Suchergebnisse

Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches. The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction. Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate in the initiation and maintenance of drug consumption and in the development of compulsion and loss of behavioral control occurring during drug addiction. The identification of the important role played by CB1 cannabinoid receptors in drug addiction encouraged the possible used of an early commercialized CB1 receptor antagonist for treating drug addiction. However, the incidence of serious psychiatric adverse events leaded to the sudden withdrawal from the market of this CB1 antagonist and all the research programs developed by pharmaceutical companies to obtain new CB1 antagonists were stopped. Currently, new research strategies are under development to target the endocannabinoid system for drug addiction avoiding these side effects, which include allosteric negative modulators of CB1 receptors and compounds targeting CB2 receptors. Recent studies showing the potential role of CB2 receptors in the addictive properties of different drugs of abuse have open a promising research opportunity to develop novel possible therapeutic approaches. ; We acknowledge the financial support of the Spanish MINECO (#SAF2017-84060-R-AEI/FEDER-UE), Instituto de Salud Carlos III-RETICS(##RD16/0017/0020), Ministerio de Sanidad, Servicios Sociales e Igualdad-Plan Nacional Sobre Drogas (#PNSD-2017I068), and the Generalitat de Catalunya-AGAUR ((#2017-SGR-669 and #ICREA Acadèmia2015) and the European Commission-DG RTD (#FP7-HEALTH-F2-2013-602891-NeuroPain) to RM. FEDER funding support is also acknowledged. This work was supported by Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU) (RD16/0017/0012), The Basque Government (BCG IT764-13) and MINECO/FEDER, UE(SAF2015-65034-R) to PG. This research was supported by Instituto de Salud Carlos III (RETICS, RD12/0028/0019, RD16/0017/0014 and RD06/0001/1004), Plan Nacional Sobre Drogas (PNSD 2016/016 and 2007/061), Ministerio de Economía y Competitividad (FIS, PI14/00438) and Ministerio de Ciencia e Innovación (SAF2008-01106) to JM

BACKGROUND: Hypocretin (orexin) signaling is involved in drug addiction. In this study, we investigated the role of these hypothalamic neuropeptides in nicotine withdrawal by using behavioral and neuroanatomical approaches. METHODS: Nicotine withdrawal syndrome was precipitated by mecamylamine (2 mg/kg, subcutaneous) in C57BL/6J nicotine-dependent mice (25 mg/kg/day for 14 days) pretreated with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 (5 and 10 mg/kg, intraperitoneal), the hypocretin receptor 2 antagonist TCSOX229 (5 and 10 mg/kg, intraperitoneal), and in preprohypocretin knockout mice. c-Fos expression was analyzed in several brain areas related to nicotine dependence by immunofluorescence techniques. Retrograde tracing with rhodamine-labeled fluorescent latex microspheres was used to determine whether the hypocretin neurons project directly to the paraventricular nucleus of the hypothalamus (PVN), and SB334867 was locally administered intra-PVN (10 nmol/side) to test the specific involvement of Hcrtr-1 in this brain area during nicotine withdrawal./nRESULTS: Somatic signs of nicotine withdrawal were attenuated in mice pretreated with SB334867 and in preprohypocretin knockout mice. No changes were found in TCSOX229 pretreated animals. Nicotine withdrawal increased the percentage of hypocretin cells expressing c-Fos in the perifornical, dorsomedial, and lateral hypothalamus. In addition, the increased c-Fos expression in the PVN during withdrawal was dependent on hypocretin transmission through Hcrtr-1 activation. Hypocretin neurons directly innervate the PVN and the local infusion of SB334867 into the PVN decreased the expression of nicotine withdrawal. CONCLUSIONS: These data demonstrate that hypocretin signaling acting on Hcrtr-1 in the PVN plays a crucial role in the expression of nicotine withdrawal. ; This work was supported by the Instituto de Salud Carlos III grants #PI07/0559,/n#PI10/00316, and #RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science/nand Technology (Consolider-C, #SAF2007-64062), the Catalan Government/n(SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies/n(ICREA Academia program). A Plaza-Zabala is a recipient of a predoctoral fellowship/nfrom the Spanish Ministry of Education

BACKGROUND: The treatment of neuropathic pain is unsatisfactory at the present moment and the sigma 1 receptor has been identified as a new potential target for neuropathic pain. The aim of this study was to use an operant self-administration model to reveal the potential interest of a new sigma 1 receptor antagonist, S1RA, in chronic pain that was developed in mice by a partial ligation of the sciatic nerve. METHODS: Once that chronic pain had reached a steady state, mice were trained to maintain an operant behaviour to self-administer S1RA. The possible abuse liability of the analgesic compound was determined by evaluating operant self-administration in sham-operated mice. The influence of S1RA on the anhedonic state related to chronic pain was also evaluated by measuring the preference for palatable drink (2% sucrose solution) using a recently validated and highly sensitive behavioural device. RESULTS: Nerve-injured mice, but not sham-operated animals, acquired the operant responding to obtain S1RA (6 mg/kg/infusion). After 10 days of S1RA self-administration, neuropathic pain was significantly reduced in nerve-injured mice. In addition, an anhedonic state was revealed in nerve-injured mice by a decreased consumption of palatable drink, which was significantly attenuated by S1RA (25 mg/kg). CONCLUSIONS: These results reveal the analgesic efficacy of the sigma antagonist, S1RA, in neuropathic pain associated with an improvement of the emotional negative state and that was devoided of reinforcing effects. The operant responses evaluated in this new mouse model can have a high predictive value to estimate the clinical benefit/risk ratio of new analgesic compounds to treat chronic pain, such as S1RA. ; S1RA was provided by Esteve as a gift within research projects funded by the CENIT program (CEN-20061005) from the Centro para el Desarollo Technológico Industrial from the Spanish Ministry of Science and Innovation (#SAF2007-64062), "Redes temáticas de investigación cooperativa en salud (RETICS) del Instituto de Salud Carlos III (RD06/001/001). Red de trastornos adictivos (RTA)", the Catalan Government (SGR2009-00131), the ICREA Foundation (ICREA Academia-2008) and the DG Research of the European Commission (PHECOMP, #LSHM-CT-2007-037669)

Cocaine addiction causes serious health problems, and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of the PLCB1 gene to cocaine addictive properties using Plcb1+/- mice. First, we performed a general phenotypic characterization and found that Plcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. To conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine-seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction. ; This work was supported by the Spanish 'Ministerio de Economía y Competitividad-MINECO' (#SAF2017-84060-RAEI/FEDER-UE), the Spanish 'Instituto de Salud Carlos III, RETICS-RTA' (#RD12/0028/0023), the 'Generalitat de Catalunya, AGAUR' (#2017 SGR-669), 'ICREA-Acadèmia' (#2015) and the Spanish 'Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas' (#PNSD-2017I068) to RM, 'Fundació La Marató-TV3' (#2016/20-30) and 'Plan Nacional Sobre Drogas of the Spanish Ministry of Health' (#PNSD-2019I006) to EMG, Spanish 'Ministerio de Ciencia, Innovación y Universidades' (#RTI2018-100968-B-100), Spanish 'Ministerio de Economía y Competitividad' (#SAF2015-68341-R), 'AGAURGeneralitat de Catalunya' (#2017-SGR-738) and Spanish 'Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas' (#PNSD-2017I050) to BC and (#PNSD-2020I042) to NFC. The research leading to these results has also received funding from the European Union H2020 Program [H2020/2014-2020] under grant agreements n° 667302 (CoCA), 643051 (MiND) and 728018 (Eat2beNICE). JCD was supported by the H2020 CoCA and Eat2beNICE projects

An understanding of the neurobiological mechanisms involved in the regulation of fear is essential for the development of new treatments for anxiety disorders, such as phobias, panic, and post-traumatic stress disorders (PTSD). Orexins, also known as hypocretins, are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system. Although this system was initially believed to be primarily involved in the regulation of feeding behavior, recent studies have shown that orexins also modulate neural circuits implicated in the expression and extinction of fear memories. Here, we discuss recent findings involving orexins in anxiety disorders and current clinical trials using orexin ligands that could be applied to identify new therapies for diseases characterized by pathological fear. ; This work was supported by the Instituto de Salud Carlos III grants, #PI13/00042 and #RD12/0028/0023 (RTA-RETICS), by the Spanish Ministry of Science #SAF2011-29864 and #SAF2014-59648-P, National Plan on Drugs #2014I019, and the Catalan Government (SGR2014-1547).

Background: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. Methods: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. Results: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. Conclusion: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts. ; This work was partially supported by research grants FIS (PI15/01934 and PI18/01022) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R and #AEI-SAF2017-84060-R-FEDER from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain; and also by Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2015), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), the Catalan Goverment (Agency for Management of University and Research Grants [2017SGR696] and Department of Health [STL002/16/00250]; the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT); and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). MA-R is funded by a predoctoral Río Hortega contract from the Instituto de Salud Carlos III (ISCIII, CM19/00190), co-funded by the European Social Fund "Investing in your future". OC-R is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP20/00165), co-funded by the Europeran Social Fund "Investing in your future". JM-P is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund "Investing in your future". JS is funded by a predoctoral PERIS contract (SLT002/16/00250) from the Catalan Government. MJ is a professor under the "Serra Hunter" programme (Generalitat de Catalunya).

Beta-2 (β2) nicotinic acetylcholine receptor subunits have been particularly related with nicotine reinforcement. However, the importance of these subunits in the chronic aspects of nicotine addiction has not been established. In this study we evaluated the role of ventral tegmental area (VTA) β2 receptor subunits in the acquisition and maintenance of nicotine self-administration. We used an operant mouse model of intravenous self-administration of different doses of nicotine (15, 30, and 60 μg/kg/infusion) during 10 days in constitutive knockout mice lacking β2 receptor subunits (β2KO), wild-type (WT) controls, mice with β2 receptor subunits re-expressed in the VTA using a lentiviral vector (β2-VEC), and control knockout mice with a sham injection (KO-GFP). The results showed that β2KO mice did not reliably acquire nicotine self-administration at any of the doses tested, while WT controls showed dose-dependent acquisition of this behaviour. β2-VEC mice readily acquired and maintained nicotine self-administration at the effective dose of 15 μg/kg/infusion, while sham KO-GFP mice did not. The recovery of the WT phenotype by the re-expression of β2 receptor subunits within the VTA supports the role of this specific population in nicotine reinforcement, and reveals that they are sufficient for the acquisition and maintenance of systemic nicotine self-administration. ; This work was supported by the Spanish "Instituto de Salud Carlos III" (RD06/001/001 and PI10/01708), FEDER funds, and Ministerio de Ciencia e Innovación (SAF2007-64062), the Catalan Government (SGR2009-00131), an FP7 ERANET programme (NICO-GENE), the ICREA Foundation (ICREA Academia-2008), and a post-doctoral fellowship from CONACyT to AHS

Osteoarthritis is the most common musculoskeletal disease worldwide, often characterized by degradation of the articular cartilage, chronic joint pain and disability. Cognitive dysfunction, anxiety and depression are common comorbidities that impact the quality of life of these patients. In this study, we evaluated the involvement of sigma-1 receptor (σ1R) on the nociceptive, cognitive and emotional alterations associated with chronic osteoarthritis pain. Monosodium iodoacetate (MIA) was injected into the knee of Swiss-albino CD1 mice to induce osteoarthritis pain, which then received a repeated treatment with the σ1R antagonist E-52862 or its vehicle. Nociceptive responses and motor performance were assessed with the von Frey and the Catwalk gait tests. Cognitive alterations were evaluated using the novel object recognition task, anxiety-like behavior with the elevated plus maze and the zero-maze tests, whereas depressive-like responses were determined using the forced swimming test. We also studied the local effect of the σ1R antagonist on cartilage degradation, and its central effects on microglial reactivity in the medial prefrontal cortex. MIA induced mechanical allodynia and gait abnormalities that were prevented by the chronic treatment with the σ1R antagonist. E-52862 also reduced the memory impairment and the depressive-like behavior associated to osteoarthritis pain. Interestingly, the effect of E-52862 on depressive-like behavior was not accompanied by a modification of anxiety-like behavior. The pain-relieving effects of the σ1R antagonist were not due to a local effect on the articular cartilage, since E-52862 treatment did not modify the histological alterations of the knee joints. However, E-52862 induced central effects revealed by a reduction of the cortical microgliosis observed in mice with osteoarthritis pain. These findings show that σ1R antagonism inhibits mechanical hypersensitivity, cognitive deficits and depressive-like states associated with osteoarthritis pain in mice. These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception. ; We acknowledge the financial support of the European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), and AGAUR (ICREA Academia Award 2015). MC is the recipient of an Industrial Doctorate contract from the Catalan Government and Laboratorios Esteve (AGAUR, #2014-DI-040). Partial support from FEDER funds is also acknowledged.

High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations. ; This work was supported by the European Commission, FP7 (#HEALTH‐F2‐2013‐602891) to R.M.; the Spanish Ministerio de Economía y Competitividad‐MINECO (#SAF2014‐59648‐P‐FEDER), the Spanish Instituto de Salud Carlos III, RETICS‐RTA (#RD12/0028/0023‐FEDER) and the Generalitat de Catalunya, AGAUR (#2014‐SGR‐1547) to R.M. The financial support of the Fundació La Marató‐TV3 (#201620‐30) is also acknowledged. We would like to thank the Advance Light Microscopy Unit of the Center for Genomic Regulation for their technical assistance on the acquisition and processing of microscopy images. S. M‐N. was supported by CAPES fellowship of the Brazilian Government (Programa Ciência Sem Fronteiras).

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment. ; This work was partially supported by Instituto de Salud Carlos III (Madrid, Spain) through the research grants PI15/01934, PI18/01022, and PI21/01361 to J.M.F.-R. and PI20/01090 (co-funded by the European Regional Development Fund. "A way to make Europe") to J.M.-P.; the Catalan Government (AGAUR, #SGR2017-0734, ICREA Academia Award 2021) to J.M.F.-R.; the Spanish Ministry of Science, Innovation and Universities (PID2019-105969GB-I00); Generalitat Valenciana (Prometeo/2018/133), Spain; and Fondo Europeo de Desarrollo Regional (FEDER) funds to A.M. This work was also supported by the European Commission (FP7, NeuroPain #2013-602891); the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2020) to R.M.; the Spanish Instituto ...

Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine-rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An up-regulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the down-regulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain sub-populations of smokers. ; This work was supported by the Spanish "Ministerio de Ciencia e Innovación" (#SAF2007-64062) and "Instituto de Salud Carlos III" (#RD06/001/001, PI070709 and PI070559), the Catalan Government (SGR2009-00131), the ICREA Foundation (ICREA Academia-2008), NIDA (1R01-DA01 6768-0111) and the DG Research of the European Commission (NEWMOOD LSHM-CT-2004-503474; GENADDICT, #LSHM-CT-2004-05166; and PHECOMP, #LSHM-CT-2007-037669). J.M.T and E.M.G. are post-doctoral fellows of Instituto de Salud Carlos III "Contratos posdoctorales de perfeccionamiento Sara Borrell".

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is a recreational drug widely used by adolescents and young adults. Although its rewarding effects are well established, there is controversy on its addictive potential. We aimed to compare the consequences of active and passive MDMA administration on gene expression in the mouse brain since all previous studies were based on passive MDMA administration. We used a yoked-control operant intravenous self-administration paradigm combined with microarray technology. Transcriptomic profiles of ventral striatum, frontal cortex, dorsal raphe nucleus and hippocampus were analysed in mice divided in contingent MDMA, yoked MDMA and yoked saline groups, and several changes were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The comparison of contingent MDMA and yoked MDMA vs. yoked saline mice allowed the identification of differential expression in several genes, most of them with immunological and inflammatory functions, but others being involved in neuroadaptation. In the comparison of contingent MDMA vs. yoked MDMA administration, hippocampus and the dorsal raphe nucleus showed statistically significant changes. The altered expression of several genes involved in neuroadaptative changes and synapse function, which may be related to learning self-administration behaviour, could be validated in these two brain structures. In conclusion, our study shows a strong effect of MDMA administration on the expression of immunological and inflammatory genes in all the four brain regions studied. In addition, experiments on MDMA self-administration suggest that the dorsal raphe nucleus and hippocampus may be involved in active MDMA-seeking behaviour, and show specific alterations on gene expression that support the addictive potential of this drug. ; This work was supported by the Spanish 'Ministerio de Ciencia e Innovación (MICINN)'(SAF2007-64062), 'Instituto de Salud Carlos III' (RD06/001/001 and PI070709), the Catalan Government (SGR2009-00131 and SGR2009-00971), the ICREA Foundation (ICREA Academia-2008), 'Plan Nacional Sobre Drogas' (PNSD#2009/022 and PNSD#2009/026), Fundació 'La Marató/nde TV3' (2007) and the DG Research of the European Commission (GENADDICT, LSHM-CT-2004-05166; and PHECOMP, LSHM-CT-2007-037669). Partial support from FEDER funds is/nalso acknowledged. MR is a recipient of a Miguel de Servet contract from 'Instituto de Salud Carlos III-MICINN' (Spain) and NF-C was supported by a fellowship from the Biomedical Network/nResearch Centre on Rare Diseases (CIBERER)

Background: Vagus nerve stimulation (VNS) using non-invasive approaches have attracted great attention due to their anti-epileptic, anti-depressive and pro-cognitive effects. It has been proposed that auricular transcutaneous VNS (atVNS) could benefit intellectual disability disorders, but preclinical data supporting this idea is limited. Objective: To develop an atVNS device for mice and to test its efficacy on memory performance in naïve mice and in a mouse model for intellectual disability. Methods: Naïve outbreed CD-1 mice and a model for fragile X syndrome, the Fmr1 knockout (Fmr1KO), were used to assess the effect of atVNS in the novel object-recognition memory performance. Results: We found that atVNS significantly improves memory persistence in naïve mice. Notably, atVNS was efficacious in normalizing the object-recognition memory deficit in the Fmr1KO model. Conclusion: Our data show that atVNS improves memory persistence in naïve mice and in a model of intellectual disability and support further studies taking advantage of preclinical mouse models of cognitive disorders. ; This work was supported by a Predoctoral fellowship from Jerome Lejeune Foundation (Spanish division) (A.V.-O.) and from "la Caixa" Foundation (ID 100010434), LCF/BQ/IN18/11660012 and European Union's Horizon 2020 research and innovation programme under the Marie Slodowska-Curie grant agreement No. 713673 (C.B.-P.). Ministerio de Economía, Innovación y Competitividad (MINECO) [#RTI2018-099282-B-I00 to A.O., #SAF2017-84060-R to R.M.]; the Instituto de Salud Carlos III [#RD16/0017/0020 to R.M.]; the Generalitat de Catalunya [2017SGR-669 to R.M.]; the ICREA (Institució Catalana de Recerca i Estudis Avançats) Acadèmia to A.O., A.I. and R.M.; Grant "Unidad de Excelencia María de Maeztu", funded by the MINECO [#MDM-2014-0370]; PLAN E (Plan Español para el Estímulo de la Economía y el Empleo). FEDER (Fondo Europeo de Desarrollo Regional) funding is also acknowledged

A major problem in treating obesity is the high rate of relapse to abnormal food-taking habits after maintaining an energy balanced diet. Alterations of eating behavior such as compulsive-like behavior and lack of self-control over food intake play a critical role in relapse. In this study, we used an operant paradigm of food-seeking behavior on two different diet-induced obesity models, a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity or for unhealthy food regularly consumed in our societies. A reduced operant performance and motivation for the hedonic value of palatable chocolate pellets was revealed in both obesity mouse models. However, only mice exposed to high-fat diet showed an increased compulsive-like behavior in the absence of the reinforcer further characterized by impaired operant learning, enhanced impulsivity and intensified inflexibility. We used principal component analysis to globally identify the specific behaviors responsible for the differences among diet groups. Learning impairment and inflexible behaviors contributed to a first principal component, explaining the largest proportion of the variance in the high-fat diet mice phenotype. Reinforcement, impulsion and compulsion were the main contributors to the second principal component explaining the differences in the chocolate-mixture mice behavioral phenotype. These behaviors were not exclusive of chocolate group because some high-fat individuals showed similar values on this component. These data indicate that extended access to hypercaloric diets differentially modifies operant behavior learning, behavioral flexibility, impulsive-like and compulsive-like behavior, and these effects were dependent on the exposure to each specific diet. ; This work was supported by the DG Research of the European Commission FP7 (#HEALTH-F2 2013-602891 and PHECOMP #LHSM-CT-2007-037669), the Spanish 'RETICS-Instituto de Salud Carlos III' (#RD16/0017/0020), the Spanish 'Ministerio de Economia y Competitividad' (#SAF-2014-59648P), the 'Plan nacional sobre drogas' (#PNSD-2013-5068), the Catalan Government 'AGAUR-Generalitat de Catalunya' (#2014-SGR-1547) and the Catalan foundation 'La Marató de TV3' (#2016/20-30). The laboratory of M.D. is supported by DIUE de la Generalitat de Catalunya (Grups consolidats SGR 2014/1125). This work was supported by Fondation Jérôme Lejeune (Paris, France), MINECO (SAF2013-49129-C2-1-R), CDTI ('Smartfoods') and EU (Era Net Neuron PCIN-2013-060). The CRG is a Center of Excellence Severo Ochoa SEV-2012-0208. The CIBER of Rare Diseases is an initiative of the ISCIII. The laboratory of C.N. acknowledges the funding from the Spanish Ministry of Economy and Finance (MINECO), grant number BFU2011-28575. J.E. receivedthe FI grant from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya

Recent studies have revealed that sequence variants in genes encoding the α3/α5/β4 nicotinic acetylcholine receptor subunits are associated with nicotine dependence. In this study, we evaluated two specific aspects of executive functioning related to drug addiction (impulsivity and working memory) in transgenic mice over expressing α3/α5/β4 nicotinic receptor subunits. Impulsivity and working memory were evaluated in an operant delayed alternation task, where mice must inhibit responding between 2 and 8s in order to receive food reinforcement. Working memory was also evaluated in a spontaneous alternation task in an open field. Transgenic mice showed less impulsive-like behavior than wild-type controls, and this behavioral phenotype was related to the number of copies of the transgene. Thus, transgenic Line 22 (16-28 copies) showed a more pronounced phenotype than Line 30 (4-5 copies). Overexpression of these subunits in Line 22 reduced spontaneous alternation behavior suggesting deficits in working memory processing in this particular paradigm. These results reveal the involvement of α3/α5/β4 nicotinic receptor subunits in working memory and impulsivity, two behavioral traits directly related to the vulnerability to develop nicotine dependence. ; Funding for this study was provided by the DG Research of the European Commission (PHECOMP, no. LHSM-CT-2007-037669), the Spanish 'Instituto de Salud Carlos III' (RD06/001/001; PI082038/nand PI10/01708, EU/FIS PS09102673, ERARare), the Spanish 'Ministerio de Educación y Ciencia' (SAF2007-64062; SAF2007-60827; SAF2007-31093-E; SAF2010-16427), Fundación Ramón Areces, Reina Sofia, Marató TV3, and CIBERER, The Catalan Government (SGR2009-00131; 2009SGR-1313) and the ICREA Foundation (ICREA Academia-2008)