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Giovanni MARSICANO




Principal Investigator

Phone : 33(0)5 57 57 37 56 / 33(0)5 57 57 37 61
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Cursus:
PhD à l'Institut Max-Planck de Munich (1997-2001)
Post-Doc, Institut Max-Planck, Munich (2001-2004)
CR1 Neurocentre Magendie, Bordeaux (2007)






154 publication(s) since Mai 1996:


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* equal contribution
The indicated IF have been collected by the Web of Sciences in


07/01/2020 | Neuron   IF 14.4
Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity.
Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A

Abstract:
Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca(2+) elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca(2+), stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.




09/12/2019 | J Neurosci Methods   IF 2.8
Alpha technology: A powerful tool to detect mouse brain intracellular signaling events.
Zanese M*, Tomaselli G*, Roullot-Lacarriere V, Moreau M, Bellocchio L, Grel A, Marsicano G, Sans N, Vallee M, Revest JM

Abstract:
BACKGROUND: Phosphorylation by protein kinases is a fundamental molecular process involved in the regulation of signaling activities in living organisms. Understanding this complex network of phosphorylation, especially phosphoproteins, is a necessary step for grasping the basis of cellular pathophysiology. Studying brain intracellular signaling is a particularly complex task due to the heterogeneous complex nature of the brain tissue, which consists of many embedded structures. NEW METHOD: Overcoming this degree of complexity requires a technology with a high throughput and economical in the amount of biological material used, so that a large number of signaling pathways may be analyzed in a large number of samples. We have turned to Alpha (Amplified Luminescent Proximity Homogeneous Assay) technology. COMPARISON WITH EXISTING METHOD: Western blot is certainly the most commonly used method to measure the phosphorylation state of proteins. Even though Western blot is an accurate and reliable method for analyzing modifications of proteins, it is a time-consuming and large amounts of samples are required. Those two parameters are critical when the goal of the research is to comprehend multi-signaling proteic events so as to analyze several targets from small brain areas. RESULT: Here we demonstrate that Alpha technology is particularly suitable for studying brain signaling pathways by allowing rapid, sensitive, reproducible and semi-quantitative detection of phosphoproteins from individual mouse brain tissue homogenates and from cell fractionation and synaptosomal preparations of mouse hippocampus. CONCLUSION: Alpha technology represents a major experimental step forward in unraveling the brain phosphoprotein-related molecular mechanisms involved in brain-related disorders.




24/10/2019 | Psychoneuroendocrinology   IF 4
The ergogenic impact of the glucocorticoid prednisolone does not translate into increased running motivation in mice.
Redon B, Violleau C, Georges F, Marsicano G, Chaouloff F

Abstract:
Glucocorticoids, such as prednisolone, are considered sport doping agents owing to their ergogenic properties. These are accounted for by peripheral mechanisms associated with energetic and anti-inflammatory processes. However, because glucocorticoids target brain tissues, it is likely that these ergogenic impacts are associated with central effects. One of these might be reward motivation, which relies on glucocorticoid receptor-expressing mesocorticolimbic dopaminergic neurons. In keeping with this possibility, this study has explored in mice whether repeated prednisolone administration (5 or 15mug/ml of drinking water for 10 days) affected intrinsic motivation for running, a strong reinforcer in rodents. Running motivation was assessed by means of a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses under fixed (FR), and then progressive (PR), ratio reinforcement schedules. Sub-chronic ingestion of prednisolone decreased the running distance covered during each rewarded sequence under FR schedules. This finding did not extend to wheel-running performances in mice provided free (i.e. unconditioned) wheel-running opportunities. Running motivation, as estimated under a PR reinforcement schedule, was found to be decreased (lowest concentration) or to remain unaffected (highest concentration) by prednisolone concentration. Lastly, an inter-individual analysis of the respective effects of prednisolone on muscular endurance (as assessed in the wire grid-hanging test) and on running motivation indicated that the former was not predictive of the latter. This observation suggests that prednisolone ergogenic impacts might occur without any concomitant increase in intrinsic exercise motivation.




11/08/2019 | j pers   IF 3.1
Stability and change of basic personal values in early adolescence: A 2-year longitudinal study.
Vecchione M, Schwartz SH, Davidov E, Cieciuch J, Alessandri G, Marsicano G

Abstract:
OBJECTIVE: We examined patterns of change and stability in the whole set of 10 Schwartz values over 2 years during early adolescence. METHOD: Participants completed the Portrait Values Questionnaire repeatedly throughout the junior high school years. The study involved six waves of data and a total of 382 respondents aged 10 years at the first measurement occasion (43% female). We investigated multiple types of stability in the values: mean-level, rank-order, and ipsative stability. RESULTS: At the mean-level, self-enhancement, and Openness to change values increased in importance. Self-direction and hedonism values showed the greatest increase-about one-third of a standard deviation. Conservation and self-transcendence values did not change with the exception of tradition, which decreased slightly. After correcting for measurement error, rank-order stability coefficients ranged from .39 (hedonism) to .77 (power). Correlations between value hierarchies measured 2 years apart were >/=.85 for 75% of respondents, and



Abstract:
OBJECTIVE: The hypothalamic paraventricular nucleus (PVN) is a key target of the melanocortin system, which orchestrates behavioral and metabolic responses depending on energy availability. The mechanistic target of rapamycin complex 1 (mTORC1) and the endocannabinoid type 1 receptor (CB1R) pathways are two key signaling systems involved in the regulation of energy balance whose activity closely depends upon energy availability. Here we tested the hypothesis that modulation of mTORC1 and CB1R signaling regulates excitatory glutamatergic inputs onto the PVN. METHODS: Patch-clamp recordings in C57BL/6J mice, in mice lacking the mTORC1 component Rptor or CB1R in pro-opio-melanocortin (POMC) neurons, combined with pharmacology targeting mTORC1, the melanocortin receptor type 4 (MC4R), or the endocannabinoid system under chow or a hypercaloric diet. RESULTS: Acute pharmacological inhibition of mTORC1 in C57BL/6J mice decreased glutamatergic inputs onto the PVN via a mechanism requiring modulation of MC4R, endocannabinoid 2-AG mobilization by PVN parvocellular neurons, and retrograde activation of presynaptic CB1R. Further electrophysiology studies using mice lacking mTORC1 activity or CB1R in POMC neurons indicated that the observed effects involved mTORC1 and CB1R-dependent regulation of glutamate release from POMC neurons. Finally, energy surfeit caused by hypercaloric high-fat diet feeding, rapidly and time-dependently altered the glutamatergic inputs onto parvocellular neurons and the ability of mTORC1 and CB1R signaling to modulate such excitatory activity. CONCLUSIONS: These findings pinpoint the relationship between mTORC1 and endocannabinoid-CB1R signaling in the regulation of the POMC-mediated glutamatergic inputs onto PVN parvocellular neurons and its rapid alteration in conditions favoring the development of obesity.




02/07/2019 | Curr Biol   IF 9.2
CB1 Receptors in the Anterior Piriform Cortex Control Odor Preference Memory.
Terral G, Busquets-Garcia A, Varilh M, Achicallende S, Cannich A, Bellocchio L, Bonilla-Del Rio I, Massa F, Puente N, Soria-Gomez E, Grandes P, Ferreira G, Marsicano G

Abstract:
The retrieval of odor-related memories shapes animal behavior. The anterior piriform cortex (aPC) is the largest part of the olfactory cortex, and it plays important roles in olfactory processing and memory. However, it is still unclear whether specific cellular mechanisms in the aPC control olfactory memory, depending on the appetitive or aversive nature of the stimuli involved. Cannabinoid-type 1 (CB1) receptors are present in the aPC (aPC-CB1), but their potential impact on olfactory memory was never explored. Here, we used a combination of behavioral, genetic, anatomical, and electrophysiological approaches to characterize the functions of aPC-CB1 receptors in the regulation of appetitive and aversive olfactory memory. Pharmacological blockade or genetic deletion of aPC-CB1 receptors specifically impaired the retrieval of conditioned odor preference (COP). Interestingly, expression of conditioned odor aversion (COA) was unaffected by local CB1 receptor blockade, indicating that the role of aPC endocannabinoid signaling is selective for retrieval of appetitive memory. Anatomical investigations revealed that CB1 receptors are highly expressed on aPC GABAergic interneurons, and ex vivo electrophysiological recordings showed that their pharmacological activation reduces miniature inhibitory post-synaptic currents (mIPSCs) onto aPC semilunar (SL), but not pyramidal principal neurons. COP retrieval, but not COA, was associated with a specific CB1-receptor-dependent decrease of mIPSCs in SL cells. Altogether, these data indicate that aPC-CB1 receptor-dependent mechanisms physiologically control the retrieval of olfactory memory, depending on odor valence and engaging modulation of local inhibitory transmission.




07/03/2019 | JCI Insight   IF 6
The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors.
Muguruza C, Redon B, Fois GR, Hurel I, Scocard A, Nguyen C, Stevens C, Soria-Gomez E, Varilh M, Cannich A, Daniault J, Busquets-Garcia A, Pelliccia T, Caille S, Georges F, Marsicano G, Chaouloff F

Abstract:
The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.




2019 | front pharmacol   IF 3.8
Beyond the Activity-Based Anorexia Model: Reinforcing Values of Exercise and Feeding Examined in Stressed Adolescent Male and Female Mice.
Hurel I, Redon B, Scocard A, Malezieux M, Marsicano G, Chaouloff F

Abstract:
Anorexia nervosa (AN), mostly observed in female adolescents, is the most fatal mental illness. Its core is a motivational imbalance between exercise and feeding in favor of the former. The most privileged animal model of AN is the 'activity-based anorexia' (ABA) model wherein partly starved rodents housed with running wheels exercise at the expense of feeding. However, the ABA model bears face and construct validity limits, including its inability to specifically assess running motivation and feeding motivation. As infant/adolescent trauma is a precipitating factor in AN, this study first analyzed post-weaning isolation rearing (PWIR) impacts on body weights and wheel-running performances in female mice exposed to an ABA protocol. Next, we studied through operant conditioning protocols i) whether food restriction affects in a sex-dependent manner running motivation before ii) investigating how PWIR and sex affect running and feeding drives under ad libitum fed conditions and food restriction. Besides amplifying ABA-elicited body weight reductions, PWIR stimulated wheel-running activities in anticipation of feeding in female mice, suggesting increased running motivation. To confirm this hypothesis, we used a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses. It was first observed that food restriction increased running motivation in male, but not female, mice. When fed grouped and PWIR mice were tested for their running and palatable feeding drives, all mice, excepted PWIR males, displayed increased nose poke responses for running over feeding. This was true when rewards were proposed alone or within a concurrent test. The increased preference for running over feeding in fed females did not extend to running performances (time, distance) during each rewarded sequence, confirming that motivation for, and performance during, running are independent entities. With food restriction, mice displayed a sex-independent increase in their preference for feeding over running in both group-housed and PWIR conditions. This study shows that the ABA model does not specifically capture running and feeding drives, i.e. components known to be affected in AN.




23/08/2018 | Neuron   IF 14.4
Hippocampal CB1 Receptors Control Incidental Associations.
Busquets-Garcia A, Oliveira da Cruz JF, Terral G, Zottola ACP, Soria-Gomez E, Contini A, Martin H, Redon B, Varilh M, Ioannidou C, Drago F, Massa F, Fioramonti X, Trifilieff P, Ferreira G, Marsicano G

Abstract:
By priming brain circuits, associations between low-salience stimuli often guide future behavioral choices through a process known as mediated or inferred learning. However, the precise neurobiological mechanisms of these incidental associations are largely unknown. Using sensory preconditioning procedures, we show that type 1 cannabinoid receptors (CB1R) in hippocampal GABAergic neurons are necessary and sufficient for mediated but not direct learning. Deletion and re-expression of CB1R in hippocampal GABAergic neurons abolishes and rescues mediated learning, respectively. Interestingly, paired presentations of low-salience sensory cues induce a specific protein synthesis-dependent enhancement of hippocampal CB1R expression and facilitate long-term synaptic plasticity at inhibitory synapses. CB1R blockade or chemogenetic manipulations of hippocampal GABAergic neurons upon preconditioning affect incidental associations, as revealed by impaired mediated learning. Thus, CB1R-dependent control of inhibitory hippocampal neurotransmission mediates incidental associations, allowing future associative inference, a fundamental process for everyday life, which is altered in major neuropsychiatric diseases.




06/06/2018 | Neuron   IF 14.4
Astroglial CB1 Receptors Determine Synaptic D-Serine Availability to Enable Recognition Memory.
Robin LM*, Cruz J*, Oliveira da Cruz JF, Langlais VC, Martin-Fernandez M, Metna-Laurent M, Busquets-Garcia A, Bellocchio L, Soria-Gomez E, Papouin T, Varilh M, Sherwood MW, Belluomo I, Balcells G, Matias I, Bosier B, Drago F, Van Eeckhaut A, Smolders I, Georges F, Araque A, Panatier A, Oliet SHR*, Marsicano G*

Abstract:
Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB1 receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB1 receptors from astroglial cells (GFAP-CB1-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB1 receptors increased intracellular astroglial Ca(2+) levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB1-KO displayed lower occupancy of the co-agonist binding site of synaptic hippocampal NMDARs. Finally, elevation of D-serine levels fully rescued LTP and memory impairments of GFAP-CB1-KO mice. These data reveal a novel mechanism of in vivo astroglial control of memory and synaptic plasticity via the D-serine-dependent control of NMDARs.