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  • 1.
    Andersson, Gustav
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Orädd, Greger
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå Centre for Comparative Biology (UCCB).
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Novikov, Lev N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    In vivo Diffusion Tensor Imaging, Diffusion Kurtosis Imaging, and Tractography of a Sciatic Nerve Injury Model in Rat at 9.4T2018Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 8, artikel-id 12911Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries result in severe loss of sensory and motor functions in the afflicted limb. There is a lack of standardised models to non-invasively study degeneration, regeneration, and normalisation of neuronal microstructure in peripheral nerves. This study aimed to develop a non-invasive evaluation of peripheral nerve injuries, using diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and tractography on a rat model of sciatic nerve injury. 10 female Sprague Dawley rats were exposed to sciatic nerve neurotmesis and studied using a 9.4 T magnet, by performing DTI and DKI of the sciatic nerve before and 4 weeks after injury. The distal nerve stump showed a decrease in fractional anisotropy (FA), mean kurtosis (MK), axonal water fraction (AWF), and radial and axonal kurtosis (RK, AK) after injury. The proximal stump showed a significant decrease in axial diffusivity (AD) and increase of MK and AK as compared with the uninjured nerve. Both mean diffusivity (MD) and radial diffusivity (RD) increased in the distal stump after injury. Tractography visualised the sciatic nerve and the site of injury, as well as local variations of the diffusion parameters following injury. In summary, the described method detects changes both proximal and distal to the nerve injury.

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  • 2.
    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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  • 3.
    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

  • 4.
    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, ISSN 1663-4365, 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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  • 5. Hamodeh, Salah
    et al.
    Bozkurt, Ayse
    Mao, Haian
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Department of Cognitive Neurology, HIH for Clinical Brain Research, Otfried-Müller-Str. 27, 72076 Tübingen, Germany.
    Uncovering specific changes in network wiring underlying the primate cerebrotype2017Ingår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 222, nr 7, s. 3255-3266Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Regular scaling of brain networks during evolution has been proposed to be the major process leading to enlarged brains. Alternative views, however, suggest that deviations from regular scaling were crucial to the evolution of the primate brain and the emergence of different cerebrotypes. Here, we examined the scaling within the major link between the cerebellum and the cerebral cortex by studying the deep cerebellar nuclei (DCN). We compared the major axonal and dendritic wiring in the DCN of rodents and monkeys in search of regular scaling. We were able to confirm regular scaling within the density of neurons, the general dendritic length per neuron and the Purkinje cell axon length. However, we also observed specific modification of the scaling rules within the primates' largest and phylogenetically newest DCN, the dentate nucleus (LN/dentate). Our analysis shows a deviation from regular scaling in the predicted dendritic length per neuron in the LN/dentate. This reduction in the dendritic length is also associated with a smaller dendritic region-of-influence of these neurons. We also detected specific changes in the dendritic diameter distribution, supporting the theory that there is a shift in the neuronal population of the LN/dentate towards neurons that exhibit spatially restricted, clustered branching trees. The smaller dendritic fields would enable a larger number of network modules to be accommodated in the primate LN/dentate and would provide an explanation for the unique folded structure of the primate LN/dentate. Our results show that, in some brain regions, connectivity maximization (i.e., an increase of dendritic fields) is not the sole optimum and that increases in the number of network modules may be important for the emergence of a divergent primate cerebrotype.

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  • 6. Houston, Catriona M.
    et al.
    Diamanti, Efthymia
    Diamantaki, Maria
    Kutsarova, Elena
    Cook, Anna
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Department Cognitive Neurology, HertieInstitute for Clinical Brain Research, University of Tübingen, Germany.
    Brickley, Stephen G.
    Exploring the significance of morphological diversity for cerebellar granule cell excitability2017Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikel-id 46147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The relatively simple and compact morphology of cerebellar granule cells (CGCs) has led to the view that heterogeneity in CGC shape has negligible impact upon the integration of mossy fibre (MF) information. Following electrophysiological recording, 3D models were constructed from high-resolution imaging data to identify morphological features that could influence the coding of MF input patterns by adult CGCs. Quantification of MF and CGC morphology provided evidence that CGCs could be connected to the multiple rosettes that arise from a single MF input. Predictions from our computational models propose that MF inputs could be more densely encoded within the CGC layer than previous models suggest. Moreover, those MF signals arriving onto the dendrite closest to the axon will generate greater CGC excitation. However, the impact of this morphological variability on MF input selectivity will be attenuated by high levels of CGC inhibition providing further flexibility to the MF. CGC pathway. These features could be particularly important when considering the integration of multimodal MF sensory input by individual CGCs.

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  • 7.
    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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  • 8. Mao, Haian
    et al.
    Hamodeh, Salah
    Skodras, Angelos
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Quantitative organization of the excitatory synapses of the primate cerebellar nuclei: further evidence for a specialized architecture underlying the primate cerebellum2019Ingår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 224, nr 6, s. 1987-1998Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cerebellar intrinsic connectivity is of remarkable regularity with a similar build repeated many times over. However, several modifications of this basic circuitry occur that can provide important clues to evolutionary adaptations. We have observed differences in the wiring of the cerebellar output structures (the deep cerebellar nuclei, DCN) with higher dendritic length density in the phylogenetically newer DCN. In rats, we showed that an increase in wiring is associated with an increase in the presynaptic vesicular glutamate transporter 1 (vGluT1). In this study, we have extended our analysis to the rhesus monkey and can show similarities and differences between the two species. The similarities confirm a higher density in vGluT1+ boutons in the lateral (LN/dentate) and posterior interpositus nucleus compared to the phylogenetically older DCN. In general, we also observe a lower density of vGluT1 and 2+boutons in the monkey, which however, yields a similar number of excitatory boutons per neuron in both species. The only exception is the vGlut1+boutons in the macaque LN/dentate, which showed a significantly lower number of vGluT1+boutons per neuron. We also detected a higher percentage of co-labelled vGluT1 and 2 boutons in the macaque than we found in the rat. In summary, these results confirm that the hyposcalled dendrites of the monkey LN/dentate also show a lower number of vGluT1+boutons per neuron. These results provide further support of our model relating the dendritic morphology of the LN/dentate neurons to the morphology of the specially enlarged LN/dentate nucleus in primates.

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  • 9. Mao, Haian
    et al.
    Hamodeh, Salah
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Department of Cognitive Neurology, HIH for Clinical Brain Research, Tübingen, Germany.
    Quantitative Comparison Of Vesicular Glutamate Transporters in rat Deep Cerebellar Nuclei2018Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 376, s. 152-161Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The excitatory synapses of the rat deep cerebellar nuclei (DCN) were quantitatively analyzed by vesicular glutamate transporter 1 and 2 (vGluT1 and vGluT2) immunolabeling. We calculated the number and sizes of the labeled boutons and compared them between lateral/dentate nucleus (LN/DN), posterior interposed nucleus (PIN), anterior interposed nucleus (AIN), and medial nucleus (MN). The density of vGluT1+ boutons differs significantly within these nuclei. In contrast, the vGluT2+ bouton density is more similar between different nuclei. The phylogenetically newer DCN (LN/DN and PIN) have a 39% higher density of vGluT1+ boutons than the phylogenetically older DCN (AIN and MN). The volume of vGluT1+ boutons does not differ between the DCN, however the average volume of vGluT2+ boutons is larger in MN. In summary, our current results confirm and extend our previous findings showing that the increase in dendritic and axonal wiring in phylogenetically newer DCN is associated with an increase in vGluT1+ bouton density.

  • 10.
    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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  • 11.
    Mao, Haian
    et al.
    Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
    Xiao, Wenwu
    Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
    Hao, Zengming
    Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
    Wen, Shengjun
    Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research, Otfried-Müller Str. 27, Tübingen, Germany.
    Yang, Huaichun
    Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
    Sultan, Fahad
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wang, Chuhuai
    Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
    Cerebellar transcranial direct current stimulation modulates anticipatory postural adjustments in healthy adults2023Ingår i: Cerebellum, ISSN 1473-4222, E-ISSN 1473-4230, Vol. 23, nr 2, s. 383-390Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During forward swinging of the arm, the central nervous system must anticipate the effect of upraising upon the body. Little is known about the cerebellar network that coordinates these anticipatory postural adjustments (APAs). Stimulating different cerebellar regions with transcranial direct current stimulation (tDCS) and with different polarities modulated the APAs. We used surface electromyography (sEMG) to measure muscle activities in a bilateral rapid shoulder flexion task. The onset of APAs was altered after tDCS over the vermis, while the postural stability and the kinematics of arm raising were not affected. To our knowledge, this is the first human cerebellar-tDCS (c-tDCS) study to separate cerebellar involvement in core muscle APAs in bilateral rapid shoulder flexion. These data contribute to our understanding of the cerebellar network supporting APAs in healthy adults. Modulated APAs of the erector spinae by tDCS on the vermis may be related to altered cerebellar brain inhibition (CBI), suggesting the importance of the vermal-cerebral connections in APAs regulation.

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  • 12.
    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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  • 13.
    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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