Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research

Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long–Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D2/D3 receptor agonist pramipexole (0.1 mg kg−1, subcutaneous) or the psychostimulant amphetamine (0.5 mg kg−1, intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species

The cardiomyocyte "redox rheostat": Redox signalling via the AMPK-mTOR axis and regulation of gene and protein expression balancing survival and death.

Reactive oxygen species (ROS) play a key role in development of heart failure but, at a cellular level, their effects range from cytoprotection to induction of cell death. Understanding how this is regulated is crucial to develop novel strategies to ameliorate only the detrimental effects. Here, we revisited the fundamental hypothesis that the level of ROS per se is a key factor in the cellular response by applying different concentrations of H2O2 to cardiomyocytes. High concentrations rapidly reduced intracellular ATP and inhibited protein synthesis. This was associated with activation of AMPK which phosphorylated and inhibited Raptor, a crucial component of mTOR complex-1 that regulates protein synthesis. Inhibition of protein synthesis by high concentrations of H2O2 prevents synthesis of immediate early gene products required for downstream gene expression, and such mRNAs (many encoding proteins required to deal with oxidant stress) were only induced by lower concentrations. Lower concentrations of H2O2 promoted mTOR phosphorylation, associated with differential recruitment of some mRNAs to the polysomes for translation. Some of the upregulated genes induced by low H2O2 levels are cytoprotective. We identified p21Cip1/WAF1 as one such protein, and preventing its upregulation enhanced the rate of cardiomyocyte apoptosis. The data support the concept of a "redox rheostat" in which different degrees of ROS influence cell energetics and intracellular signalling pathways to regulate mRNA and protein expression. This sliding scale determines cell fate, modulating survival vs death

Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes

Background: Endothelin-1 stimulates Gq protein-coupled receptors to promote proliferation in dividing cells or hypertrophy in terminally differentiated cardiomyocytes. In cardiomyocytes, endothelin-1 rapidly (within minutes) stimulates protein kinase signaling, including extracellular-signal regulated kinases 1/2 (ERK1/2; though not ERK5), with phenotypic/physiological changes developing from approximately 12 h. Hypertrophy is associated with changes in mRNA/protein expression, presumably consequent to protein kinase signaling, but the connections between early, transient signaling events and developed hypertrophy are unknown. Results: Using microarrays, we defined the early transcriptional responses of neonatal rat cardiomyocytes to endothelin-1 over 4 h, differentiating between immediate early gene (IEG) and second phase RNAs with cycloheximide. IEGs exhibited differential temporal and transient regulation, with expression of second phase RNAs within 1 h. Of transcripts upregulated at 30 minutes encoding established proteins, 28 were inhibited >50% by U0126 (which inhibits ERK1/2/5 signaling), with 9 inhibited 25-50%. Expression of only four transcripts was not inhibited. At 1 h, most RNAs (approximately 67%) were equally changed in total and polysomal RNA with approximately 17% of transcripts increased to a greater extent in polysomes. Thus, changes in expression of most protein-coding RNAs should be reflected in protein synthesis. However, approximately 16% of transcripts were essentially excluded from the polysomes, including some protein-coding mRNAs, presumably inefficiently translated. Conclusion: The phasic, temporal regulation of early transcriptional responses induced by endothelin-1 in cardiomyocytes indicates that, even in terminally differentiated cells, signals are propagated beyond the primary signaling pathways through transcriptional networks leading to phenotypic changes (that is, hypertrophy). Furthermore, ERK1/2 signaling plays a major role in this response

Shake table testing of a tuned mass damper inerter (Tmdi)-equipped structure and nonlinear dynamic modeling under harmonic excitations

This paper presents preliminary experimental results from a novel shaking table testing campaign investigating the dynamic response of a two-degree-of-freedom (2DOF) physical specimen with a grounded inerter under harmonic base excitation and contributes a nonlinear dynamic model capturing the behavior of the test specimen. The latter consists of a primary mass connected to the ground through a high damping rubber isolator (HDRI) and a secondary mass connected to the primary mass through a second HDRI. Further, a flywheel-based rack-and-pinion inerter prototype device is used to connect the secondary mass to the ground. The resulting specimen resembles the tuned mass damper inerter (TMDI) configuration with grounded inerter analytically defined and numerically assessed by the authors in a number of previous publications. Physical specimens with three different inerter coefficients are tested on the shake table under sine-sweep excitation with three different amplitudes. Experimental frequency response functions (FRFs) are derived manifesting a softening nonlinear behavior of the specimens and enhanced vibration suppression with increased inerter coefficient. Further, a 2DOF parametric nonlinear model of the specimen is established accounting for non-ideal inerter device behavior and its potential to characterize experimental response time-histories, FRFs, and force-displacement relationships of the HDRIs and of the inerter is verified

Linguistic deficiencies in primary progressive multiple sclerosis

The aim of the present study is to investigate the linguistic profile of patients with Primary Progressive Multiple Sclerosis (PPMS) in relation to linguistic deficits associated with specific brain areas. Ten adults with PPMS were tested for the needs of the study and compared with healthy participants. The Boston Aphasia Naming Test, namely the tasks of listening comprehension, repetition, and reading comprehension, were administered. Results showed that the group of participants with PPMS had significantly lower performance in the above-mentioned tasks of comprehension compared to the control group. The findings are discussed

Effect of Soil-Structure Interaction on Nonlinear Dynamic Response of Reinforced Concrete Structures

Investigating the nonlinear dynamic response of reinforced concrete (RC) structures is of significant importance in understanding the expected behavior of these structures under dynamic loading. This becomes more crucial during the design of new or the assessment of the existing RC structures that are located in seismically active areas. The numerical simulation of this problem through the use of detailed 3D modeling is still a subject that has not been investigated thoroughly due to the significant challenges related to numerical instabilities and excessive computational demand, especially when the soil–structure interaction (SSI) phenomenon is accounted for. This study aims at presenting a nonlinear simulation tool to investigate this numerically cumbersome problem in order to provide further inside into the SSI effect on RC structures under nonlinear dynamic loading conditions. A detailed 3D numerical model of full-scale RC structures considering the SSI effect through modeling the nonlinear frame and soil domain is performed and discussed herein. The constructed models are subjected to dynamic loading conditions and an elaborate investigation is presented considering different type of structures, material properties of soil domains and depths. The RC structures and the soil domains are modeled through 8-noded hexahedral isoparametric elements, where the steel bar reinforcement of concrete is modeled as embedded beam and truss finite elements. The Ramberg–Osgood constitutive law was used for modeling the soil domain. It was shown that the SSI effect can significantly increase the flexibility of the system, altering the nonlinear dynamic response of the RC frames causing local damages that are not observed when the fixed-base model is analyzed. Furthermore, it was found that the structures founded on soft soil developed larger base-shear compared to the fixed-base model which is attributed to resonance phenomena connected to the SSI effect and the imposed accelerograms

Nanoscale noncollinear spin textures in thin Films of a D_2d Heusler compound

Magnetic nano-objects, namely antiskyrmions and Bloch skyrmions, have been found to coexist in single-crystalline lamellae formed from bulk crystals of inverse tetragonal Heusler compounds with D2d symmetry. Here evidence is shown for magnetic nano-objects in epitaxial thin films of Mn2RhSn formed by magnetron sputtering. These nano-objects exhibit a wide range of sizes with stability with respect to magnetic field and temperature that is similar to single-crystalline lamellae. However, the nano-objects do not form well-defined arrays, nor is any evidence found for helical spin textures. This is speculated to likely be a consequence of the poorer homogeneity of chemical ordering in the thin films. However, evidence is found for elliptically distorted nano-objects along perpendicular crystallographic directions within the epitaxial films, which is consistent with elliptical Bloch skyrmions observed in single-crystalline lamellae. Thus, these measurements provide strong evidence for the formation of noncollinear spin textures in thin films of Mn2RhSn. Using these films, it is shown that individual nano-objects can be deleted using a local magnetic field from a magnetic tip and collections of nano-objects can be similarly written. These observations suggest a path toward the use of these objects in thin films with D2d symmetry as magnetic memory elements