Realising the therapeutic potential of neuroactive steroid modulators of the GABA_A receptor

In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders

Lentificación académica en estudiantes de la UNSJ : relaciones entre factores socioculturales iniciales y trayectorias académicas

La presente ponencia retoma las estrategias metodológicas y los principales resultados obtenidos en el proyecto de investigación denominado: "Aportes a la comprensión del rendimiento académico de los estudiantes de la UNSJ: un estudio de factores socio culturales iniciales y trayectorias académicas universitarias" ejecutado durante los años 2014 y 2015 en el Instituto de Investigaciones Socio Económicas de la Facultad de Ciencias Sociales perteneciente a la Universidad Nacional de San Juan. En este trabajo se pretende, desde una perspectiva descriptiva y comprensiva, entender cómo se constituyen las relaciones existentes entre los factores socioculturales iniciales de los estudiantes y lentificación académica sufrida por ellos, respecto a la propuesta curricular de formación de grado. De esa forma, se intenta lograr avanzar en la compresión de las posiciones y disposiciones del estudiante ante la formación profesional.Fil: Guevara, Hilda Mabel. Universidad Nacional de San Juan.Fil: Belelli, Sandra. Universidad Nacional de San Juan.Fil: Castillo, Gonzalo. Universidad Nacional de San Juan

La actuación del contador público en el cambio del régimen patrimonial matrimonial según el nuevo Código Civil y Comercial de la Nación

El 8 de octubre de 2014 se realizó la publicación en el Boletín oficial de la ley 26.994 que sancionó la implementación del nuevo Código Civil y Comercial de la República Argentina. Esta nueva norma trajo consigo diversas modificaciones abiertas a distintos tipos de interpretaciones, estudios y/o análisis entre las cuales se encuentra la posibilidad de adoptar un nuevo régimen Matrimonial Patrimonial. Es decir que una pareja antes de iniciar su matrimonio puede optar ya sea por el régimen de Comunidad o el régimen de separación de bienes como normas que van a regir el antes y el después de la gestión de bienes y deudas de la sociedad conyugal. Como así también se permite que una vez adoptado uno de los regímenes se pueda cambiar por otro. Cuando una pareja decide abandonar el régimen de comunidad y adoptar el régimen de separación de bienes se abre la puerta a nuevas fuentes laborales para profesionales de diferentes campos entre los cuales se encuentra el Contador Público. La actuación, idoneidad y capacidad del mismo es fundamental para llevar a cabo esta tarea, lo que se explica en este trabajo, donde se analiza el rol del Contador Público en la extinción por cambio del régimen patrimonial matrimonial encontrándose vigente el matrimonio y se analizan los distintos regímenes que permite adoptar la legislación vigente.Fil: Belelli, María José. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Gofre, Katherina E.. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Lazzaro, Jimena. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas

The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABA_A receptor-mediated inhibition

Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics. Inhibition of TC neurons is mediated predominantly by a combination of phasic and tonic inhibition, together with a recently described ‘spillover’ mode of inhibition, generated by the dynamic recruitment of extrasynaptic γ-aminobutyric acid (GABA)(A) receptors (GABA(A)Rs). Previous studies demonstrated that the intravenous anaesthetic etomidate enhances tonic and phasic inhibition in TC relay neurons, but it is not known how etomidate may influence spillover inhibition. Moreover, it is unclear how etomidate influences the excitability of TC neurons. Thus, to investigate the relative contribution of synaptic (α1β2γ2) and extrasynaptic (α4β2δ) GABA(A)Rs to the thalamic effects of etomidate, we performed whole-cell recordings from mouse TC neurons lacking synaptic (α1(0/0)) or extrasynaptic (δ(0/0)) GABA(A)Rs. Etomidate (3 μm) significantly inhibited action-potential discharge in a manner that was dependent on facilitation of both synaptic and extrasynaptic GABA(A)Rs, although enhanced tonic inhibition was dominant in this respect. Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABA(A)Rs, which was significantly prolonged in the presence of etomidate. Thus, etomidate greatly enhanced the transient suppression of TC spike trains by evoked inhibitory postsynaptic potentials. Collectively, these results suggest that the deactivation of thalamus observed during etomidate-induced anaesthesia involves potentiation of tonic and phasic inhibition, and implicate amplification of spillover inhibition as a novel mechanism to regulate the gating of sensory information through the thalamus during anaesthetic states

Carbon balance assessment of a natural steppe of southern Siberia by multiple constraint approach

Steppe ecosystems represent an interesting case in which the assessment of carbon balance may be performed through a cross validation of the eddy covariance measurements against ecological inventory estimates of carbon exchanges (Ehman et al., 2002; Curtis et al., 2002). <br><br> Indeed, the widespread presence of ideal conditions for the applicability of the eddy covariance technique, as vast and homogeneous grass vegetation cover over flat terrains (Baldocchi, 2003), make steppes a suitable ground to ensure a constrain to flux estimates with independent methodological approaches. <br><br> We report about the analysis of the carbon cycle of a true steppe ecosystem in southern Siberia during the growing season of 2004 in the framework of the TCOS-Siberia project activities performed by continuous monitoring of CO<sub>2</sub> fluxes at ecosystem scale by the eddy covariance method, fortnightly samplings of phytomass, and ingrowth cores extractions for NPP assessment, and weekly measurements of heterotrophic component of soil CO<sub>2</sub> effluxes obtained by an experiment of root exclusion. <br><br> The carbon balance of the monitored natural steppe was, according to micrometeorological measurements, a sink of carbon of 151.7±36.9 g C m<sup>−2</sup>, cumulated during the growing season from May to September. This result was in agreement with the independent estimate through ecological inventory which yielded a sink of 150.1 g C m<sup>−2</sup> although this method was characterized by a large uncertainty (±130%) considering the 95% confidence interval of the estimate. Uncertainties in belowground process estimates account for a large part of the error. Thus, in particular efforts to better quantify the dynamics of root biomass (growth and turnover) have to be undertaken in order to reduce the uncertainties in the assessment of NPP. This assessment should be preferably based on the application of multiple methods, each one characterized by its own merits and flaws

Tonic inhibition of accumbal spiny neurons by extrasynaptic 4 GABAA receptors modulates the actions of psychostimulants

Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/− or α4−/− mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/− mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4D1−/−) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4−/− or α4D1−/− mice, blocked cocaine enhancement of CPP. In comparison, α4D2−/− mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors

CO2 fluxes and ecosystem dynamics at five European treeless peatlands – merging data and process oriented modeling

The carbon dioxide (CO2) exchange of five different peatland systems across Europe with a wide gradient in land use intensity, water table depth, soil fertility and climate was simulated with the process oriented CoupModel. The aim of the study was to find out whether CO2 fluxes, measured at different sites, can be explained by common processes and parameters or to what extend a site specific configuration is needed. The model was calibrated to fit measured CO2 fluxes, soil temperature, snow depth and leaf area index (LAI) and resulting differences in model parameters were analyzed. Finding site independent model parameters would mean that differences in the measured fluxes could be explained solely by model input data: water table, meteorological data, management and soil inventory data. Seasonal variability in the major fluxes was well captured, when a site independent configuration was utilized for most of the parameters. Parameters that differed between sites included the rate of soil organic decomposition, photosynthetic efficiency, and regulation of the mobile carbon (C) pool from senescence to shooting in the next year. The largest difference between sites was the rate coefficient for heterotrophic respiration. Setting it to a common value would lead to underestimation of mean total respiration by a factor of 2.8 up to an overestimation by a factor of 4. Despite testing a wide range of different responses to soil water and temperature, rate coefficients for heterotrophic respiration were consistently the lowest on formerly drained sites and the highest on the managed sites. Substrate decomposability, pH and vegetation characteristics are possible explanations for the differences in decomposition rates. Specific parameter values for the timing of plant shooting and senescence, the photosynthesis response to temperature, litter fall and plant respiration rates, leaf morphology and allocation fractions of new assimilates, were not needed, even though the gradient in site latitude ranged from 48° N (southern Germany) to 68° N (northern Finland) differed largely in their vegetation. This was also true for common parameters defining the moisture and temperature response for decomposition, leading to the conclusion that a site specific interpretation of these processes is not necessary. In contrast, the rate of soil organic decomposition, photosynthetic efficiency, and the regulation of the mobile carbon pool need to be estimated from available information on specific soil conditions, vegetation and management of the ecosystems, to be able to describe CO2 fluxes under different condition

An estimate of the terrestrial carbon budget of Russia using inventory-based, eddy covariance and inversion methods

We determine the carbon balance of Russia, including Ukraine, Belarus and Kazakhstan using inventory based, eddy covariance, Dynamic Global Vegetation Models (DGVM), and inversion methods. Our current best estimate of the net biosphere to atmosphere flux is -0.66 Pg C yr-1. This sink is primarily caused by forests that using two independent methods are estimated to take up -0.69 Pg C yr-1. Using inverse models yields an average net biosphere to atmosphere flux of the same value with a interannual variability of 35%. The total estimated biosphere to atmosphere flux from eddy covariance observations over a limited number of sites amounts to -1 Pg C yr-1. Fires emit 137 to 121 Tg C yr-1 using two different methods. The interannual variability of fire emissions is large, up to a factor 0.5 to 3. Smaller fluxes to the ocean and inland lakes, trade are also accounted for. Our best estimate for the Russian net biosphere to atmosphere flux then amounts to -659 Tg C yr-1 as the average of the inverse models of -653 Tg C yr-1, bottom up -563 Tg C yr-1 and the independent landscape approach of -761 Tg C yr-1. These three methods agree well within their error bounds, so there is good consistency between bottom up and top down methods. The best estimate of the net land to atmosphere flux, including the fossil fuel emissions is -145 to -73 Tg C yr-1. Estimated methane emissions vary considerably with one inventory-based estimate providing a net land to atmosphere flux of 12.6 Tg C-CH4yr-1 and an independent model estimate for the boreal and Arctic zones of Eurasia of 27.6 Tg C-CH4yr-1