Quantitative evaluation of orofacial motor function in mice: The pasta gnawing test, a voluntary and stress-free behavior test

AbstractBackgroundEvaluation of motor deficits in rodents is mostly restricted to limb motor tests that are often high stressors for the animals.New methodTo test rodents for orofacial motor impairments in a stress-free environment, we established the pasta gnawing test by measuring the biting noise of mice that eat a piece of spaghetti. Two parameters were evaluated, the biting speed and the biting peaks per biting episode. To evaluate the power of this test compared to commonly used limb motor and muscle strength tests, three mouse models of Parkinson’s disease, amyotrophic lateral sclerosis and Niemann-Pick disease were tested in the pasta gnawing test, RotaRod and wire suspension test.ResultsOur results show that the pasta gnawing test reliably displays orofacial motor deficits.Comparison with existing methodsThe test is especially useful as additional motor test in early onset disease models, since it shows first deficits later than the RotaRod or wire suspension test. The test depends on a voluntary eating behavior of the animal with only a short-time food deprivation and should thus be stress-free.ConclusionsThe pasta gnawing test represents a valuable tool to analyze orofacial motor deficits in different early onset disease models

Synchronisation in networks of delay-coupled type-I excitable systems

We use a generic model for type-I excitability (known as the SNIPER or SNIC model) to describe the local dynamics of nodes within a network in the presence of non-zero coupling delays. Utilising the method of the Master Stability Function, we investigate the stability of the zero-lag synchronised dynamics of the network nodes and its dependence on the two coupling parameters, namely the coupling strength and delay time. Unlike in the FitzHugh-Nagumo model (a model for type-II excitability), there are parameter ranges where the stability of synchronisation depends on the coupling strength and delay time. One important implication of these results is that there exist complex networks for which the adding of inhibitory links in a small-world fashion may not only lead to a loss of stable synchronisation, but may also restabilise synchronisation or introduce multiple transitions between synchronisation and desynchronisation. To underline the scope of our results, we show using the Stuart-Landau model that such multiple transitions do not only occur in excitable systems, but also in oscillatory ones.Comment: 10 pages, 9 figure

Understanding the enhanced synchronization of delay-coupled networks with fluctuating topology

We study the dynamics of networks with coupling delay, from which the connectivity changes over time. The synchronization properties are shown to depend on the interplay of three time scales: the internal time scale of the dynamics, the coupling delay along the network links and time scale at which the topology changes. Concentrating on a linearized model, we develop an analytical theory for the stability of a synchronized solution. In two limit cases the system can be reduced to an “effective” topology: In the fast switching approximation, when the network fluctuations are much faster than the internal time scale and the coupling delay, the effective network topology is the arithmetic mean over the different topologies. In the slow network limit, when the network fluctuation time scale is equal to the coupling delay, the effective adjacency matrix is the geometric mean over the adjacency matrices of the different topologies. In the intermediate regime the system shows a sensitive dependence on the ratio of time scales, and specific topologies, reproduced as well by numerical simulations. Our results are shown to describe the synchronization properties of fluctuating networks of delay-coupled chaotic maps

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay

Stable Mutated tau441 Transfected SH-SY5Y Cells as Screening Tool for Alzheimer’s Disease Drug Candidates

The role of hyperphosphorylation of the microtubule-associated protein tau in the pathological processes of several neurodegenerative diseases is becoming better understood. Consequently, development of new compounds capable of preventing tau hyperphosphorylation is an increasingly hot topic. For this reason, dependable in vitro and in vivo models that reflect tau hyperphosphorylation in human diseases are needed. In this study, we generated and validated an in vitro model appropriate to test potential curative and preventive compound effects on tau phosphorylation. For this purpose, a stably transfected SH-SY5Y cell line was constructed over-expressing mutant human tau441 (SH-SY5Y-TMHT441). Analyses of expression levels and tau phosphorylation status in untreated cells confirmed relevance to human diseases. Subsequently, the effect of different established kinase inhibitors on tau phosphorylation (e.g., residues Thr231, Thr181, and Ser396) was examined. It was shown with several methods including immunosorbent assays and mass spectrometry that the phosphorylation pattern of tau in SH-SY5Y-TMHT441 cells can be reliably modulated by these compounds, specifically targeting JNK, GSK-3, CDK1/5, and CK1. These four protein kinases are known to be involved in in vivo tau phosphorylation and are therefore authentic indicators for the suitability of this new cell culture model for tauopathies

Data for: Homozygosity of BACHD rats not only causes strong behavioral deficits in female rats but also a reduced breeding success

Raw data of experiments shown in main manuscript and statistical results of ANOVA shown in Figure 6.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Leukotriene Signaling as a Target in α-Synucleinopathies

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB