Neuro-Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

Aims: Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants. Methods: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39 × 106 mesenchymal and hemopoietic human stem cells, containing 5 × 105 of CD34+ cells), which showed anti-inflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle. Results: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Cell-treated mutants had reduced muscle atrophy and lumbar motor neuron degeneration. This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3ß (GSK-3ß). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group. Conclusion: The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation. © 2019 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons LtdWe thank ?5-100? Russian Excellence Program, Prof. Daniel C. Anthony, Diana Babayevskaya, and Arina Kosakova for their highly valuable contribution. ?Neuro-Cells? preparation was provided by Neuroplast BV, Maastricht, Netherlands

Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors

Background: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2−/−) are naturally highly aggressive, while heterozygous mice (Tph2+/−) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically ‘susceptible’ heterozygous mice (Tph2+/−). Methods: Tph2+/− male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. Results: Stressed Tph2+/− mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/− mice. Limitations: Rescue experiments would help to verify causal relationships of reported changes. Conclusions: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes. © 2020 The Authors602805Seventh Framework Programme, FP7Deutsche Forschungsgemeinschaft, DFG: CRC TRR 58 A1/A5Horizon 2020 Framework Programme, H2020: 728018Russian Foundation for Basic Research, RFBR: 15-04-03602Deutsche Forschungsgemeinschaft, DFGRussian Foundation for Basic Research, RFBRThe authors’ work reported here was supported Deutsche Forschungsgemeinschaft (DFG: CRC TRR 58 A1/A5), the European Union's Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype) and the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE) (to KPL and TS), the “5-100” Russian Academic Excellence Project (to KPL and TS) and the Russian Foundation of Basic Research (RFBR Grant No. 15-04-03602 to TS). We appreciate the valuable technical help of Dr. Joao Costa-Nunes and Dolores Bonopartos with this project

Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2: Evidence for Altered Myelination-Related Processes

The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2−/−) mice. In heterozygous male mice (Tph2+/−), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2+/− mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2+/− females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2+/− mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Seventh Framework Programme, FP7: 602805; Deutsche Forschungsgemeinschaft, DFG: CRC TRR58A1/A5; Russian Academy of Sciences, РАН: N0520-2019-0031; Horizon 2020: 101007642, 728018Funding: The authors’ animal work reported here was supported by Deutsche Forschungsgemein-schaft (DFG:CRC TRR58A1/A5), the European Union’s Seventh Framework Programme (FP7/2007– 2013) under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNice) (to K.P.L. and T.S.) and Grant No. 101007642 (PhytoAPP) (to D.A. and T.S.), and Swiss-Russian Cooperation grant RPG Russia 2020 (to S.W. and K.P.L.). Molecular data analysis was supported by RAS N0520-2019-0031 (to E.S. and T.S.). The sponsors had no role in study design, in the collection, analysis, and interpretation of data; in the writing of the report, and in the decision to submit the article for publication

Wounding induces dedifferentiation of epidermal Gata6+ cells and acquisition of stem cell properties

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Microstructure and electrical resistance evolution during sintering of a Ag nanoparticle paste

International audienceSilver nanoparticle pastes are promising materials for high temperature interconnection particularly above 400 °C. Reliability is a major concern in interconnection and it mainly depends on the behavior under the stress induced by thermal cycling. The joint microstructure is then a crucial parameter for reliability and determines the electrical, mechanical and thermal properties. Here, an investigation procedure is proposed to describe the microstructure of a joint and to monitor its evolution in real-time during the sintering. Combining electron and x-ray diffraction with electrical resistance measurement and secondary ion mass spectroscopy, our method is used on a sample made out of a home-made silver nanoparticle paste. The influence of the chemical composition of the paste on the microstructure is discussed as well as the compatibility of the paste for oxide interconnection. © 2015 IOP Publishing Ltd

Microstructure and electrical resistance evolution during sintering of a Ag nanoparticle paste

Silver nanoparticle pastes are promising materials for high temperature interconnection particularly above 400 °C. Reliability is a major concern in interconnection and it mainly depends on the behavior under the stress induced by thermal cycling. The joint microstructure is then a crucial parameter for reliability and determines the electrical, mechanical and thermal properties. Here, an investigation procedure is proposed to describe the microstructure of a joint and to monitor its evolution in real-time during the sintering. Combining electron and x-ray diffraction with electrical resistance measurement and secondary ion mass spectroscopy, our method is used on a sample made out of a home-made silver nanoparticle paste. The influence of the chemical composition of the paste on the microstructure is discussed as well as the compatibility of the paste for oxide interconnection. © 2015 IOP Publishing Ltd

Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5(-/-)) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5(-/-) mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5(-/-) mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5(-/-) mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5(-/-) mice. Together, St3gal5(-/-) mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities