CB1 Cannabinoid Receptor Expression in the Striatum: Association with Corticostriatal Circuits and Developmental Regulation

Corticostriatal circuits mediate various aspects of goal-directed behavior and are critically important for basal ganglia-related disorders. Activity in these circuits is regulated by the endocannabinoid system via stimulation of CB1 cannabinoid receptors. CB1 receptors are highly expressed in projection neurons and select interneurons of the striatum, but expression levels vary considerably between different striatal regions (functional domains). We investigated CB1 receptor expression within specific corticostriatal circuits by mapping CB1 mRNA levels in striatal sectors defined by their cortical inputs in rats. We also assessed changes in CB1 expression in the striatum during development. Our results show that CB1 expression is highest in juveniles (P25) and then progressively decreases toward adolescent (P40) and adult (P70) levels. At every age, CB1 receptors are predominantly expressed in sensorimotor striatal sectors, with considerably lower expression in associative and limbic sectors. Moreover, for most corticostriatal circuits there is an inverse relationship between cortical and striatal expression levels. Thus, striatal sectors with high CB1 expression (sensorimotor sectors) tend to receive inputs from cortical areas with low expression, while striatal sectors with low expression (associative/limbic sectors) receive inputs from cortical regions with higher expression (medial prefrontal cortex). In so far as CB1 mRNA levels reflect receptor function, our findings suggest differential CB1 signaling between different developmental stages and between sensorimotor and associative/limbic circuits. The regional distribution of CB1 receptor expression in the striatum further suggests that, in sensorimotor sectors, CB1 receptors mostly regulate GABA inputs from local axon collaterals of projection neurons, whereas in associative/limbic sectors, CB1 regulation of GABA inputs from interneurons and glutamate inputs may be more important

Transcranial direct current stimulation for memory enhancement: from clinical research to animal models

There is a growing demand for new brain-enhancing technologies to improve mental performance, both for patients with cognitive disorders and for healthy individuals. Transcranial direct current stimulation (tDCS) is a non-invasive, painless, and easy to use neuromodulatory technique that can improve performance on a variety of cognitive tasks in humans despite its exact mode of action remains unclear. We have conducted a mini-review of the literature to first briefly summarize the growing amount of data from clinical trials assessing the efficacy of tDCS, focusing exclusively on learning and memory performances in healthy human subjects and in patients with depression, schizophrenia, and other neurological disorders. We then discuss these findings in the context of the strikingly few studies resulting from animal research. Finally, we highlight future directions and limitations in this field and emphasize the need to develop translational studies to better understand how tDCS improves memory, a necessary condition before it can be used as a therapeutic tool

Transcranial electrical and magnetic stimulation (tES and TMS) for addiction medicine: A consensus paper on the present state of the science and the road ahead

There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data – emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

GPR88: A putative signaling molecule predominantly expressed in the striatum: Cellular localization and developmental regulation

International audienc

Quand le cerveau succombe aux addictions: Facteurs de vulnérabilité, implication des circuits cortico-striataux et développement d’une technique de neuromodulation pour favoriser le sevrage: Apports d’études précliniques

Lʼétude des phénomènes liés à lʼaddiction constitue le fil conducteur de ce travail. Pour ce faire, jʼai utilisé des modèles animaux (rats, souris) et mon approche était intégrative (du comportement à la biologie cellulaire et moléculaire) et, lorsque cela pouvait sʼappliquer, translationnelle (études cliniques et précliniques menées en parallèle). Après une description de mes principales réalisations portant sur les deux versants de mon travail : enseignement et recherche, jʼexpose une rétrospective de mes recherches. Dans une troisième partie se trouve une sélection représentative de mes principales publications. Mes premiers travaux portaient sur la différence de vulnérabilité aux drogues entre les individus et aux facteurs qui la contrôlent. Je me suis intéressé à un facteur environnemental, le stress, en particulier lorsquʼil est appliqué de manière précoce au cours du développement de lʼindividu. Ainsi, jʼai évalué les conséquences dʼun stress in utero chez le rat sur la sensibilité aux effets de lʼalcool et la propension à consommer à lʼâge adult

Impact du stress prénatal

Le stress prenatal augmente la vulnerabilIte a certames substances d abus chez le rat. L objectif de cette thèse était de déterminer si un stress subit in utero pouvait moduler durablement la vulnérabilité à l'éthanol. Deux aspects de Ia vulnérabilité ont été explorés: 1) la sensibilité aux effets produits par une administration d'éthanol: 2) la propension à consommer cette substance. Comparés aux témoins, les animaux adolescents stressés étaient moins sensibles aux effets d'une injection d'éthanol au niveau hormonal (activation de l'axe c0l1icotrope) et neurobiologique (activation des défenses anti¬oxydantes dans l'hippocampe). Une alcoolisation chronique avait un effet délétère sur la mémoire des rats témoins. mais de façon surprenante améliorait les performances mnésiques des stressés. Ces effets pourraient être sous-tendus par les modulations opposées des récepteurs mGlu observées dans l'hippocampe après l'alcoolisation. Chez des animaux mâles isolés (1 rat par cage), le stress prénatal n'altérait pas la préférence pour l'éthanol Cependant. un traitement chronique à l'éthanol augmentait spécifiquement chez les animaux stressés les quantités de [Delta]FosB (un facteur de transcription impliqué dans la vulnérabilité à la consommation de drogues) dans le noyau accumbens. Chez des femelles adolescentes, les conditions d'élevage (rats isolés ou par paires) modulaient différemment la consommation d'alcool des stressées et témoins. Ces données indiquent que le stress prénatal modifie durablement la vulnérabilité à l'éthanol chez le rat et soulignent l'importance de prendre en compte l'histoire de l'individu. même très précoce. pour appréhender la genèse des conduites addictives.In rats, exposure to prenatal stress leads to a greater vulnerabiliy to several drugs of abuse (i.e. psychostimulants and opiates). The aim of the present work was to examine the impact of a prenatal stress (restraint stress of the pregnant dam) on ethanol vulnerability in adolescent and adult rats. Two distinct aspects of the vulnerability were evaluated : 1) the individual differences in the ethanol sensitivity: 2) the spontaneous consumption of ethanol Prenatally stressed rats were less sensitive than control rats to the effects of an ethanol injection during adolescence at the hormonal (HPA. axis activation) and neural (antioxidant defences in the hippocampus) levels. A chronic ethanol treatment induces memory impairments in control rats, whereas it has a beneficial effect on memory in rat subjected to a prenatal stress. These opposite effects could be mediated by the differential modulation of metabotropic glutamate receptors' levels in the hippocampus reported after the ethanol exposure. Prenatal stress has no impact on ethanol preference in isolated male rats. However. a chronic êlhanol treatment increased selectively the [Delta]FosB levels. a transcription factor involved in the vulnerability to drugs consumption, in the nucleus accumbens of prenatally stressed rats. Finally, we observed in female rats interplay between prenatal stress and rearing conditions on the ethanol consumption. Together, these data indicate that prenatal stress, in interaction with other experimental factors, can affect the ethanol sensitivity and consumption. They stress the importance to consider early life events in the study of the addictive behaviour genesis

Addiction-related gene regulation: Risks of exposure to cognitive enhancers vs. other psychostimulants

International audienc

Vulnérabilité à l'éthanol chez le rat adolescent et adulte (impact du stress prénatal)

LILLE1-BU (590092102) / SudocSudocFranceF

Vortioxetine for Cognitive Enhancement in Major Depression: From Animal Models to Clinical Research

International audienc