Leptin modulation of locomotor and emotional behaviors : the role of STAT3 signaling in dopamine neurons

La leptine circule en proportion de la masse graisseuse du corps et la transduction de son signal à travers la forme longue de son récepteur via un certain nombre de voies neurales , y compris MAPK, PI3-K ,AMPK et JAK2 - STAT3 . Il faut noter que STAT3 constitue une voie clée au récepteur de la leptine par laquelle la leptine module l'expression des gènes impliqués dans la régulation du bilan énergétique. La plupart des recherches ont porté sur la fonction du récepteur de la leptine au sein de l' hypothalamus, en particulier la fonction du récepteur de la leptine dans le noyau arqué. Toutefois, les récepteurs de la leptine sont également exprimés sur les neurones dopaminergiques de l'aire tégmentale ventrale et la leptine agit sur cette région du cerveau pour influencer la prise alimentaire, la motivation, la locomotion, l'anxiété et la transmission de la dopamine. De plus, la leptine active la STAT3 dans les dopaminergiques et GABAergiques populations neuronales. Bien que ces résultats contribuent à notre compréhension des multiples actions de la leptine dans le système nerveux central, il reste à résoudre les cellules et la signalisation du récepteur de la leptine qui sont responsables des effets neurocomportementaux de la leptine dans le mésencéphale. Visant à déterminer la contribution de la voie de signalisation STAT3 dans les neurones dopaminergiques du mésencéphale, nous avons généré une lignée de souris knockout conditionnel dans lequel l'activation du gène de STAT3 sur son résidu tyrosine 705 ( Tyr 705 ) est absent spécifiquement dans les neurones dopaminergiques. Avec l'utilisation de ce modèle de souris génétique, nous avons évalué l'impact de l'ablation de la signalisation STAT3 dans les neurones dopaminergiques sur un certain nombre de fonctions liées à la dopamine, y compris l'alimentation, la locomotion, les comportements liés à la récompense, l'émotion et la libération de dopamine dans le noyau accumbens. Fait intéressant, nous avons observé un dimorphisme sexuel dans le phénotype des souris STAT3DAT-KO. L'activation de la voie de signalisation STAT3 dans les neurones dopaminergiques est responsable de l'action de la leptine dans la réduction de la locomotion, récompense liée à l'activité physique, et de l'augmentation de la libération et de la disponibilité de la dopamine chez les souris mâles. Cependant, il ne module pas le comportement émotionnel. D'autre part, les souris femelles STAT3DAT-KO augmentent les niveaux d'anxiété et les niveaux plasmatiques de corticostérone, sans provoquer de changements de la dépression. Cependant, la perte d'activation de STAT3 dans les neurones dopaminergiques ne module pas le comportement locomoteur chez les souris femelles. Notamment, les actions de la leptine dans le mésencéphale pour influencer le comportement alimentaire ne sont pas médiées par l'activation de STAT3 dans les neurones dopaminergiques, considérant que les souris mâles et femelles ont un comportement alimentaire normal. Nos résultats démontrent que la voie de signalisation STAT3 dans les neurones dopaminergiques est responsable des effets anxiolytiques de la leptine, et soutient l'hypothèse que la leptine communique l'état d'énergie du corps (i.e. la relation entre la dépense et les apports énergétiques) pour les régions mésolimbiques pour atténuer les effets de motivation et de récompense de plusieurs comportements qui servent à réhabiliter ou à épuiser les réserves d'énergie. En outre, ce travail souligne l'importance d'étudier la modulation de la signalisation de la leptine dans différente types de cellules, afin d'identifier les voies de signalisation et les mécanismes cellulaires impliqués dans les différentes fonctions neuro-comportementales de la leptine.

Synthesis and Characterization of Magnetic Nanoparticles with High Magnetization and Good Oxidation Resistibility

Magnetic nanoparticles attract increasing attention because of their current and potential biomedical applications, such as, magnetically targeted and controlled drug delivery, magnetic hyperthermia and magnetic extraction. Increased magnetization can lead to improved performance in targeting and retention in drug delivery and a higher efficiency in biomaterials extraction. We reported an approach to synthesize iron contained magnetic nanoparticles with high magnetization and good oxidation resistibility by pyrolysis of iron pentacarbonyl (Fe(CO)[subscript 5]) in methane (CH[subscript 4]). Using the high reactivity of Fe nanoparticles, decomposition of CH[subscript 4] on the Fe nanoparticles leads to the formation of nanocrystalline iron carbides at a temperature below 260°C. Structural investigation indicated that the as-synthesized nanoparticles contained crystalline bcc Fe, iron carbides and spinel iron oxide. The Mössbauer and DSC results testified that the as-synthesized nanoparticle contained three crystalline iron carbide phases, which converted to Fe[subscript 3]C after a heat treatment. Surface analysis suggested that the as-synthesized and subsequently heated iron-iron carbide particles were coated by iron oxide, which originated from oxidization of surface Fe atoms. The heat-treated nanoparticles exhibited a magnetization of 160 emu/g, which is two times of that of currently used spinel iron oxide nanoparticles. After heating in an acidic solution with a pH value of 5 at 60°C for 20 h, the nanoparticles retained 90 percentage of the magnetization.

Neurobiology of expectancy effects and omission of reinforcement on behavior

The reinforcement omission effects have been traditionally interpreted in terms of: behavioral facilitation after reinforcement omission induced by primary frustration or behavioral suppression after reinforcement delivery induced by postconsummatory states. The studies reviewed here indicate that amygdala is involved in modulation of these effects. However, the fact that amygdala lesions, extensive or selective, can eliminate, reduce and enhance the omission effects makes it difficult to understand how it is the exact nature of their involvement. The amygdala is related to several functions that depend on its connections with other brain systems. Thus, it is necessary to consider the involvement of a more complex neural network in the modulation of the reinforcement omission effects. The connection of amygdala subareas to cortical and subcortical structures may be involved in this modulation since they also are linked to processes related to reward and expectancy.

Promoting the health of marginalized populations in Ecuador through international collaboration and educational innovations

This paper examines two innovative educational initiatives for the Ecuadorian public health workforce: a Canadian-funded Masters programme in ecosystem approaches to health that focuses on building capacity to manage environmental health risks sustainably; and the training of Ecuadorians at the Latin American School of Medicine in Cuba (known as Escuela Latinoamericana de Medicina in Spanish). We apply a typology for analysing how training programmes address the needs of marginalized populations and build capacity for addressing health determinants. We highlight some ways we can learn from such training programmes with particular regard to lessons, barriers and opportunities for their sustainability at the local, national and international levels and for pursuing similar initiatives in other countries and contexts. We conclude that educational efforts focused on the challenges of marginalization and the determinants of health require explicit attention not only to the knowledge, attitudes and skills of graduates but also on effectively engaging the health settings and systems that will reinforce the establishment and retention of capacity in low- and middle-income settings where this is most needed.

Effects of dietary supplementation with selenium enriched yeast or sodium selenite on selenium tissue distribution and meat quality in lambs

The objective was to determine the concentration of total selenium (Se) and the proportion of total Se comprised as selenomethionine (SeMet) and selenocysteine (SeCys), as well as meat quality in terms of oxidative stability in post mortem tissues of lambs offered diets with an increasing dose rate of selenized enriched yeast (SY), or sodium selenite (SS). Fifty lambs were offered, for a period of 112 d, a total mixed ration which had either been supplemented with SY (0, 0.11, 0.21 or 0.31 mg/kg DM to give total Se contents of 0.19, 0.3, 0.4 and 0.5 mg Se/kg DM for treatments T1, T2, T3 and T4, respectively) or SS (0.11 mg/kg DM to give 0.3 mg Se/kg DM total Se [T5]). At enrolment and at 28, 56, 84 and 112 d following enrolment, blood samples were taken for Se and Se species determination, as well as glutathione peroxidase (GSH-Px) activity. At the end of the study lambs were euthanased and samples of heart, liver, kidney, and skeletal muscle were retained for Se and Se species determination. Tissue GSH-Px activity and thiobarbituric acid reactive substances (TBARS) were determined in Longissimus Thoracis. The incorporation into the diet of ascending concentrations of Se as SY increased whole blood total Se and the proportion of total Se comprised as SeMet, and erythrocyte GSH-Px activity. Comparable doses of SS supplementation did not result in significant differences between these parameters. With the exception of kidney tissue, all other tissues showed a dose dependant response to increasing concentrations of dietary SY, such that total Se and SeMet increased. Selenium content of Psoas Major was higher in animals fed SY when compared to a similar dose of SS, indicating improvements in Se availability and retention. There were no significant treatment effects on meat quality assessments GHS-Px and TBARS, reflecting the lack of difference in the proportion of total Se that was comprised as SeCys. However, oxidative stability improved marginally with ascending tissue Se content, providing an indication of a linear dose response whereby TBARS improved with ascending SY inclusion.

Polymer-drug conjugates: current status and future trends

Polymer conjugates are nano-sized, multicomponent constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The "technology platform'' of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these "nanomedicines".

Synthesis and biological in vitro evaluation of novel PEG-psoralen conjugates

Psoralens are well-known photosensitizers, and 8- methoxypsoralen and 4,5',8-trimethylpsoralen are widely used in photomedicine as "psoralens plus UVA therapy" (PUVA), in photopheresis, and in sterilization of blood preparations. In an attempt to improve the therapeutic efficiency of PUVA therapy and photopheresis, four poly(ethylene glycol) (PEG)-psoralen conjugates were synthesized to promote tumor targeting by the enhanced permeability and retention (EPR) effect. Peptide linkers were used to exploit specific enzymatic cleavage by lysosomal proteases. A new psoralen, 4-hydroxymethyl-4', 8-dimethylpsoralen (6), suitable for polymer conjugation was synthesized. The hydroxy group allowed exploring different strategies for PEG conjugation, and linkages with different stability such ester or urethanes were obtained. PEG (5 kDa) was covalently conjugated to the new psoralen derivative using four different linkages, namely, (i) direct ester bond (7), (ii) ester linkage with a peptide spacer (8), (iii) a carbamic linker (9), and (iv) a carbamic linker with a peptide spacer (12). The stability of these new conjugates was assessed at different pHs, in plasma and following incubation with cathepsin B. Conjugates 7 and 8 were rapidly hydrolyzed in plasma, while 9 was stable in buffer and in the presence of cathepsin B. As expected, only the conjugates containing the peptide linker released the drug in presence of cathepsin B. In vitro evaluation of the cytotoxic activity in the presence and absence of light was carried out in two cell lines (MCF-7 and A375 cells). Conjugates 7 and 8 displayed a similar activity to the free drug (probably due to the low stability of the ester linkage). Interestingly, the conjugates containing the carbamate linkage (9 and 12) were completely inactive in the dark (IC50 > 100 mu M in both cell lines). However, antiproliferative activity become apparent after UV irradiation. Conjugate 12 appears to be the most promising for future in vivo evaluation, since it was relatively stable in plasma, which should allow tumor targeting and drug release to occur by cathepsin B-mediated hydrolysis.

Making the least active pay: a simulation of rewards and penalties under Demand Side Participation programs

The orthodox approach for incentivising Demand Side Participation (DSP) programs is that utility losses from capital, installation and planning costs should be recovered under financial incentive mechanisms which aim to ensure that utilities have the right incentives to implement DSP activities. The recent national smart metering roll-out in the UK implies that this approach needs to be reassessed since utilities will recover the capital costs associated with DSP technology through bills. This paper introduces a reward and penalty mechanism focusing on residential users. DSP planning costs are recovered through payments from those consumers who do not react to peak signals. Those consumers who do react are rewarded by paying lower bills. Because real-time incentives to residential consumers tend to fail due to the negligible amounts associated with net gains (and losses) or individual users, in the proposed mechanism the regulator determines benchmarks which are matched against responses to signals and caps the level of rewards/penalties to avoid market distortions. The paper presents an overview of existing financial incentive mechanisms for DSP; introduces the reward/penalty mechanism aimed at fostering DSP under the hypothesis of smart metering roll-out; considers the costs faced by utilities for DSP programs; assesses linear rate effects and value changes; introduces compensatory weights for those consumers who have physical or financial impediments; and shows findings based on simulation runs on three discrete levels of elasticity.

How reward modulates mimicry: EMG evidence of greater automatic facial mimicry of more rewarding faces

Spontaneous mimicry is a marker of empathy. Conditions characterized by reduced spontaneous mimicry (e.g., autism) also display deficits in sensitivity to social rewards. We tested if spontaneous mimicry of socially rewarding stimuli (happy faces) depends on the reward value of stimuli in 32 typical participants. An evaluative conditioning paradigm was used to associate different reward values with neutral target faces. Subsequently, electromyographic activity over the Zygomaticus Major was measured whilst participants watched video clips of the faces making happy expressions. Higher Zygomaticus Major activity was found in response to happy faces conditioned with high reward versus low reward. Moreover, autistic traits in the general population modulated the extent of spontaneous mimicry of happy faces. This suggests a link between reward and spontaneous mimicry and provides a possible underlying mechanism for the reduced response to social rewards seen in autism.

Investigation of sainfoin (Onobrychis viciifolia) cultivar differences on nitrogen balance and fecal egg count in artificially infected lambs

Research in ruminant nutrition and helminth control with forages, which contain condensed tannins (CT), suggests that varying responses may depend not only on CT concentration but also on CT composition. An experiment was designed to test this by feeding 2 dried sainfoin cultivars (Visnovsky and Perly), which differed in CT properties, to lambs that were artificially infected with the abomasal blood-sucking nematode Haemonchus contortus. Twenty-four infected lambs received one of these 2 cultivars; the feeds were either untreated or treated with the CT-binding polyethylene glycol over 4 wk (n = 6). The 2 cultivars were also fed to 2 × 6 uninfected lambs. Nutrient digestibility, N balance, ADG, plasma urea together with indicators of infection [fecal egg count (FEC), abomasal worm count, per capita female fecundity, erythrocytic indices, and serum protein] were determined. The specific effects of sainfoin cultivar, CT, and infection were evaluated by contrast analysis. Digestibility of both NDF and ADF were lower (P < 0.001) with Perly compared to Visnovsky. The apparent nutrient digestibility was reduced (P < 0.001) by CT. However, no clear cultivar effects were evident on N excretion and retention. Condensed tannins reduced (P = 0.05) body N retention and shifted (P < 0.001) N excretion from urine to feces. Unlike cultivar and CT, infection decreased (P = 0.002) ADG. Plasma urea concentration was lower (P = 0.007) in Perly- compared to Visnovsky-fed lambs and was decreased (P < 0.001) by CT. Plasma concentrations of essential and semi-essential AA were increased (P < 0.001) by CT. The groups of infected lambs did not clearly differ in abomasal worm counts and erythrocytic indicators. In the last 2 to 3 wk of the experiment, FEC was lower (P ≤ 0.01) when feeding CT. The lack of substantial cultivar effects suggests that the differences in CT properties may have been too small to result in nutritional and anthelmintic effects. The present results indicate that sainfoin CT had a mitigating effect on FEC and, consequently, pasture infectivity. However, the reduction was too low to expect any significant benefits in an Haemonchus-dominated system. Therefore, the use of sainfoin for controlling H. contortus should only be one component within an integrated worm control system.

Estimated dietary intakes and sources of flavanols in the German population (German National Nutrition Survey II)

Background/Objectives Data from intervention studies suggest a beneficial effect of flavanols on vascular health. However, insufficient data on their intake have delayed the assessment of their health benefits. The aim of this study was to estimate intake of flavanols and their main sources among people living in Germany. Subjects/Methods Data from diet history interviews of the German National Nutrition Survey II for 15,371 people across Germany aged 14–80 years were analyzed. The FLAVIOLA Flavanol Food Composition Database was compiled using the latest US Department of Agriculture and Phenol-Explorer Databases and expanded to include recipes and retention factors. Results Mean intake of total flavanols, flavan-3-ol monomers, proanthocyanidins (PA), and theaflavins in Germany was 386, 120, 196, and 70 mg/day, respectively. Women had higher intakes of total flavanols (399 mg/day) than men (372 mg/day) in all age groups, with the exception of the elderly. Similar results were observed for monomers (108 mg/day for men, 131 mg/day for women) and PA (190 mg/day; 203 mg/day), although intake of theaflavins was higher in men (74 mg/day; 66 mg/day). There was an age gradient with an increase in total flavanols, monomers, and theaflavins across the age groups. The major contributor of total flavanols in all subjects was pome fruits (27 %) followed by black tea (25 %). Conclusions This study demonstrated age- and sex-related variations in the intake and sources of dietary flavanols in Germany. The current analysis will provide a valuable tool in clarifying and confirming the potential health benefits of flavanols.

Reduced neural response to reward following 7 days treatment with the cannabinoid CB1 antagonist rimonabant in healthy volunteers

Reduced subjective experience of reward (anhedonia) is a key symptom of major depression. The anti-obesity drug and cannabinoid type 1 receptor (CB(1)) antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use and was recently withdrawn from the market because of these adverse effects. Using a functional magnetic resonance imaging (fMRI) model of reward we hypothesized that rimonabant would impair reward processing. Twenty-two healthy participants were randomly allocated to receive rimonabant (20 mg), or placebo, for 7 d in a double-blind, parallel group design. We used fMRI to measure the neural response to rewarding (sight and/or flavour of chocolate) and aversive (sight of mouldy strawberries and/or an unpleasant strawberry taste) stimuli on the final day of drug treatment. Rimonabant reduced the neural response to chocolate stimuli in key reward areas such as the ventral striatum and the orbitofrontal cortex. Rimonabant also decreased neural responses to the aversive stimulus condition in the caudate nucleus and ventral striatum, but increased lateral orbitofrontal activations to the aversive sight and taste of strawberry condition. Our findings are the first to show that the anti-obesity drug rimonabant inhibits the neural processing of rewarding food stimuli in humans. This plausibly underlies its ability to promote weight loss, but may also indicate a mechanism for inducing anhedonia which could lead to the increased risk of depressive symptomatology seen in clinical use. fMRI may be a useful method of screening novel agents for unwanted effects on reward and associated clinical adverse reactions.

Autistic traits moderate the impact of reward learning on social behaviour

A deficit in empathy has been suggested to underlie social behavioural atypicalities in autism. A parallel theoretical account proposes that reduced social motivation (i.e., low responsivity to social rewards) can account for the said atypicalities. Recent evidence suggests that autistic traits modulate the link between reward and proxy metrics related to empathy. Using an evaluative conditioning paradigm to associate high and low rewards with faces, a previous study has shown that individuals high in autistic traits show reduced spontaneous facial mimicry of faces associated with high vs. low reward. This observation raises the possibility that autistic traits modulate the magnitude of evaluative conditioning. To test this, we investigated (a) if autistic traits could modulate the ability to implicitly associate a reward value to a social stimulus (reward learning/conditioning, using the Implicit Association Task, IAT); (b) if the learned association could modulate participants’ prosocial behaviour (i.e., social reciprocity, measured using the cyberball task); (c) if the strength of this modulation was influenced by autistic traits. In 43 neurotypical participants, we found that autistic traits moderated the relationship of social reward learning on prosocial behaviour but not reward learning itself. This evidence suggests that while autistic traits do not directly influence social reward learning, they modulate the relationship of social rewards with prosocial behaviour

Effects of forage source and extruded linseed supplementation on methane emissions from growing dairy cattle of differing body weights

Changes in diet carbohydrate amount and type (i.e., starch vs. fiber) and dietary oil supplements can affect ruminant methane emissions. Our objectives were to measure methane emissions, whole-tract digestibility, and energy and nitrogen utilization from growing dairy cattle at 2 body weight (BW) ranges, fed diets containing either high maize silage (MS) or high grass silage (GS), without or with supplemental oil from extruded linseed (ELS). Four Holstein-Friesian heifers aged 13 mo (BW range from start to finish of 382 to 526 kg) were used in experiment 1, whereas 4 lighter heifers aged 12 mo (BW range from start to finish of 292 to 419 kg) were used in experiment 2. Diets were fed as total mixed rations with forage dry matter (DM) containing high MS or high GS and concentrates in proportions (forage:concentrate, DM basis) of either 75:25 (experiment 1) or 60:40 (experiment 2), respectively. Diets were supplemented without or with ELS (Lintec[AU1: Add manufacturer name and location.]; 260 g of oil/ kg of DM) at 6% of ration DM. Each experiment was a 4 × 4 Latin square design with 33-d periods, with measurements during d 29 to 33 while animals were housed in respiration chambers. Heifers fed MS at a heavier BW (experiment 1) emitted 20% less methane per unit of DM intake (yield) compared with GS (21.4 vs. 26.6, respectively). However, when repeated with heifers of a lower BW (experiment 2), methane yield did not differ between the 2 diets (26.6 g/kg of DM intake). Differences in heifer BW had no overall effect on methane emissions, except when expressed as grams per kilogram of digestible organic matter (OMD) intake (32.4 vs. 36.6, heavy vs. light heifers). Heavier heifers fed MS in experiment 1 had a greater DM intake (9.4 kg/d) and lower OMD (755 g/kg), but no difference in N utilization (31% of N intake) compared with heifers fed GS (7.9 kg/d and 799 g/kg, respectively). Tissue energy retention was nearly double for heifers fed MS compared with GS in experiment 1 (15 vs. 8% of energy intake, respectively). Heifers fed MS in experiment 2 had similar DM intake (7.2 kg/d) and retention of energy (5% of intake energy) and N (28% of N intake), compared with GS-fed heifers, but OMD was lower (741 vs. 765 g/kg, respectively). No effect of ELS was noted on any of the variables measured, irrespective of animal BW, and this was likely due to the relatively low amount of supplemental oil provided. Differences in heifer BW did not markedly influence dietary effects on methane emissions. Differences in methane yield were attributable to differences in dietary starch and fiber composition associated with forage type and source.

Negative anticipatory contrast: Does it involve anticipation of an impending reward?

Negative anticipatory contrast (NAC) corresponds to the suppression in consumption of a first rewarding substance (e.g., saccharin 0.15%) when it is followed daily by a second preferred substance (e.g., sucrose 32%). The NAC has been interpreted as resulting from anticipation of the impending preferred reward and its comparison with the currently available first reward [Flaherty, CF., Rowan, G.A., 1985. Anticipatory contrast: within-subjects analysis. Anim. Learn. Behav. 13, 2-5]. In this context, one should expect that devaluation of the preferred substance after the establishment of the NAC would either reduce or abolish the contrast effect. However, contrary to this prediction, the results of the present study show that the NAC is insensitive to devaluation of the second, preferred, substance. This allows one to question that interpretation. The results reported in this study support the view that the NAC effect is controlled by memory of the relative value of the first solution, which is updated daily by means of both a gustatory and/or post-ingestive comparison of the first and second solutions, and memory of past pairings. (C) 2010 Elsevier B.V. All rights reserved.