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

Lithium Abundances in the Solar Twins 16 CYG A and B and the Solar Analog alpha CEN A, Calibration of the 6707 Angstrom Li Region Linelist, and Implications

We present high resolution (R ˜45,000-70,000) and very high S/N (˜1,000) spectroscopy of the Li I 6707 Å region in each component of the binary solar twins 16 Cyg A and B, the solar analog alpha Cen A, and alpha Cen B. Spectra of 16 Cyg were obtained with the University of Hawai\u27i 2.2-m, McDonald Observatory 2.1-m, and Keck 10-m telescopes and have been independently reduced. Comparison of spectral synthesis and the 16 Cyg data, and corresponding similarly obtained solar data, yields 7Li abundances which show excellent concordance between the various data sets. Despite differing in Teff by only 35-40 K, the Li abundances of 16 Cyg A and B differ by a factor of \u3e=4.5. The solar photospheric abundance is intermediate to the two values. This intermediacy indicates that the Sun, whose highly depleted photospheric Li abundance is in gross conflict with standard stellar models, is not an isolated anomaly in its Li abundance evolution. A similar conclusion is reached via comparison of alpha Cen A and metal-rich Hyades dwarfs. The difference in the 16 Cyg components\u27 abundances suggests, though does not directly establish, a slow (possibly rotationally-induced) mixing mechanism operating below the surface convection zone in these stars. Indeed, the Li abundance difference can be viewed as an analog to the Li abundance dispersion seen in cool stars of similar Teff in open and globular clusters, and in Galactic field halo stars. It is possible, in principle anyway, that the low Li abundances of the Sun and 16 Cyg B with respect to 16 Cyg A may be related to the presence of a planetary companion; Li abundances of 47 UMa, and HD 114762 might further support such a connection between planets/disks, angular momentum evolution, and photospheric Li abundances. Due to a variety of uncertainties, however, any conclusions remain tenuous and speculative at this time. Finally, as an interesting aside, we show that current line list uncertainties in the delta6707 region suggest that claims of very small 6Li/7Li ratios ( 0.01) inferred from analysis of the solar photospheric spectrum are overly optimistic-though not necessarily incorrect

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography

Objective Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. Methods Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. Results Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. Significance About one third of the subjects implanted with bilateral MTL electrodes required \u3e1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions. Key Points Ambulatory electrocorticograms were obtained in patients implanted with a responsive neurostimulator and bilateral mesial temporal intracranial electrodes. In patients with bilateral seizures, the average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13, range 0–376). Some patients suspected to have bilateral MTL seizures after standard diagnostic localization evaluations had only unilateral electrographic seizures. Chronic ambulatory ECoG samples provide naturalistic data that complement inpatient monitoring, and may contribute information that affects treatment decisions

Deletion of alpha-synuclein decreases impulsivity in mice

The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication

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

Epsilon Indi Ba, Bb: a detailed study of the nearest known brown dwarfs

The discovery of epsilon Indi Ba, Bb, a binary brown dwarf system very close to the Sun, makes possible a concerted campaign to characterise the physical parameters of two T dwarfs. Recent observations suggest substellar atmospheric and evolutionary models may be inconsistent with observations, but there have been few conclusive tests to date. We therefore aim to characterise these benchmark brown dwarfs to place constraints on such models. We have obtained high angular resolution optical, near-infrared, and thermal-infrared imaging and medium-resolution (up to R~5000) spectroscopy of epsilon Indi Ba, Bb with the ESO VLT and present VRIzJHKL'M' broad-band photometry and 0.63--5.1 micron spectroscopy of the individual components. Furthermore, we use deep AO-imaging to place upper limits on the (model-dependent) mass of any further system members. We derive luminosities of log L/L_sun = -4.699+/-0.017 and -5.232+/-0.020 for epsilon Indi Ba, Bb, respectively, and using the dynamical system mass and COND03 evolutionary models predict a system age of 3.7--4.3 Gyr, in excess of previous estimates and recent predictions from observations of these brown dwarfs. Moreover, the effective temperatures of 1352--1385 K and 976--1011 K predicted from the COND03 evolutionary models, for epsilon Indi Ba and Bb respectively, are in disagreement with those derived from the comparison of our data with the BT-Settl atmospheric models where we find effective temperatures of 1300--1340 K and 880--940 K, for epsilon Indi Ba and Bb respectively, with surface gravities of log g=5.25 and 5.50. Finally, we show that spectroscopically determined effective temperatures and surface gravities for ultra-cool dwarfs can lead to underestimated masses even where precise luminosity constraints are available.Comment: 27 pages, 30 figures, 9 tables, accepted for publication in Astronomy and Astrophysic

Electron affinities of the first- and second- row atoms: benchmark ab initio and density functional calculations

A benchmark ab initio and density functional (DFT) study has been carried out on the electron affinities of the first- and second-row atoms. The ab initio study involves basis sets of $spdfgh$ and $spdfghi$ quality, extrapolations to the 1-particle basis set limit, and a combination of the CCSD(T), CCSDT, and full CI electron correlation methods. Scalar relativistic and spin-orbit coupling effects were taken into account. On average, the best ab initio results agree to better than 0.001 eV with the most recent experimental results. Correcting for imperfections in the CCSD(T) method improves the mean absolute error by an order of magnitude, while for accurate results on the second-row atoms inclusion of relativistic corrections is essential. The latter are significantly overestimated at the SCF level; for accurate spin-orbit splitting constants of second-row atoms inclusion of (2s,2p) correlation is essential. In the DFT calculations it is found that results for the 1st-row atoms are very sensitive to the exchange functional, while those for second-row atoms are rather more sensitive to the correlation functional. While the LYP correlation functional works best for first-row atoms, its PW91 counterpart appears to be preferable for second-row atoms. Among ``pure DFT'' (nonhybrid) functionals, G96PW91 (Gill 1996 exchange combined with Perdew-Wang 1991 correlation) puts in the best overall performance. The best results overall are obtained with the 1-parameter hybrid modified Perdew-Wang (mPW1) exchange functionals of Adamo and Barone [J. Chem. Phys. {\bf 108}, 664 (1998)], with mPW1LYP yielding the best results for first-row, and mPW1PW91 for second-row atoms. Indications exist that a hybrid of the type $a$ mPW1LYP + $(1-a)$ mPW1PW91 yields better results than either of the constituent functionals.Comment: Phys. Rev. A, in press (revised version, review of issues concerning DFT and electron affinities added

Relationship between psychological and biological factors and physical activity and exercise behaviour in Filipino students

The aim of the present study was threefold. Firstly, it investigated whether a general measure or specific measure of motivational orientation was better in describing the relationship between motivation and exercise behaviour. Secondly, it examined the relationship between the four most popular indirect methods of body composition assessment and physical activity and exercise patterns. Thirdly, the interaction between motivation and body composition on physical activity and exercise behaviour was explored in a sample of 275 Filipino male and female students. Males were found to have higher levels of exercise whereas females had higher levels of physical activity. Furthermore, general self-motivation together with body weight and percentage body fat were found to be the best predictor of exercise behaviour whereas the tension/pressure subscale of the ‘Intrinsic Motivation Inventory’ (IMI) was the best predictor of levels of physical activity. However, significant gender differences were observed. That is, for the males only self-motivation and for the females only body weight and BMI predicted exercise behaviour. Also, tension/pressure predicted physical activity levels for the females but not the males. No inverse relationship was found between the four body composition measures and exercise and physical activity behaviour. The results support the notion that the psychobiological approach might be particularly relevant for high intensity exercise situations but also highlights some important gender differences. Finally, the results of this study emphasise the need for more cross-cultural research

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