Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis.

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.

Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging.

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.

An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy in neuroscience.

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.

Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning.

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.

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice.

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.

Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination.

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.

Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling.

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-3ß, 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.