Suchergebnisse

The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology. ; This work was supported by INSERM, the University of Bordeaux and the Aquitaine Region (to VDG, PVP, GM, UM), by the Fondation pour la Recherche Medicale (DRM20101220445), the Human Frontiers Science Program, and the Agence Nationale de la Recherche (ANR Blanc ANR-13BSV4–0006-02) (to GM), the DG Research of the European Commission FP7 [#HEALTH-F2 2013–602891 (to RM), HEALTH-60319 and ERC–2010–StG–260515 (to GM)], the Spanish 'RETICS-Instituto de Salud Carlos III' (#RD12/0028/0023), the Spanish 'Ministerio de Ciencia e Innovación' (#SAF2011–29864, no. SAF2011–29864, #SAF2013-40592-R, no. SAF2013-40592-R) and the Catalan Government 'AGAUR-Generalitat de Catalunya' (#2009SGR00731 and #2014-SGR-1547) (to RM), The Basque Government grant BCG IT764-13, Ministerio de Economía y Competitividad (MINECO) grant BFU2012-33334, University of the Basque Country UPV/EHU UFI11/41 and Red de Trastornos Adictivos - Instituto de Salud Carlos III grant RD12/0028/0004 (to PG). The FEDER funds support is also acknowledged. EM-G was supported by a 'Sara Borrell' post-doctoral fellowship from the Spanish 'Instituto de Salud Carlos III'. FK was supported by an Aquitaine Region post-doctoral grant

BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders. ; This work was supported by the Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, and Université de Strasbourg; the Fondation pour la Recherche Médicale (Grant No. FRM FDT20120925269), the U.S. National Institutes of Health (National Institute of Drug Addiction, Grant No. 05010, and National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658); the Spanish Instituto de Salud Carlos III (Red de Trastornos Adictivos, Grant No. RD06/001/001), the Spanish Ministerio de Ciencia e Innovación (No. Ministerio de Ciencia e Innovación [Grant No. SAF2011-29864]), the Catalan Government (Grant No. SGR2009-00131), and Institucio Catalana de Recerca i Estudis Avançats Academia-2008; and NeuroPain (Framework programme 7, European Union)

Background: GTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice. Methods: By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients. Results: Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs. Conclusion: Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model. ; This work was supported by grants from the Spanish Ministry of Health (FIS 04/0433, to VC), the Spanish Ministry of Science and Education (SAF2004-6382, to LPJ and BFU2006-04406/BMC, to JLB) and the VI Framework Programme of the European Union (LSHG-CT-2006-037627, to LPJ). JL was supported by a FPI Fellowship (SAF2001-3941) and VC is a FIS Investigator.

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis. ; This work was partially funded by the Instituto de Salud Carlos III (Madrid, Spain) through the project PI15/01934, PI18/01022, PI21/01361) to J.M.F.-R. and the project PI20/01090 (co-funded by the European Regional Development Fund . "A way to make Europe") to J.M.-P., the grants SAF2015-65878-R from the Ministry of Economy and Competitiveness , Prometeo/2018/A/133 from Generalitat Valenciana, Spain and also by the Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013- 602891 ), the Catalan Government (AGAUR, #SGR2017-669 , #2017 SGR- 734, ICREA Academia Award 2015 to R.M. and ICREA Academia Award 2022 to J.M.F.R.), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020 ), 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). CIBERobn is also co-funded by the European Regional Development Fund. We also acknowledge the funding from the Spanish Ministry of Science, Innovation and Universities ( RTI2018-099200-B-I00 ), and the Generalitat of Catalonia (Agency for Management of University and Research grants ( 2017SGR696 ) and Department of Health (SLT002/16/00250)) to R.M M.A.-R. is funded by the Instituto de Salud Carlos III , Río Hortega ( CM19/00190 ). J.M.-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." A.C.-N. is funded by the Instituto de Salud Carlos III , Sara Borrell. MMG was funded by the Spanish Ministry of Science, Innovation and Universities RTI2018-094248-B-I00.