The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation

International audienceThe subthalamic nucleus (STN) belongs to the basal ganglia and is the current target for the surgical treatment of neurological and psychiatric disorders such as Parkinson's Disease (PD) and obsessive compulsive disorders (OCD), but also a proposed site for the treatment of addiction. It is therefore very important to understand its functions in order to anticipate and prevent possible side-effects in the patients. Although the involvement of the STN is well documented in motor, cognitive and motivational processes, less is known regarding emotional processes. Here we have investigated the direct consequences of STN inactivation by excitotoxic lesions on emotional processing and reinforcement in the rat. We have used various behavioral procedures to assess affect for neutral, positive and negative reinforcers in STN lesioned rats. STN lesions reduced affective responses for positive (sweet solutions) and negative (electric foot shock, Lithium Chloride-induced sickness) reinforcers while they had no effect on responses for a more neutral reinforcer (novelty induced place preference (NIPP)). Furthermore, when given the choice between saccharine, a sweet but non caloric solution, and glucose, a more bland but caloric solution, in contrast to sham animals that preferred saccharine, STN lesioned animals preferred glucose over saccharine. Taken altogether these results reveal that STN plays a critical role in emotional processing. These results, in line with some clinical observations in PD patients subjected to STN surgery, suggest possible emotional side-effects of treatments targeting the STN. They also suggest that the increased motivation for sucrose previously reported cannot be due to increased pleasure, but could be responsible for the decreased motivation for cocaine reported after STN inactivation

Differential vulnerability to the punishment of cocaine related behaviours: effects of locus of punishment, cocaine taking history and alternative reinforcer availability.

BACKGROUND: The availability of alternative reinforcement has been shown to reduce drug use, but it remains unclear whether it facilitates a reduction or cessation of drug seeking or taking. OBJECTIVES: We compared the effects of punishment of cocaine seeking or taking behaviour after brief or extended cocaine-taking histories when behavioural reallocation was facilitated or not by making available an alternative ingestive reinforcer (sucrose). METHODS: In the first experiment, punishment of either seeking or taking responses was introduced immediately after training on the seeking-taking chained schedule. In the second experiment, punishment of cocaine seeking was introduced after 12 additional days of either 1 or 6 h daily access to cocaine self-administration. In both experiments, beginning 1 week before the introduction of punishment, a subset of rats had concurrent nose poke access to sucrose while seeking or taking cocaine. RESULTS: The presence of an alternative source of reinforcement markedly facilitated behavioural reallocation from punished cocaine taking after acquisition. It also facilitated punishment-induced suppression of cocaine seeking after an extensive cocaine self-administration history likely by prompting goal-directed motivational control over drug use. However, a significant proportion of rats were deemed compulsive-maintaining drug use after an extensive cocaine history despite the presence of abstinence-promoting positive and negative incentives. CONCLUSION: Making available an alternative reinforcer facilitates disengagement from punished cocaine use through at least two different processes but remains ineffective in a subpopulation of vulnerable animals, which continued to seek cocaine despite the aversive consequence of punishment and the presence of the alternative positive reinforcer.This work was supported by the United Kingdom Medical Research Council (MRC) Grant to BJE (G9536855) and was conducted within the MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute. The authors declare no conflicts of interest.This is the final published version, which can also be found on the publisher's website here: http://download.springer.com/static/pdf/914/art%253A10.1007%252Fs00213-014-3648-5.pdf?auth66=1404987650_ca63ac8614a2994c56b0f619563ee6af&ext=.pd

Contact resistances in trigate and FinFET devices in a Non-Equilibrium Green's Functions approach

We compute the contact resistances $R_{\rm c}$ in trigate and FinFET devices with widths and heights in the 4 to 24 nm range using a Non-Equilibrium Green's Functions approach. Electron-phonon, surface roughness and Coulomb scattering are taken into account. We show that $R_{\rm c}$ represents a significant part of the total resistance of devices with sub-30 nm gate lengths. The analysis of the quasi-Fermi level profile reveals that the spacers between the heavily doped source/drain and the gate are major contributors to the contact resistance. The conductance is indeed limited by the poor electrostatic control over the carrier density under the spacers. We then disentangle the ballistic and diffusive components of $R_{\rm c}$, and analyze the impact of different design parameters (cross section and doping profile in the contacts) on the electrical performances of the devices. The contact resistance and variability rapidly increase when the cross sectional area of the channel goes below $\simeq 50$ nm$^2$. We also highlight the role of the charges trapped at the interface between silicon and the spacer material.Comment: 16 pages, 15 figure

ESKIMO1 Disruption in Arabidopsis Alters Vascular Tissue and Impairs Water Transport

Water economy in agricultural practices is an issue that is being addressed through studies aimed at understanding both plant water-use efficiency (WUE), i.e. biomass produced per water consumed, and responses to water shortage. In the model species Arabidopsis thaliana, the ESKIMO1 (ESK1) gene has been described as involved in freezing, cold and salt tolerance as well as in water economy: esk1 mutants have very low evapo-transpiration rates and high water-use efficiency. In order to establish ESK1 function, detailed characterization of esk1 mutants has been carried out. The stress hormone ABA (abscisic acid) was present at high levels in esk1 compared to wild type, nevertheless, the weak water loss of esk1 was independent of stomata closure through ABA biosynthesis, as combining mutant in this pathway with esk1 led to additive phenotypes. Measurement of root hydraulic conductivity suggests that the esk1 vegetative apparatus suffers water deficit due to a defect in water transport. ESK1 promoter-driven reporter gene expression was observed in xylem and fibers, the vascular tissue responsible for the transport of water and mineral nutrients from the soil to the shoots, via the roots. Moreover, in cross sections of hypocotyls, roots and stems, esk1 xylem vessels were collapsed. Finally, using Fourier-Transform Infrared (FTIR) spectroscopy, severe chemical modifications of xylem cell wall composition were highlighted in the esk1 mutants. Taken together our findings show that ESK1 is necessary for the production of functional xylem vessels, through its implication in the laying down of secondary cell wall components

Prédispositions aux toxicomanies (influence de la recherche de nouveauté, de l'anxiété et de la dépression sur la vulnérabilité à différents agents toxicomanogènes)

Il est communément admis qu'il existe chez l'homme comme chez l'animal, une grande variabilité de susceptibilité aux drogues. Certains traits de personnalité et comportements pathologiques couramment observé chez les toxicomanes est la recherche de nouveauté. De plus, certains auteurs ont observé que les sujets anxieux et dépressifs abusent aussi fréquemment de drogues. Nous avons donc recherché chez l'animal, l'influence respective de ces différents facteurs comportementaux dans la vulnérabilité aux agents toxicomanogènes. Dans un premier temps, nous avons donc comparé au sein de populations de rat de la souche Wistar, l'influence de la réponse à la nouveauté, selon qu'elle est présentée de façon imposée ou dans une situation de libre choix, sur la vulnérabilité aux effets de différents agents appétitifs naturels et toxicomanogènes. La réactivité à la nouveauté imposée est associée à une plus grande sensibilité aux effets appétitifs d'une faible dose d'amphétamine et à une moindre consommation d'amphétamine, de morphine et de saccharose. A l'opposé, la préférence pour la nouveauté s'accompagne globalement d'une moindre sensibilité aux effets appétitifs de faibles doses d'amphétamine et de cocaïne et d'une plus grande consommation orale d'amphétamine, de morphine, d'éthanol et de saccharose. Les hauts répondeurs à la nouveauté imposée seraient plus sensibles aux drogues et auraient donc besoin d'en consommer moins pour être contentés. Les animaux exprimant une plus grande préférence pour la nouveauté seraient moins sensibles aux effets des drogues et auraient besoin de quantités notablement plus importantes pour obtenir un niveau optimal de stimulation. Ils seraient plus sensibles aux phénomènes de renforcement positif. Alors que les réponses à la nouveauté semblent présager principalement de la sensibilité à de faibles quantités de drogue, l'anxiété et la résignation semblent davantage influencer la réponse aux plus fortes quantités de drogue. Ainsi l'anxiété déterminée sur les épreuves du double compartiment blanc/noir et du labyrinthe en croix surélevé, au sein de populations générales de rats de la souche Wistar ne prédit pas la préférence de place conditionnée induite par de faibles doses de cocaïne, d'amphétamine et de morphine. Toutefois, elle favorise l'appétence pour de plus fortes doses de cocaïne et d'amphétamine. De la même façon, l'anxiété n'influence pas la consommation orale d'amphétamine à partir de solutions faiblement concentrées, mais les anxieux consomment moins d'amphétamine que les non anxieux lorsque celle-ci est présentée dans une solution plus concentrée. De plus les animaux anxieux supportent moins bien une réduction de la concentration de la solution alcoolisée ou une privation d'éthanol, suggérant qu'ils sont plus sensibles aux phénomènes de renforcement négatif et présenteraient ainsi une propension accrue à la rechute. Chez les rats mâles, la durée d'immobilité dans l'épreuve de la nage forcée ne présage pas de la sensibilité aux effets appétitifs de faibles doses d'amphétamine, de cocaïne et de morphine. Au sein de populations hétérogènes de souris mâles et femelles de la souche CD1, nous avons pu établir que l'immobilité dans l'épreuve de suspension par la queue est prédictive de l'anhédonie induite par des stress chroniques légers chez les femelles mais pas chez les mâles. De plus, les femelles les plus résignées dans l'épreuve de la suspension par la queue consomment plus d'éthanol à partir d'une solution fortement concentrée et développent une plus grande préférence de place conditionnée induite par une forte dose d'éthanol que les femelles non résignées. Ces résultats semblent donc montrer que les réponses à la nouveauté d'une part et l'anxiété et la résignation d'autre part seraient impliquées de manière différente dans la vulnérabilité aux drogues.It is the commonly accepted that a wide variability exists in susceptibility to drug of abuse, both in human and non-human animals. Some personality trait and pathological behaviours are frequently associated with drug addiction. For example, novelty seeking is often observed in drug abuser, and anxious and depressive individuals also frequently abuse drugs. The purpose of this investigation was to examine the respective influence of these factors on the vulnerability to drug addiction. In the first phase, we compared the influence of responses to both forced and free-choice novelty within a population of Wistar rats. The reactivity to forced novelty was associated with a higher sensitivity to the rewarding effects of a low dose of amphetamine and with a lower oral consumption of amphetamine, morphine and sucrose..In the second phase, we compared the influences of anxiety and helplessness on vulnerability to drug of abuse. In Wistar rats, anxiety was associated with greater conditioned place preference induced by high, but not low, doses of cocaine and amphetamine. In addition, anxiety was not associated with a greater consumption of a low concentration of amphetamine solutions, but anxious animals consumed less of a higher concentration of amphetamine solution than non-anxious animals Similar to anxiety, helplessness was not associated to any difference in drug sensitivity Taken together these results suggest that responses to novelty, anxiety and helplessness are associated with different aspects of vulnerability to drugs of abuse.ROUEN-BU Sciences (764512102) / SudocSudocFranceF

La chirurgie au secours des addictions

Initialement développée pour le traitement de pathologies neurologiques, comme la maladie de Parkinson, la stimulation cérébrale profonde est actuellement utilisée dans certaines pathologies psychiatriques telles que les troubles obsessionnels compulsifs ou la dépression. Elle commence à être envisagée, voire appliquée, comme traitement de certaines addictions. Nous faisons le point dans cette revue sur l’évolution des discussions sur l’intérêt de cette approche thérapeutique, et discutons en particulier les arguments expérimentaux orientant le choix vers les deux cibles cérébrales les plus pertinentes pour traiter les addictions par stimulation cérébrale profonde : le noyau accumbens (NAc) et le noyau sous-thalamique (NST)

First evidence of a hyperdirect prefrontal pathway in the primate: precise organization for new insights on subthalamic nucleus functions

International audienceA commentary on The organization of prefrontalsubthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulatio

Social modulation of drug use and drug addiction

International audienc