429 research outputs found
Basal ganglia, drug addiction and the neuroscience of maladaptive habits
The mammalian brain has developed memory systems mediating rigid, yet evolutionarily adaptive patterns of responding to invariant environmental stimuli and internal demands. Such memory systems promote the recall of specific response templates and the execution of inflexible actions to liberate buffering capacity for performing conscious, explicit cognitive processing. The dopamine-innervated neostriatum is central to the ability to learn such consistent associations between stimuli and actions implicitly. Controlled by their outcome when initially learned, actions succumb through iteration to the influence of triggering stimuli and progressively detach themselves from the pleasurable results originally produced, thereby becoming pervasive habits. This might be the case for drug-seeking and drug-taking behaviours, actions learned in part through dopamine-dependent drug-induced reinforcement when the drug is first experienced. With extended drug use, however, drugseeking actions might become conditioned to, and triggered by, specific exteroceptive stimuli and/or affective states, gradually becoming irrepressible forms of responding. We will review neuroanatomical, neuropharmacological and behavioural evidence suggesting that the basal ganglia play a prominent role in the shaping of drug addiction, here regarded as a pathological modification of otherwise adaptive habit learning systems mediated by the basal ganglia.peer-reviewe
Pranlukast Antagonizes CD49f and Reduces Sternness in Triple-Negative Breast Cancer Cells
Introduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clini-cally tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces con-formational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transacti-vation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients
Motor Decline in Clinically Presymptomatic Spinocerebellar Ataxia Type 2 Gene Carriers
BACKGROUND: Motor deficits are a critical component of the clinical characteristics of patients with spinocerebellar ataxia type 2. However, there is no current information on the preclinical manifestation of those motor deficits in presymptomatic gene carriers. To further understand and characterize the onset of the clinical manifestation in this disease, we tested presymptomatic spinocerebellar ataxia type 2 gene carriers, and volunteers, in a task that evaluates their motor performance and their motor learning capabilities. METHODS AND FINDINGS: 28 presymptomatic spinocerebellar ataxia type 2 gene carriers and an equal number of control volunteers matched for age and gender participated in the study. Both groups were tested in a prism adaptation task known to be sensible to both motor performance and visuomotor learning deficits. Our results clearly show that although motor learning capabilities are intact, motor performance deficits are present even years before the clinical manifestation of the disease start. CONCLUSIONS: The results show a clear deficit in motor performance that can be detected years before the clinical onset of the disease. This motor performance deficit appears before any motor learning or clinical manifestations of the disease. These observations identify the performance coefficient as an objective and quantitative physiological biomarker that could be useful to assess the efficiency of different therapeutic agents
Estimation of coupling between oscillators from short time series via phase dynamics modeling: limitations and application to EEG data
We demonstrate in numerical experiments that estimators of strength and
directionality of coupling between oscillators based on modeling of their phase
dynamics [D.A. Smirnov and B.P. Bezruchko, Phys. Rev. E 68, 046209 (2003)] are
widely applicable. Namely, although the expressions for the estimators and
their confidence bands are derived for linear uncoupled oscillators under the
influence of independent sources of Gaussian white noise, they turn out to
allow reliable characterization of coupling from relatively short time series
for different properties of noise, significant phase nonlinearity of the
oscillators, and non-vanishing coupling between them. We apply the estimators
to analyze a two-channel human intracranial epileptic electroencephalogram
(EEG) recording with the purpose of epileptic focus localization.Comment: 22 pages, 7 figures, the paper is to be published in Chaos, 2005,
vol.15, issue 2, see http://chaos.aip.org
Mechanisms explaining transitions between tonic and phasic firing in neuronal populations as predicted by a low dimensional firing rate model
Several firing patterns experimentally observed in neural populations have
been successfully correlated to animal behavior. Population bursting, hereby
regarded as a period of high firing rate followed by a period of quiescence, is
typically observed in groups of neurons during behavior. Biophysical
membrane-potential models of single cell bursting involve at least three
equations. Extending such models to study the collective behavior of neural
populations involves thousands of equations and can be very expensive
computationally. For this reason, low dimensional population models that
capture biophysical aspects of networks are needed.
\noindent The present paper uses a firing-rate model to study mechanisms that
trigger and stop transitions between tonic and phasic population firing. These
mechanisms are captured through a two-dimensional system, which can potentially
be extended to include interactions between different areas of the nervous
system with a small number of equations. The typical behavior of midbrain
dopaminergic neurons in the rodent is used as an example to illustrate and
interpret our results.
\noindent The model presented here can be used as a building block to study
interactions between networks of neurons. This theoretical approach may help
contextualize and understand the factors involved in regulating burst firing in
populations and how it may modulate distinct aspects of behavior.Comment: 25 pages (including references and appendices); 12 figures uploaded
as separate file
The 2HWC HAWC Observatory Gamma Ray Catalog
We present the first catalog of TeV gamma-ray sources realized with the
recently completed High Altitude Water Cherenkov Observatory (HAWC). It is the
most sensitive wide field-of-view TeV telescope currently in operation, with a
1-year survey sensitivity of ~5-10% of the flux of the Crab Nebula. With an
instantaneous field of view >1.5 sr and >90% duty cycle, it continuously
surveys and monitors the sky for gamma ray energies between hundreds GeV and
tens of TeV.
HAWC is located in Mexico at a latitude of 19 degree North and was completed
in March 2015. Here, we present the 2HWC catalog, which is the result of the
first source search realized with the complete HAWC detector. Realized with 507
days of data and represents the most sensitive TeV survey to date for such a
large fraction of the sky. A total of 39 sources were detected, with an
expected contamination of 0.5 due to background fluctuation. Out of these
sources, 16 are more than one degree away from any previously reported TeV
source. The source list, including the position measurement, spectrum
measurement, and uncertainties, is reported. Seven of the detected sources may
be associated with pulsar wind nebulae, two with supernova remnants, two with
blazars, and the remaining 23 have no firm identification yet.Comment: Submitted 2017/02/09 to the Astrophysical Journa
The Sensitivity of HAWC to High-Mass Dark Matter Annihilations
The High Altitude Water Cherenkov (HAWC) observatory is a wide field-of-view
detector sensitive to gamma rays of 100 GeV to a few hundred TeV. Located in
central Mexico at 19 degrees North latitude and 4100 m above sea level, HAWC
will observe gamma rays and cosmic rays with an array of water Cherenkov
detectors. The full HAWC array is scheduled to be operational in Spring 2015.
In this paper, we study the HAWC sensitivity to the gamma-ray signatures of
high-mass (multi- TeV) dark matter annihilation. The HAWC observatory will be
sensitive to diverse searches for dark matter annihilation, including
annihilation from extended dark matter sources, the diffuse gamma-ray emission
from dark matter annihilation, and gamma-ray emission from non-luminous dark
matter subhalos. Here we consider the HAWC sensitivity to a subset of these
sources, including dwarf galaxies, the M31 galaxy, the Virgo cluster, and the
Galactic center. We simulate the HAWC response to gamma rays from these sources
in several well-motivated dark matter annihilation channels. If no gamma-ray
excess is observed, we show the limits HAWC can place on the dark matter
cross-section from these sources. In particular, in the case of dark matter
annihilation into gauge bosons, HAWC will be able to detect a narrow range of
dark matter masses to cross-sections below thermal. HAWC should also be
sensitive to non-thermal cross-sections for masses up to nearly 1000 TeV. The
constraints placed by HAWC on the dark matter cross-section from known sources
should be competitive with current limits in the mass range where HAWC has
similar sensitivity. HAWC can additionally explore higher dark matter masses
than are currently constrained.Comment: 15 pages, 4 figures, version to be published in PR
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