Dietary manipulation and caloric restriction in the development of mouse models relevant to neurological diseases

AbstractManipulation of diet such as increasing the level of fat or inducing insulin resistance has been shown to exacerbate the pathology in several animal models of neurological disease. Caloric restriction, however, has been demonstrated to extend the life span of many organisms. Reduced calorie consumption appears to increase the resistance of neurons to intracellular and extracellular stress and consequently improves the behavioural phenotype in animal models of neurological diseases, such as Alzheimer's disease. We review the evidence from a variety of mouse models that diet is a risk factor that can significantly contribute to the development of neurological diseases

On-going frontal alpha rhythms are dominant in passive state and desynchronize in active state in adult gray mouse lemurs

The gray mouse lemur (Microcebus murinus) is considered a useful primate model for translational research. In the framework of IMI PharmaCog project (Grant Agreement n°115009, www.pharmacog.org), we tested the hypothesis that spectral electroencephalographic (EEG) markers of motor and locomotor activity in gray mouse lemurs reflect typical movement-related desynchronization of alpha rhythms (about 8-12 Hz) in humans. To this aim, EEG (bipolar electrodes in frontal cortex) and electromyographic (EMG; bipolar electrodes sutured in neck muscles) data were recorded in 13 male adult (about 3 years) lemurs. Artifact-free EEG segments during active state (gross movements, exploratory movements or locomotor activity) and awake passive state (no sleep) were selected on the basis of instrumental measures of animal behavior, and were used as an input for EEG power density analysis. Results showed a clear peak of EEG power density at alpha range (7-9 Hz) during passive state. During active state, there was a reduction in alpha power density (8-12 Hz) and an increase of power density at slow frequencies (1-4 Hz). Relative EMG activity was related to EEG power density at 2-4 Hz (positive correlation) and at 8-12 Hz (negative correlation). These results suggest for the first time that the primate gray mouse lemurs and humans may share basic neurophysiologic mechanisms of synchronization of frontal alpha rhythms in awake passive state and their desynchronization during motor and locomotor activity. These EEG markers may be an ideal experimental model for translational basic (motor science) and applied (pharmacological and non-pharmacological interventions) research in Neurophysiology

P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The purinergic receptor P2x7 is expressed on myeloid cells as well as on CNS glial cells, and P2x7 activation has been shown to increase both glial and T-cell activation. These properties suggest a role in the development of autoimmune disease including multiple sclerosis.</p> <p>Methods</p> <p>The animal model of MS, experimental autoimmune encephalomyelitis (EAE) using myelin oligodendrocyte glycoprotein (MOG) peptide residues 35–55 was induced in wildtype C57BL6 mice and in P2x7 deficient mice ('P2x7 mice') that were backcrossed to C57BL6 mice. Disease progression was monitored by appearance of clinical signs, immunocytochemical staining to assess brain inflammation and neuronal damage, and by measurement of Tcell cytokine production.</p> <p>Results</p> <p>The incidence of EAE disease in P2x7 mice was reduced 4-fold compared to the wildtype mice; however the P2x7 mice that became ill had similar days of onset and clinical scores as the wildtype mice. Splenic T-cells isolated from P2x7 null mice produced greater IFNγ and IL-17 (from 3 to 12 fold greater levels) than wildtype cells, however cytokine production from P2x7 derived cells was not increased by a selective P2x7 agonist as was cytokine production from wildtype cells. Although infiltrating cells were detected in brains of both the P2x7 and wildtype mice, astroglial activation and axonal damage was reduced versus wildtype mice, and the distribution of astroglial activation was markedly distinct in the two strains. In contrast, microglial activation was similar in the two strains.</p> <p>Conclusion</p> <p>P2x7 deficiency resulted in compensatory changes leading to increased T-cell cytokine production, and activated T-cells were detected in the brains of P2x7 null mice with no clinical signs. However, the greatly reduced incidence of disease suggests that an initiating event is absent in these mice, and points to a role for astroglial P2x7 in development of EAE disease.</p

Octodon degus: A Model for the Cognitive Impairment Associated with Alzheimer's Disease

Octodon degus (O. degus) is a diurnal rodent that spontaneously develops several physiopathological conditions, analogous in many cases to those experienced by humans. In light of this, O. degus has recently been identified as a very valuable animal model for research in several medical fields, especially those concerned with neurodegenerative diseases in which risk is associated with ageing. O. degus spontaneously develops β-amyloid deposits analogous to those observed in some cases of Alzheimer’s disease (AD). Moreover, these deposits are thought to be the key feature for AD diagnosis, and one of the suggested causes of cell loss and cognitive deficit. This review aims to bring together information to support O. degus as a valuable model for the study of cerebral aging

Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes

BACKGROUND: Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration. METHODS: TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg(-1)) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation. RESULTS: At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this. CONCLUSION: These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing

Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins

In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ-null mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ-null compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists

The mouse Gene Expression Database (GXD): 2019 update.

The mouse Gene Expression Database (GXD) is an extensive, well-curated community resource freely available at www.informatics.jax.org/expression.shtml. Covering all developmental stages, GXD includes data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments in wild-type and mutant mice. GXD\u27s gene expression information is integrated with the other data in Mouse Genome Informatics and interconnected with other databases, placing these data in the larger biological and biomedical context. Since the last report, the ability of GXD to provide insights into the molecular mechanisms of development and disease has been greatly enhanced by the addition of new data and by the implementation of new web features. These include: improvements to the Differential Gene Expression Data Search, facilitating searches for genes that have been shown to be exclusively expressed in a specified structure and/or developmental stage; an enhanced anatomy browser that now provides access to expression data and phenotype data for a given anatomical structure; direct access to the wild-type gene expression data for the tissues affected in a specific mutant; and a comparison matrix that juxtaposes tissues where a gene is normally expressed against tissues, where mutations in that gene cause abnormalities

The embodied becoming of autism and childhood: a storytelling methodology

In this article I explore a methodology of storytelling as a means of bringing together research around autism and childhood in a new way, as a site of the embodied becoming of autism and childhood. Through reflection on an ethnographic story of embodiment, the body is explored as a site of knowledge production that contests its dominantly storied subjectivation as a ‘disordered’ child. Storytelling is used to experiment with a line of flight from the autistic-child-research assemblage into new spaces of potential and possibility where the becomings of bodies within the collision of autism and childhood can be celebrated

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotyp

Plant functional traits have globally consistent effects on competition.

Phenotypic traits and their associated trade-offs have been shown to have globally consistent effects on individual plant physiological functions, but how these effects scale up to influence competition, a key driver of community assembly in terrestrial vegetation, has remained unclear. Here we use growth data from more than 3 million trees in over 140,000 plots across the world to show how three key functional traits--wood density, specific leaf area and maximum height--consistently influence competitive interactions. Fast maximum growth of a species was correlated negatively with its wood density in all biomes, and positively with its specific leaf area in most biomes. Low wood density was also correlated with a low ability to tolerate competition and a low competitive effect on neighbours, while high specific leaf area was correlated with a low competitive effect. Thus, traits generate trade-offs between performance with competition versus performance without competition, a fundamental ingredient in the classical hypothesis that the coexistence of plant species is enabled via differentiation in their successional strategies. Competition within species was stronger than between species, but an increase in trait dissimilarity between species had little influence in weakening competition. No benefit of dissimilarity was detected for specific leaf area or wood density, and only a weak benefit for maximum height. Our trait-based approach to modelling competition makes generalization possible across the forest ecosystems of the world and their highly diverse species composition.We are especially grateful to the researchers whose long-term commitment to establish and maintain forest plots and their associated databases made this study possible, and to those who granted us data access: forest inventories and permanent plots of New Zealand, Spain (MAGRAMA), France, Switzerland, Sweden, US and Canada (for the provinces of Quebec provided by the Ministère des Ressources Naturelles du Québec, Ontario provided by OnTAP’s Growth and Yield Program of the Ontario Ministry of Natural Resources, Saskatchewan, Manitoba, New Brunswick, Newfoundland and Labrador), CTFS (BCI and LTER-Luquillo), Taiwan (Fushan), Cirad (Paracou with funding by CEBA, ANR-10-LABX-25-01), Cirad, MEFCP and ICRA (M’Baïki) and Japan. We thank MPI-BGC Jena, who host TRY, and the international funding networks supporting TRY (IGBP, DIVERSITAS, GLP, NERC, QUEST, FRB and GIS Climate). G.K. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Program (Demo-Traits project, no. 299340). The working group that initiated this synthesis was supported by Macquarie University and by Australian Research Council through a fellowship to M.W.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1647