Long-term coding of personal and universal associations underlying the memory web in the human brain

Neurons in the medial temporal lobe (MTL), a critical area for declarative memory, have been shown to change their tuning in associative learning tasks. Yet, it is unclear how durable these neuronal representations are and if they outlast the execution of the task. To address this issue, we studied the responses of MTL neurons in neurosurgical patients to known concepts (people and places). Using association scores provided by the patients and a web-based metric, here we show that whenever MTL neurons respond to more than one concept, these concepts are typically related. Furthermore, the degree of association between concepts could be successfully predicted based on the neurons’ response patterns. These results provide evidence for a long-term involvement of MTL neurons in the representation of durable associations, a hallmark of human declarative memory

Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies

Archaeological perspectives for northern Patagonia: Cueva Huenul 1 Site (Neuquen Province, Argentina)

Northern Neuquén Province (Pehuenches Dept., Argentina) is barely known from an archaeological perspective, though it is centrally placed in terms of several large-scale key issues in the peopling of South America: the extinction of the megafauna and its causes, early human presence, and the existence of archaeological discontinuities during the Mid-Holocene. In this paper we present the first body of paleoecological and archaeological data for Cueva Huenul 1 site, recently excavated, which offers a sedimentary sequence extending during the last of 16.000 calendar years. Initially, we present a chrono-stratigraphic frame for the site, including new tephro-chronological information. On this basis, four temporal components are defined, providing the historical scheme for the analysis of the recovered evidences that include: archaeofaunas (paleontological and archaeological), archaeobotany, lithic and ceramic technology, and rockart. These results at a site scale provide a first approach to a discussion of macro-regional processes, as well as the basis for the continuation of our research.El norte de la provincia de Neuquén (Depto. Pehuenches, Argentina) es muy poco conocido a nivel arqueológico, a pesar de estar ubicado en una posición central en relación con distintos temas clave del poblamiento humano de Sudamérica, incluyendo la extinción de la megafauna y sus causas, el poblamiento humano inicial y la existencia de discontinuidades arqueológicas en el Holoceno medio. En este trabajo se presenta el primer cuerpo de resultados paleoecológicos y arqueológicos para el sitio Cueva Huenul 1, recientemente excavado, que ofrece una secuencia sedimentaria que se extiende durante los últimos 16.000 años calendáricos. Estas evidencias incluyen el desarrollo de un marco crono-estratigráfico para el sitio, que aporta novedosa información tefro-cronológica. A partir de este análisis, se definen cuatro componentes temporales, sobre los cuales se asienta el estudio de los materiales recuperados: evidencias faunísticas (paleontológicas y arqueológicas), arqueobotánicas, líticas, cerámicas y de arte rupestre. Estos resultados en escala de sitio proveen una primera instancia de evaluación de procesos en escala macro-regional, así como las bases para la continuación de este proyecto.Facultad de Ciencias Naturales y Muse

An Efficient Coding Hypothesis Links Sparsity and Selectivity of Neural Responses

To what extent are sensory responses in the brain compatible with first-order principles? The efficient coding hypothesis projects that neurons use as few spikes as possible to faithfully represent natural stimuli. However, many sparsely firing neurons in higher brain areas seem to violate this hypothesis in that they respond more to familiar stimuli than to nonfamiliar stimuli. We reconcile this discrepancy by showing that efficient sensory responses give rise to stimulus selectivity that depends on the stimulus-independent firing threshold and the balance between excitatory and inhibitory inputs. We construct a cost function that enforces minimal firing rates in model neurons by linearly punishing suprathreshold synaptic currents. By contrast, subthreshold currents are punished quadratically, which allows us to optimally reconstruct sensory inputs from elicited responses. We train synaptic currents on many renditions of a particular bird's own song (BOS) and few renditions of conspecific birds' songs (CONs). During training, model neurons develop a response selectivity with complex dependence on the firing threshold. At low thresholds, they fire densely and prefer CON and the reverse BOS (REV) over BOS. However, at high thresholds or when hyperpolarized, they fire sparsely and prefer BOS over REV and over CON. Based on this selectivity reversal, our model suggests that preference for a highly familiar stimulus corresponds to a high-threshold or strong-inhibition regime of an efficient coding strategy. Our findings apply to songbird mirror neurons, and in general, they suggest that the brain may be endowed with simple mechanisms to rapidly change selectivity of neural responses to focus sensory processing on either familiar or nonfamiliar stimuli. In summary, we find support for the efficient coding hypothesis and provide new insights into the interplay between the sparsity and selectivity of neural responses

Dual coding with STDP in a spiking recurrent neural network model of the hippocampus.

The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli. It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location. These findings have led to the hypothesis that the hippocampus operates using a dual (rate and temporal) coding system. To investigate the phenomenon of dual coding in the hippocampus, we examine a spiking recurrent network model with theta coded neural dynamics and an STDP rule that mediates rate-coded Hebbian learning when pre- and post-synaptic firing is stochastic. We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues. This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology. Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain

Bright light therapy versus physical exercise to prevent co-morbid depression and obesity in adolescents and young adults with attention-deficit/hyperactivity disorder: study protocol for a randomized controlled trial

Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day– night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD. Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up. This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.The trial is funded by the EU Framework Programme for Research and Innovation, Horizon 2020 (Project no. 667302). Funding period: January 2016–December 2020. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Some local funds additionally contributed to carry out this study, especially for the preparation of the interventions: FBO research activity is by the Spanish Ministry of Economy and Competitiveness – MINECO (RYC-2011-09011) and by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Unit of Excellence on Exercise and Health (UCEES)

Improved upper limits on the stochastic gravitational-wave background from 2009-2010 LIGO and Virgo data

Paper producido por "The LIGO Scientific Collaboration and the Virgo Collaboration". (En el registro se mencionan solo algunos autores de las decenas de personas que participan).Gravitational waves from a variety of sources are predicted to superpose to create a stochastic background. This background is expected to contain unique information from throughout the history of the Universe that is unavailable through standard electromagnetic observations, making its study of fundamental importance to understanding the evolution of the Universe. We carry out a search for the stochastic background with the latest data from the LIGO and Virgo detectors. Consistent with predictions from most stochastic gravitational-wave background models, the data display no evidence of a stochastic gravitational-wave signal. Assuming a gravitational-wave spectrum of ΩGWðfÞ ¼ Ωαðf=frefÞα, we place 95% confidence level upper limits on the energy density of the background in each of four frequency bands spanning 41.5–1726 Hz. In the frequency band of 41.5–169.25 Hz for a spectral index of α¼ 0, we constrain the energy density of the stochastic background to be ΩGWðfÞ <5.6 × 10−6. For the 600–1000 Hz band, ΩGWðfÞ <0.14ðf=900 HzÞ3, a factor of 2.5 lower than the best previously reported upper limits. We find ΩGWðfÞ <1.8 × 10−4 using a spectral index of zero for 170–600 Hz and ΩGWðfÞ < 1.0ðf=1300 HzÞ3 for 1000–1726 Hz, bands in which no previous direct limits have been placed. The limits in these four bands are the lowest direct measurements to date on the stochastic background. We discuss the implications of these results in light of the recent claim by the BICEP2 experiment of the possible evidence for inflationary gravitational waves.http://journals.aps.org/prl/abstract/10.1103/PhysRevLett.113.231101publishedVersionFil: Aasi, J. LIGO. California Institute of Technology; Estados Unidos de América.Fil: Maglione, C. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Maglione, C. Argentinian Gravitational Wave Group; Argentina.Fil: Quiroga, G. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Quiroga, G. Argentinian Gravitational Wave Group; Argentina.Física de Partículas y Campo

Searches for continuous gravitational waves from nine young supernova remnants

We describe directed searches for continuous gravitational waves in data from the sixth LIGO science data run. The targets were nine young supernova remnants not associated with pulsars; eight of the remnants are associated with non-pulsing suspected neutron stars. One target's parameters are uncertain enough to warrant two searches, for a total of ten. Each search covered a broad band of frequencies and first and second frequency derivatives for a fixed sky direction. The searches coherently integrated data from the two LIGO interferometers over time spans from 5.3-25.3 days using the matched-filtering F-statistic. We found no credible gravitational-wave signals. We set 95% confidence upper limits as strong (low) as $4\times10^{-25}$ on intrinsic strain, $2\times10^{-7}$ on fiducial ellipticity, and $4\times10^{-5}$ on r-mode amplitude. These beat the indirect limits from energy conservation and are within the range of theoretical predictions for neutron-star ellipticities and r-mode amplitudes.Comment: Science summary available at http://www.ligo.org/science/Publication-S6DirectedSNR/index.ph

First all-sky search for continuous gravitational waves from unknown sources in binary systems

We present the first results of an all-sky search for continuous gravitational waves from unknown spinning neutron stars in binary systems using LIGO and Virgo data. Using a specially developed analysis program, the TwoSpect algorithm, the search was carried out on data from the sixth LIGO Science Run and the second and third Virgo Science Runs. The search covers a range of frequencies from 20 Hz to 520 Hz, a range of orbital periods from 2 to ~2,254 h and a frequency- and period-dependent range of frequency modulation depths from 0.277 to 100 mHz. This corresponds to a range of projected semi-major axes of the orbit from ~0.6e-3 ls to ~6,500 ls assuming the orbit of the binary is circular. While no plausible candidate gravitational wave events survive the pipeline, upper limits are set on the analyzed data. The most sensitive 95% confidence upper limit obtained on gravitational wave strain is 2.3e-24 at 217 Hz, assuming the source waves are circularly polarized. Although this search has been optimized for circular binary orbits, the upper limits obtained remain valid for orbital eccentricities as large as 0.9. In addition, upper limits are placed on continuous gravitational wave emission from the low-mass x-ray binary Scorpius X-1 between 20 Hz and 57.25 Hz.Comment: 16 pages, 6 figure