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Publications (4 of 4) Show all publications
Mao, H., Mediavilla, T., Estévez-Silva, H., Marcellino, D. & Sultan, F. (2022). Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning. Brain Research, 1782, Article ID 147842.
Open this publication in new window or tab >>Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning
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2022 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1782, article id 147842Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
3D reconstruction, Cerebellum, Motor learning, Synapse
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-193154 (URN)10.1016/j.brainres.2022.147842 (DOI)000792764600002 ()35192848 (PubMedID)2-s2.0-85126004419 (Scopus ID)
Available from: 2022-03-22 Created: 2022-03-22 Last updated: 2023-09-05Bibliographically approved
Mediavilla, T., Özalay, Ö., Estévez-Silva, H. M., Frias, B., Orädd, G., Sultan, F. R., . . . Marcellino, D. J. (2022). Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination. eLIFE, 11, Article ID e77432.
Open this publication in new window or tab >>Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination
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2022 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e77432Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
eLife Sciences Publications, 2022
Keywords
motor skill learning, mouse, MRI, myelin, neuroscience, VBM
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-201415 (URN)10.7554/eLife.77432 (DOI)000890954100001 ()36350292 (PubMedID)2-s2.0-85142401457 (Scopus ID)
Funder
The Kempe Foundations, JCK-1922.2Magnus Bergvall Foundation, 2016-01639Swedish Research Council, 2015-01717Swedish Research Council, 2018-01047
Available from: 2022-12-01 Created: 2022-12-01 Last updated: 2023-09-05Bibliographically approved
Estévez-Silva, H. M., Mediavilla, T., Giacobbo, B. L., Liu, X., Sultan, F. R. & Marcellino, D. (2022). Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis. European Journal of Neuroscience, 55(5), 1356-1372
Open this publication in new window or tab >>Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis
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2022 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 55, no 5, p. 1356-1372Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
motor function, neuroprotection, preclinical research, pridopidine, sigma-1 receptor, SOD1G93A
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-192663 (URN)10.1111/ejn.15608 (DOI)000754221500001 ()35080077 (PubMedID)2-s2.0-85124540384 (Scopus ID)
Available from: 2022-02-21 Created: 2022-02-21 Last updated: 2023-09-05Bibliographically approved
Estévez-Silva, H. M., Cuesto, G., Romero, N., Brito-Armas, J. M., Acevedo-Arozena, A., Acebes, Á. & Marcellino, D. J. (2022). Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer’s Disease APP/PS1 Mouse Model. Neurotherapeutics, 19, 1566-1587
Open this publication in new window or tab >>Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer’s Disease APP/PS1 Mouse Model
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2022 (English)In: Neurotherapeutics, ISSN 1933-7213, Vol. 19, p. 1566-1587Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer, 2022
Keywords
ACR16, Alzheimer’s disease, Neurodegeneration, Neuroprotection, PRE-084, Sigma-1 receptor
National Category
Neurology Pharmacology and Toxicology Cell and Molecular Biology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-198498 (URN)10.1007/s13311-022-01280-1 (DOI)000836374300001 ()35917088 (PubMedID)2-s2.0-85135207109 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2022-08-09 Created: 2022-08-09 Last updated: 2022-12-01Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3706-1320

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