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

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

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

A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines

Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications

Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine

Haplotypes of the Gabra2 gene encoding the α2 subunit of the GABAA receptor (GABAAR) are associated with drug abuse, suggesting that α2-GABAARs may play an important role in the circuitry underlying drug misuse. The genetic association of Gabra2 haplotypes with cocaine addiction appears to be evident primarily in individuals who had experienced childhood trauma. Given this association of childhood trauma, cocaine abuse and the Gabra2 haplotypes, we have explored in a mouse model of early life adversity (ELA) whether such events influence the behavioral effects of cocaine and if, as suggested by the human studies, α2-GABAARs in the nucleus accumbens (NAc) are involved in these perturbed behaviors. In adult mice prior ELA caused a selective decrease of accumbal α2-subunit mRNA, resulting in a selective decrease in the number and size of the α2-subunit (but not the α1-subunit) immunoreactive clusters in NAc core medium spiny neurons (MSNs). Functionally, in adult MSNs ELA decreased the amplitude and frequency of GABAAR-mediated miniature inhibitory postsynaptic currents (mIPSCs), a profile similar to that of α2 "knock-out" (α2-/-) mice. Behaviorally, adult male ELA and α2-/- mice exhibited an enhanced locomotor response to acute cocaine and blunted sensitization upon repeated cocaine administration, when compared to their appropriate controls. Collectively, these findings reveal a neurobiological mechanism which may relate to the clinical observation that early trauma increases the risk for substance abuse disorder (SAD) in individuals harbouring haplotypic variations in the Gabra2 gene.</p

Monitoring of GHGs flux dynamics at the "Viote" mountain peatland (Eastern Alps, Italy) under climate change pressure

This presentation focuses on the alpine peatland "le Viote" (46.01 N, 11.04 E, 1560 m asl), located at the centre of a plateau in the Mt. Bondone area, in the eastern Italian Alps (Figure), where the fluxes of methane (CH4) and carbon dioxide (CO2) between the peatland ecosystem and the atmosphere have been measured by chamber technique since summer 2024. The objectives of the current research activities are to analyse the spatial and temporal variability of both GHGs with special attention to CH4 fluxes, considering the response to climatic drivers, the influence of peatland vegetation community types, hydrology and natural and anthropogenic disturbances history. These activities build on 10+ years of CO2 fluxes monitoring by eddy covariance and a more limited dataset of CH4 fluxes, providing a temporal background for detecting flux magnitude changes

The immediate and maintained effects of neurosteroids on GABA_A receptors

Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of the GABAA receptor (GABAAR), the major inhibitory receptor in the mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous allopregnanolone influences neural inhibition and behaviour, with perturbed neurosteroid levels implicated in depressive disorders. The approval of brexanolone (an allopregnanolone formulation) to treat postpartum depression (PPD) has encouraged optimism that they may provide a new approach to treat mood disorders. Elucidating how neurosteroids are distinguished from established GABAAR-active drugs, e.g. benzodiazepines, may improve understanding of depressive disorders and aid drug development for psychiatric conditions. Here, we focus on research highlighting: (1) the acute interaction of neurosteroids with GABAARs incorporating the δ subunit (δ-GABAAR) and (2) how neurosteroids may additionally act on a slower time scale to enhance expression of δ-GABAARs, thereby providing sustained therapeutic benefit.</p

Deletion of the gabra2 gene results in hypersensitivity to the acute effects of ethanol but does not alter ethanol self administration

Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABA(A) α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABA(A) α2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol's rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates, with no differences in the numbers of reinforcers earned. These data indicate a protective role for α2-subunits, against the acute sedative and ataxic effects of ethanol. However, no change was observed in ethanol self administration, suggesting the rewarding effects of ethanol remain unchange

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acidA receptor (GABAAR) β1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse