tract to the thalamus and superior colliculus using cholera toxin B. Fusion images allowed for precise anatomical identification of fluorescent signal in the detailed anatomical context provided by MR.Discussion: The possibility to anatomically map fluorescent signals on magnetic resonance (MR) images, widely used in clinical and preclinical neuroscience, would greatly benefit applications of optical imaging of mouse brain. These specific MR templates for cleared brains enable a broad range of neuroscientific applications integrating 3D optical brain imaging.
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| 17. |
- Willekens, Stefanie M. A., et al.
(författare)
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Optically Cleared Umeå brain template : An MR-based brain template and atlas for optical projection and light sheet fluorescence microscopy
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high-resolution optical imaging techniques operating in the mm-cm range, ideally suited forex vivo3D whole mouse brain imaging. Although these techniques exhibit high sensitivity and specificity for antibody-labeled targets, the provided anatomical information remains limited. To allow anatomical mapping of fluorescent signal in whole brain, we developed a novel magnetic resonance (MR) – based template with its associated tissue priors and atlas labels, specifically designed for brains subjected to tissue processing protocols required for 3D optical imaging. We investigated the effect of tissue pre-processing and clearing on brain size and morphology and developed optimized templates for BABB/Murrays clear (OCUM) and DBE/iDISCO (iOCUM) cleared brains. By creating optical-(i)OCUM fusion images using our mapping procedure, we localized dopamine transporter and translocator protein expression and tracer innervation from the eye to the lateral geniculate nucleus of thalamus and superior colliculus. These fusion images allowed for precise anatomical identification of fluorescent signal in discrete brain areas. As such, these templates enable applications in a broad range of research areas integrating optical 3D brain imaging by providing an MR template for cleared brains.
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| 18. |
- Özalay, Özgun, et al.
(författare)
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Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging
- 2024
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal’s adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.
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