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 (BPND), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BPND 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.

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.

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.

From observations in rodents, it has been suggested that the cellular basis of learning-dependent changes, detected using structural magnetic resonance imaging (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 non-linear decreases in grey matter volume (GMV) juxtaposed to non-linear increases in white matter volume (WMV) within GM that were best modelled by an asymptotic time course. Using an atlas-based cortical mask, we found non-linear 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 non-linear 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 non-linear 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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Background: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function and eventual death. Genetic background account for 10% of all ALS cases and several genes are associated with the onset and progression of disease in humans. Studies in humans have observed differences in glucose uptake in the brain using [ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG), however, no studies in animal models of ALS have been performed on the matter. The goal of this study was to evaluate ALS-related metabolic changes in [ 18 F]-FDG uptake within the brain of transgenic mice that express a mutated human SOD1 gene (hSOD1 G93A ). Methods: Animals were genotyped for the hSOD1 G93A mutation using PCR and divided into groups according to the presence (ALS) or absence (WT) of transgene. When transgenic ALS mice started to develop motor impairment, animals were scanned for 10 minutes using PET [ 18 F]-FDG. Gender-matched WT animals were scanned at similar ages as ALS animals. The images were coregistered to an [ 18 F]-FDG template and both the standardized uptake value (SUV) and the ratio of radioactivity of target regions to the mean radioactivity of the whole brain (TRR) were calculated for 19 volumes of interest. Results: Significant effects of genotype were observed in the overall metabolic activity assessed by both SUV and ratio-to-whole brain, in which ALS mice presented with lower metabolic activity in several regions when compared with age- and gender-matched WT mice. These changes were more pronounced in hippocampus, thalamus, and midbrain. A significant effect of gender was found in the SUV of several of the regions evaluated, although these gender-related differences were not observed after normalization to the whole-brain uptake. Conclusions: The differences in [ 18 F]-FDG uptake in the brain of ALS SOD1 animals suggest a significant metabolic impairment in several of the regions evaluated. Such differences might be due to a general hypometabolic state of the animals when compared to their WT littermates. These findings suggest a possible influence of disease in brain glucose uptake and open new possibilities for the understanding of the ALS pathophysiology using animal models, as well as a possible prognostic usage of [ 18 F]-FDG in ALS in humans.

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Around 12-20% of familial amyotrophic lateral sclerosis (fALS) are related to mutations in Cu/Zn superoxide dismutase (SOD1) that produce degeneration of motor neurons by a toxic gain-of-function. The insertion of the human SOD1 G93A mutation in transgenic mice produces cachexia, hindlimb paralysis and subsequent death due to SOD1 protein misfolding and aggregation. The sigma-1 receptor (S1R) prevents aberrant protein conformations by acting as a molecular chaperone. In addition, some mutations in S1R are linked to juvenile ALS indicating an important role for S1R. Here, we used a delayed onset G93A mouse model that allowed for a prolonged monitoring of preclinical symptoms before onset of the severe phenotype with subsequent death at 28-32 weeks. At 18 weeks of age, and prior to the appearance of any symptoms, S1R agonist or vehicle was continuously administered during 4 weeks by subcutaneous osmotic pumps. Mice were monitored weekly and three behavioral tests were used to monitor muscle strength, motor coordination and balance: Inverted Screen Test (IST), the Pole Test (PT) and Gait Analysis. We found that mice treated with S1R agonist were resistant to weight loss observed in vehicle treated mice and this negatively affected performance in IST and PT, where significant differences between groups were not observed. However, 5 weeks after S1R agonist treatment had ended, improved parameters in Gait Analysis were observed in treated mice compared to untreated mice. Our results indicate that a S1R agonist can modify the progression of ALS-associated motor deficits in a delayed onset SOD-1 G93A mouse model.