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  • 1.
    Estévez-Silva, Héctor M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Departamento de Ciencias Médicas Básicas, Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Giacobbo, Bruno Lima
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Liu, Xijia
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet.
    Sultan, Fahad R.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis2022Ingår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 55, nr 5, s. 1356-1372Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 2.
    Giacobbo, B.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Axelsson, J.
    Ericsson, M.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Metabolic changes in an animal model of Amyotrophic Lateral Sclerosis by [F-18]-Fluorodeoxyglucose2020Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 47, nr Suppl. 1, s. S638-S638Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    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

  • 3.
    Giacobbo, B.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Özalay, Özgun
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Ericsson, Madelene
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Axelsson, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Rieckmann, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice2022Ingår i: Frontiers in Aging Neuroscience, E-ISSN 1663-4365, Vol. 14, artikel-id 795132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 4.
    Kolan, Shrikant S
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Björk, Karl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling2019Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikel-id 4276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 5.
    Lima Giacobbo, Bruno
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Metabolic changes in an animal model of amyotrophic lateral sclerosis evaluated by [18F]-FDG positron emission tomography2021Ingår i: Translational Neurodegeneration, ISSN 2047-9158, Vol. 10, nr 1, artikel-id 21Artikel i tidskrift (Refereegranskat)
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  • 6.
    Mao, Haian
    et al.
    Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Estévez-Silva, Héctor
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Instituto de Tecnologías Biomédicas, Departamento de Ciencias Médicas Básicas, Universidad de La Laguna, Tenerife, Spain.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning2022Ingår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1782, artikel-id 147842Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 7.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Temporal dynamics of brain plasticity: characterizing brain structural changes during skill acquisition2023Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    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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  • 8.
    Mediavilla, Tomás
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Özalay, Özgun
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Estévez-Silva, Héctor M.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Frias, Barbara
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Orädd, Greger
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Sultan, Fahad R.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Brozzoli, Claudio
    IMPACT, Centre de Recherche en Neurosciences de Lyon, Lyon, France; Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden.
    Garzón, Benjamín
    Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden; Department of Psychology, University of Gothenburg, Gothenburg, Sweden.
    Lövdén, Martin
    Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden; Department of Psychology, University of Gothenburg, Gothenburg, Sweden.
    Marcellino, Daniel J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination2022Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 11, artikel-id e77432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 9.
    Willekens, Stefanie M. A.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Morini, Federico
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Orädd, Greger
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Chotiwan, Nunya
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Visa, Montse
    Karolinska Institute, Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Stockholm, Sweden.
    Berggren, Per-Olof
    Karolinska Institute, Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Stockholm, Sweden.
    Ilegems, Erwin
    Karolinska Institute, Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Stockholm, Sweden.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Optically Cleared Umeå brain template: An MR-based brain template and atlas for optical projection and light sheet fluorescence microscopyManuskript (preprint) (Övrigt vetenskapligt)
  • 10.
    Willekens, Stefanie M. A.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Morini, Federico
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Orädd, Greger
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Hahn, Max
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Chotiwan, Nunya
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Visa, Montse
    The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Berggren, Per-Olof
    The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Ilegems, Erwin
    The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy in neuroscience2024Ingår i: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 18, artikel-id 1328815Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 11.
    Özalay, Özgun
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Giacobbo, Bruno Lima
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, Groningen, Netherlands.
    Pedersen, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Orädd, Greger
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Rieckmann, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi. Umeå universitet, Medicinska fakulteten, Institutionen för diagnostik och intervention. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik. Institute for Psychology, University of the Bundeswehr Munich, Neubiberg, Germany.
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging2024Ingår i: Communications Biology, E-ISSN 2399-3642, Vol. 7, nr 1, artikel-id 210Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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