Acetylcholine (ACh) is an important neuromodulator in the nervous system implicated in many forms of cognitive and motor processing. Recent studies have used bacterial artificial chromosome (BAC) ...transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2-EYFP) to dissect cholinergic circuit connectivity and function using optogenetic approaches. We report that a mouse line used for this purpose also carries several copies of the vesicular acetylcholine transporter gene (VAChT), which leads to overexpression of functional VAChT and consequently increased cholinergic tone. We demonstrate that these mice have marked improvement in motor endurance. However, they also present severe cognitive deficits, including attention deficits and dysfunction in working memory and spatial memory. These results suggest that increased VAChT expression may disrupt critical steps in information processing. Our studies demonstrate that ChAT-ChR2-EYFP mice show altered cholinergic tone that fundamentally differentiates them from wild-type mice.
Extracting relevant properties of empirical signals generated by nonlinear, stochastic, and high-dimensional systems is a challenge of complex systems research. Open questions are how to ...differentiate chaotic signals from stochastic ones, and how to quantify nonlinear and/or high-order temporal correlations. Here we propose a new technique to reliably address both problems. Our approach follows two steps: first, we train an artificial neural network (ANN) with flicker (colored) noise to predict the value of the parameter, Formula: see text, that determines the strength of the correlation of the noise. To predict Formula: see text the ANN input features are a set of probabilities that are extracted from the time series by using symbolic ordinal analysis. Then, we input to the trained ANN the probabilities extracted from the time series of interest, and analyze the ANN output. We find that the Formula: see text value returned by the ANN is informative of the temporal correlations present in the time series. To distinguish between stochastic and chaotic signals, we exploit the fact that the difference between the permutation entropy (PE) of a given time series and the PE of flicker noise with the same Formula: see text parameter is small when the time series is stochastic, but it is large when the time series is chaotic. We validate our technique by analysing synthetic and empirical time series whose nature is well established. We also demonstrate the robustness of our approach with respect to the length of the time series and to the level of noise. We expect that our algorithm, which is freely available, will be very useful to the community.
One of the main limiting factors in the development of new magnesium (Mg) alloys with enhanced mechanical behavior is the need to use vast experimental campaigns for microstructure and property ...screening. For example, the influence of new alloying additions on the critical resolved shear stresses (CRSSs) is currently evaluated by a combination of macroscopic single-crystal experiments and crystal plasticity finite-element simulations (CPFEM). This time-consuming process could be considerably simplified by the introduction of high-throughput techniques for efficient property testing. The aim of this paper is to propose a new and fast, methodology for the estimation of the CRSSs of hexagonal close-packed metals which, moreover, requires small amounts of material. The proposed method, which combines instrumented nanoindentation and CPFEM modeling, determines CRSS values by comparison of the variation of hardness (H) for different grain orientations with the outcome of CPFEM. This novel approach has been validated in a rolled and annealed pure Mg sheet, whose H variation with grain orientation has been successfully predicted using a set of CRSSs taken from recent crystal plasticity simulations of single-crystal experiments. Moreover, the proposed methodology has been utilized to infer the effect of the alloying elements of an MN11 (Mg–1% Mn–1% Nd) alloy. The results support the hypothesis that selected rare earth intermetallic precipitates help to bring the CRSS values of basal and non-basal slip systems closer together, thus contributing to the reduced plastic anisotropy observed in these alloys.
Blazars are known for their variability on a wide range of timescales at all wavelengths. Most studies of TeV gamma-ray blazars focus on short timescales, especially during flares. With a decade of ...observations from the Fermi-LAT and VERITAS, we present an extensive study of the long-term multiwavelength radio-to-gamma-ray flux-density variability, with the addition of a couple of short-time radio-structure and optical polarization observations of the blazar 1ES 1215+303 (z = 0.130), with a focus on its gamma-ray emission from 100 MeV to 30 TeV. Multiple strong GeV gamma-ray flares, a long-term increase in the gamma-ray and optical flux baseline, and a linear correlation between these two bands are observed over the ten-year period. Typical HBL behaviors are identified in the radio morphology and broadband spectrum of the source. Three stationary features in the innermost jet are resolved by Very Long Baseline Array at 43.1, 22.2, and 15.3 GHz. We employ a two-component synchrotron self-Compton model to describe different flux states of the source, including the epoch during which an extreme shift in energy of the synchrotron peak frequency from infrared to soft X-rays is observed.
Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on ...cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.
Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and ...thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.
Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine ...or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT) from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN) and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Heart activity and long‐term function are regulated by the sympathetic and parasympathetic branches of the nervous system. Parasympathetic neurons have received increased attention recently because ...acetylcholine (ACh) has been shown to play protective roles in heart disease. However, parasympathetic innervation is sparse in the heart, raising the question of how cholinergic signaling regulates cardiomyocytes. We hypothesized that non‐neuronal secretion of ACh from cardiomyocytes plays a role in cholinergic regulation of cardiac activity. To test this possibility, we eliminated secretion of ACh exclusively from cardiomyocytes by targeting the vesicular acetylcholine transporter (VAChT). We find that lack of cardiomyocyte‐secreted ACh disturbs the regulation of cardiac activity and causes cardiomyocyte remodeling. Mutant mice present normal hemodynamic parameters under nonstressful conditions; however, following exercise, their heart rate response is increased. Moreover, hearts from mutant mice present increased oxidative stress, altered calcium signaling, remodeling, and hypertrophy. Hence, without cardiomyocyte‐derived ACh secretion, hearts from mutant mice show signs of imbalanced autonomic activity consistent with decreased cholinergic drive. These unexpected results suggest that cardiomyocyte‐derived ACh is required for maintenance of cardiac homeostasis and regulates critical signaling pathways necessary to maintain normal heart activity. We propose that this non‐neuronal source of ACh boosts parasympathetic cholinergic signaling to counterbalance sympathetic activity regulating multiple aspects of heart physiology.—Roy, A., Fields, W. C., Rocha‐Resende, C., Resende, R. R., Guatimosim, S., Prado, V. F., Gros, R., Prado, M. A. M., Cardiomyocyte‐secreted acetylcholine is required for maintenance of homeostasis in the heart. FASEB J. 27, 5072–5082 (2013). www.fasebj.org
The cervical spine is part of the axial skeleton and is responsible for protecting vital structures, such as the spinal cord and the vertebral arteries and veins. Traumatic injury to the cervical ...spine occurs in approximately 3% of blunt trauma injuries, and approximately 80% are below the level of C2. The AO Spine society divides the spine into four segments: the upper cervical spine (C0–C2), subaxial spine (C3–C7), thoracolumbar spine, and sacral spine. Various classifications have been proposed for the subaxial segment since that of Allen and Ferguson in 1982; however, none is universally accepted, and treatment remains controversial. The complex anatomy and biomechanics of the subaxial spine and the lack of a widely accepted classification system make these injuries difficult to evaluate on imaging. The Subaxial Injury Classification System (SLIC) uses fracture morphology, the integrity of discoligamentous complex, and neurological status to score the patient and determine between operative and non-operative management; however, other factors may influence management, such as time for immobilisation, osteoporosis, surgeon's experience, and hospital circumstances. SLIC classifies fracture morphology in a crescent order of severity based on Allen and Ferguson's classification. Compression fractures are the simpler ones, while both distraction injuries and translation/rotation are severe injuries, which are always associated with some degree of discoligamentous complex (DLC) injury. This article will review the indications for imaging, the basis of the SLIC classification, the different types of fracture morphology, evaluation of the DLC, and other features important in decision making in subaxial spine trauma.
Two near field models for the analysis of spatially fed planar array antennas are presented, compared and applied to a multi-frequency wideband direct layout optimization for mm-Wave 5G new radio ...(NR) indoor network coverage. One model is based on the direct application of the radiation equations directly derived from the A and F vector potentials. The second model is based on the superposition of far field contributions of all array elements, which are modelled as rectangular apertures with constant field. Despite the different assumptions made to develop both models, the degree of agreement between them in the computation of the radiated near field is very high. The relative error between the models is equal or lower than 3.2% at a plane 13λ from the array, and it decreases as the near field is computed further away from the array. Then, the faster model is employed in a general direct layout optimization procedure to shape the electromagnetic near field for application in an indoor femtocell to provide coverage with constant power in a private office. Results show that a magnitude ripple better than 1.5 dB can be achieved in an enlarged coverage area covering the whole n257 band of the 5G NR, corresponding to a 10.7% relative bandwidth.
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