Differential Calcium Dependence of Axonal Versus Somatodendritic Dopamine Release, with Characteristics of Both in the Ventral Tegmental Area

Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) exhibit somatodendritic release of DA. Previous studies indicate a difference between the Ca2+ dependence of somatodendritic DA release in the SNc and that of axonal DA release in dorsal striatum. Here, we evaluated the Ca2+ dependence of DA release in the VTA and nucleus accumbens (NAc) shell for comparison with that in the SNc and dorsal striatum. Release of DA was elicited by single-pulse stimulation in guinea-pig brain slices and monitored with subsecond resolution using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. In dorsal striatum and NAc, DA release was not detectable at extracellular Ca2+ concentrations ([Ca2+]o) below 1 mM; however, a progressive increase in evoked extracellular DA concentration ([DA]o) was seen with [Ca2+]o ≥ 1.5 mM. By contrast, in SNc and VTA, robust increases in [DA]o could be elicited in 0.25 mM [Ca2+]o that were ∼60% of those seen in 1.5 mM [Ca2+]o. In SNc, a plateau in single-pulse evoked [DA]o was seen at [Ca2+]o ≥ 1.5 mM, mirroring the release plateau reported previously for pulse-train stimulation in SNc. In VTA, however, evoked [DA]o increased progressively throughout the range of [Ca2+]o tested (up to 3.0 mM). These functional data are consistent with the microanatomy of the VTA, which includes DA axon collaterals as well as DA somata and dendrites. Differences between axonal and somatodendritic release data were quantified using Hill analysis, which showed that the Ca2+ dependence of axonal DA release is low affinity with high Ca2+ cooperativity, whereas somatodendritic release is high affinity with low cooperativity. Moreover, this analysis revealed the dual nature of DA release in the VTA, with both somatodendritic and axonal contributions

Cocaine but Not Natural Reward Self-Administration nor Passive Cocaine Infusion Produces Persistent LTP in the VTA

SummaryPersistent drug-seeking behavior is hypothesized to co-opt the brain's natural reward-motivational system. Although ventral tegmental area (VTA) dopamine (DA) neurons represent a crucial component of this system, the synaptic adaptations underlying natural rewards and drug-related motivation have not been fully elucidated. Here, we show that self-administration of cocaine, but not passive cocaine infusions, produced a persistent potentiation of VTA excitatory synapses, which was still present after 3 months abstinence. Further, enhanced synaptic function in VTA was evident even after 3 weeks of extinction training. Food or sucrose self-administration induced only a transient potentiation of VTA glutamatergic signaling. Our data show that synaptic function in VTA DA neurons is readily but reversibly enhanced by natural reward-seeking behavior, while voluntary cocaine self-administration induced a persistent synaptic enhancement that is resistant to behavioral extinction. Such persistent synaptic potentiation in VTA DA neurons may represent a fundamental cellular phenomenon driving pathological drug-seeking behavior

Reduced Nucleus Accumbens SK Channel Activity Enhances Alcohol Seeking during Abstinence

SummaryThe cellular mechanisms underlying pathological alcohol seeking remain poorly understood. Here, we show an enhancement of nucleus accumbens (NAcb) core action potential firing ex vivo after protracted abstinence from alcohol but not sucrose self-administration. Increased firing is associated with reduced small-conductance calcium-activated potassium channel (SK) currents and decreased SK3 but not SK2 subunit protein expression. Furthermore, SK activation ex vivo produces greater firing suppression in NAcb core neurons from alcohol- versus sucrose-abstinent rats. Accordingly, SK activation in the NAcb core significantly reduces alcohol but not sucrose seeking after abstinence. In contrast, NAcb shell and lateral dorsal striatal firing ex vivo are not altered after abstinence from alcohol, and SK activation in these regions has little effect on alcohol seeking. Thus, decreased NAcb core SK currents and increased excitability represents a critical mechanism that facilitates motivation to seek alcohol after abstinence

Hatano-Nelson model with a periodic potential

We study a generalisation of the Hatano-Nelson Hamiltonian in which a periodic modulation of the site energies is present in addition to the usual random distribution. The system can then become localized by disorder or develop a band gap, and the eigenspectrum shows a wide variety of topologies. We determine the phase diagram, and perform a finite size scaling analysis of the localization transition.Comment: 7 pages, 10 figure

Tailoring Anderson localization by disorder correlations in 1D speckle potentials

We study Anderson localization of single particles in continuous, correlated, one-dimensional disordered potentials. We show that tailored correlations can completely change the energy-dependence of the localization length. By considering two suitable models of disorder, we explicitly show that disorder correlations can lead to a nonmonotonic behavior of the localization length versus energy. Numerical calculations performed within the transfer-matrix approach and analytical calculations performed within the phase formalism up to order three show excellent agreement and demonstrate the effect. We finally show how the nonmonotonic behavior of the localization length with energy can be observed using expanding ultracold-atom gases

High-Throughput Screening, Discovery, and Optimization to Develop a Benzofuran Class of Hepatitis C Virus Inhibitors

Using a high-throughput, cell-based HCV luciferase reporter assay to screen a diverse small-molecule compound collection (~300 000 compounds), we identified a benzofuran compound class of HCV inhibitors. The optimization of the benzofuran scaffold led to the identification of several exemplars with potent inhibition (EC50 25 µM), and excellent selectivity (selective index = CC50/EC50, > 371-fold). The structure–activity studies culminated in the design and synthesis of a 45-compound library to comprehensively explore the anti-HCV activity. The identification, design, synthesis, and biological characterization for this benzofuran series is discussed

Psychometric properties of lift and carry test in assessing people with stroke

ObjectiveTo investigate the psychometric properties of the Lift and Carry Test (LCT) time in people with stroke.DesignCross-sectional design.SettingUniversity based neurorehabilitation laboratory.ParticipantsTwenty-four people with stroke and 24 healthy controls.Outcome measuresLift and Carry Test (LCT), Fugl-Meyer Assessment of upper extremity and lower extremity, ankle dorsiflexor and plantarflexor muscle strength, Berg Balance Scale (BBS), Timed Up and Go (TUG) and Community Integration Measure.ResultsThe mean LCT time (29.70s) in people with stroke was more than double of that in healthy controls (13.70s). The LCT showed excellent intra-rater, inter-rater and test–retest reliability [intraclass correlation coefficient (ICC) = 0.943–1.000]. The LCT times demonstrated a significant negative correlation with the BBS score (rs = −0.771) and significant positive correlations with the TUG times (rs = 0.933). There was no significant correlation between LCT times and FMA score (p > 0.05). An optimal cut-off LCT time of 15.48 s (sensitivity = 95.8%, specificity = 87.5%) was identified to differentiate between people with stroke and healthy controls (area under the curve = 0.957).ConclusionLCT is an excellent clinical test for examining advanced functional ability in people with stroke and distinguishing people with stroke from healthy controls

Disruption of a GATA4/Ankrd1 Signaling Axis in Cardiomyocytes Leads to Sarcomere Disarray: Implications for Anthracycline Cardiomyopathy

Doxorubicin (Adriamycin) is an effective anti-cancer drug, but its clinical usage is limited by a dose-dependent cardiotoxicity characterized by widespread sarcomere disarray and loss of myofilaments. Cardiac ankyrin repeat protein (CARP, ANKRD1) is a transcriptional regulatory protein that is extremely susceptible to doxorubicin; however, the mechanism(s) of doxorubicin-induced CARP depletion and its specific role in cardiomyocytes have not been completely defined. We report that doxorubicin treatment in cardiomyocytes resulted in inhibition of CARP transcription, depletion of CARP protein levels, inhibition of myofilament gene transcription, and marked sarcomere disarray. Knockdown of CARP with small interfering RNA (siRNA) similarly inhibited myofilament gene transcription and disrupted cardiomyocyte sarcomere structure. Adenoviral overexpression of CARP, however, was unable to rescue the doxorubicin-induced sarcomere disarray phenotype. Doxorubicin also induced depletion of the cardiac transcription factor GATA4 in cardiomyocytes. CARP expression is regulated in part by GATA4, prompting us to examine the relationship between GATA4 and CARP in cardiomyocytes. We show in co-transfection experiments that GATA4 operates upstream of CARP by activating the proximal CARP promoter. GATA4-siRNA knockdown in cardiomyocytes inhibited CARP expression and myofilament gene transcription, and induced extensive sarcomere disarray. Adenoviral overexpression of GATA4 (AdV-GATA4) in cardiomyocytes prior to doxorubicin exposure maintained GATA4 levels, modestly restored CARP levels, and attenuated sarcomere disarray. Interestingly, siRNA-mediated depletion of CARP completely abolished the Adv-GATA4 rescue of the doxorubicin-induced sarcomere phenotype. These data demonstrate co-dependent roles for GATA4 and CARP in regulating sarcomere gene expression and maintaining sarcomeric organization in cardiomyocytes in culture. The data further suggests that concurrent depletion of GATA4 and CARP in cardiomyocytes by doxorubicin contributes in large part to myofibrillar disarray and the overall pathophysiology of anthracycline cardiomyopathy

Relativistic quantum effects of Dirac particles simulated by ultracold atoms

Quantum simulation is a powerful tool to study a variety of problems in physics, ranging from high-energy physics to condensed-matter physics. In this article, we review the recent theoretical and experimental progress in quantum simulation of Dirac equation with tunable parameters by using ultracold neutral atoms trapped in optical lattices or subject to light-induced synthetic gauge fields. The effective theories for the quasiparticles become relativistic under certain conditions in these systems, making them ideal platforms for studying the exotic relativistic effects. We focus on the realization of one, two, and three dimensional Dirac equations as well as the detection of some relativistic effects, including particularly the well-known Zitterbewegung effect and Klein tunneling. The realization of quantum anomalous Hall effects is also briefly discussed.Comment: 22 pages, review article in Frontiers of Physics: Proceedings on Quantum Dynamics of Ultracold Atom

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio