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24/07/2020
Congratulations to Dana for a successful mid-term thesis defense!!

Dana's virtual mid-term committee took place this Friday 07/24. Professor Mickaël Naassila, Dr Jean-Michel Gaulier and Dr Daniel Choquet were impressed by Dana's excellent communication skills and scientific proficiency!






Congratulations to Fiona and Guillaume, each in their own category, for winning the Inserm professional selection exam. They are promoted to the grades of TCE and TCS respectively. Magendie thus obtained 2 promotions out of the 35 possible promotions, i.e. 5.7% of the possibilities, whereas our Inserm statutory ITA staff represents 1.4% of the national staff. Another great performance! Congratulations to our staff and to all those who supported them in their preparations.





Cannabis use can lead to effects in the brain that impact the normal functioning of users, including problems in sociability. The present paper - available now online and on July 23rd in press - explores how astrocytes, the most abundant brain cells, play a key role on the metabolic dysfunction associated with high doses of THC which results in decreased sociability in mice. The huge collaborative effort between the teams of Juan Bola–os in Salamanca and the Marsicano team allowed merging the expertise of the spanish team in brain bioenergetics and the expertise of our team in mouse in vivo experiments to better understand a novel way in which cannabinoids affect the brain.

In 2012, we showed that cannabinoid receptors are not only present on the cell membrane, but can also be present at mitochondria, the intracellular organelles whose role is to provide the cells with the energy they need [1]. This new study comes after showing that cannabinoid receptors are also located on the astroglial mitochondrial membranes [2]. These glial cells play a key role in brain energy metabolism as they transform glucose into lactate, which acts as "food" for neurons. Based on this, the paper explores how mitochondrial CB1 receptors impact astroglial bioenergetics both in vitro and in vivo. We first used astrocyte cultures where we observed that persistent activation of mitochondrial cannabinoid receptors destabilizes mitochondrial Complex I through the specific modulation of the phosphorylation status of NDUFS4, a C-I subunit important for its stability. A decrease of Complex stability decreases mitochondrial ROS levels in astrocytes affecting the activity of the transcription factor HIF1, a key regulator of glycolysis which leads to a dysfunction of glucose metabolism with a reduction of astroglial lactate levels. We next used a co-culture strategy to demonstrate that the astroglial bioenergetic alterations produced by the persistent activation of mitochondrial cannabinoid receptors resulted in an enhancement of mitochondrial ROS in neurons, among other bioenergetic alterations. In vivo, we used genetic approaches and NMR and FACS strategies to confirm the effects observed in cell cultures. We show that THC administration in mice reduces glucose-lactate conversion impacting the functioning of neurons by altering similar bioenergetic alterations. Interestingly, THC produces a persistent social interaction impairment still present 24 hours after administration that is not present in mice lacking astroglial CB1 receptors and is reversed by 1) manipulating the phosphorylation status of NDUFS4, 2) reducing neuronal mitochondrial ROS levels or 3) lactate supplementation. These findings not only suggest possible novel therapeutic targets to tackle negative effects of cannabis consumption or other conditions with social impairments, but highlight the fact that the interaction between different brain cells might be also very important to understand how the brain control our actions.

You can check the News and Views written about this study, which summarizes the main points of the paper in a very comprehensive way: https://www.nature.com/articles/d41586-020-01975-5

Contact Giovanni for any questions (Giovanni.marsicano@inserm.fr) and follow our twitter account for updates about publications and other science related events at @Marsicanolab




[1] Bénard, G., Massa, F., Puente, N., Lourenço, J., Bellocchio, L., Soria-Gómez, E., Matias, I., Delamarre, A., Metna-Laurent, M., Cannich, A., Hebert-Chatelain, E., Mulle, C., Ortega-Gutiérrez, S., Martín-Fontecha, M., Klugmann, M., Guggenhuber, S., Lutz, B., Gertsch, J., Chaouloff, F., López-Rodríguez, M. L., … Marsicano, G. (2012). Mitochondrial CB₁ receptors regulate neuronal energy metabolism. Nature neuroscience, 15(4), 558–564. DOI: 10.1038/nn.3053

[2] Gutiérrez-Rodríguez, A., Bonilla-Del Río, I., Puente, N., Gómez-Urquijo, S. M., Fontaine, C. J., Egaña-Huguet, J., Elezgarai, I., Ruehle, S., Lutz, B., Robin, L. M., Soria-Gómez, E., Bellocchio, L., Padwal, J. D., van der Stelt, M., Mendizabal-Zubiaga, J., Reguero, L., Ramos, A., Gerrikagoitia, I., Marsicano, G., & Grandes, P. (2018). Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia, 66(7), 1417–1431. DOI: 10.1002/glia.23314






The administrative staff are numerous: about fifty persons within the research units of Bordeaux Neurocampus. Their missions? Financial management, IT, event management, secretarial work… all essential jobs but little is said about them. We give the floor to one of them, Sylvie San Segundo, who works at the Neurocentre Magendie.

What are your missions at the Neurocentre Magendie?

In this research unit, the missions of research support are dissociated by poles: there is a logistics pole, a budget pole, a mission pole, a human resources pole, and an IT support pole. The logistics pole where I work carries out all the purchasing actions within the Neurocentre. My missions are therefore very varied, and include in particular expenses that can be related to scientific publications. These days, there are more than usually because the researchers have been able to devote time to it, with the confinement.

At first, the research environment was unfamiliar to me: I obtained a literary bachelor’s degree, and for 20 years I worked in a travel agency. After a professional reconversion in the small business assistance, I assisted my husband in his company, and later I applied to the Neurocentre Magendie. I had already heard of INSERM, which is the supervisory body of our unit and whose regional delegation shares the same building.

Over the years, I took on responsibilities. At the beginning there were two of us, and today there are almost three of us; I have taken over the logistics pole, dividing up the tasks, being in charge of public procurement as well as animation and communication for purchasing. Our role in supporting research is to help scientists with the administrative aspect so that they can devote themselves to fundamental research more serenely. I also have a mission as a prevention assistant: risks are often associated with laboratories, whereas there are also psychosocial risks and musculoskeletal disorders which also affect administrative staff, and for which there are prevention missions.

Finally, I also have a role in the Neurocentre’s network of prevention assistants to coordinate all curative and preventive maintenance actions related to equipment in the laboratories. This is an important range. I draw up the contracts and negotiate them within the framework of competitive bidding in order to find the best suppliers. I am therefore aware of the purely scientific aspect and the needs of the platforms and research teams.

So your day-to-day work is varied!

Yes, it does. But there are also a lot of recurring tasks: every morning I check my e-mails, the orders that come in, because we have eleven research teams, five technical platforms, so there are a lot of needs, but every day is different. When we are not teleworking, the doors of our office are always open, we exchange with the researchers, technicians, live agents.

Besides diversity, what do you particularly like about your work?

What I like most is the teamwork with my colleagues and the interaction with the other poles. This is fundamental for me. With my twenty years’ experience in a travel agency, I was particularly interested in the relationship with the public, being able to interact, providing a service, and I found it here. I have the same relationship with the agents as I had with my clients in the past. I have to be able to listen to them, relieve them of all administrative constraints, accompany them.

I also like to coordinate or participate in group actions. The network of prevention assistants is the ideal terrain for this. With the first phase of deconfinement that we went through, the network was very effective; we set up working groups to divide up the tasks among ourselves, at the site level. The network has found its full meaning in this context. That’s also what I like about my work: being able to work with other people, in good understanding, and thus in this case to participate in the advancement of research. At the beginning of the deconfinement, when I went to the office once a week, the site was empty, so I was sad (laughs). Since we have returned to face-to-face work, even partially, and by making sure that the barrier gestures are respected, it’s nice to be able to talk to my colleagues, to have a little coffee from time to time: I missed that.





Star-Shaped Brain Cells Shed Light on the Link Between Cannabis Use and Sociability

Press review:
- Communiqué de presse Inserm

- Bordeaux Neurocampus

- France 3 Nouvelle-Aquitaine

Cannabis use can lead to behavioral changes, including reduced social interactions in some individuals. To better understand the phenomenon, Inserm researcher Giovanni Marsicano and his team from NeuroCenter Magendie (Inserm/Université de Bordeaux), in collaboration with Juan Bolaños’ team from the University of Salamanca, have identified for the first time in mice the cerebral mechanisms underlying the relationship between cannabis and reduced sociability. Their findings have been published in Nature.

Regular exposure to cannabis may have a harmful impact on sociability. For some consumers, studies show that it may lead to withdrawal and reduced social interactions. However, the brain network and the mechanisms involved in this relationship were unclear until now.

In order to learn more about the subject, a group led by Inserm researcher Giovanni Marsicano at NeuroCenter Magendie (Inserm/Université de Bordeaux)[1] has joined forces with a Spanish team from the University of Salamanca led by Juan Bolaños[2].

More broadly, their work is aimed at improving our knowledge of how cannabinoid receptors (the brain receptors that interact with chemical compounds in cannabis) work.

In their study published in the journal Nature, the researchers show that after exposure to cannabis, behavioral changes related to sociability occur as a result of the activation of specific cannabinoid receptors, located in star-shaped cells of the central nervous system called astrocytes.

Cannabinoid receptors and mitochondria

These findings are the result of almost a decade of hard work. In 2012, Marsicano and his team had made a surprising discovery: cannabinoid receptors are not only present on the cell membrane, as previously believed. Some of these receptors are also located on the membrane of the mitochondria, the intracellular organelles whose role is to provide the cells with the energy they need.

This new study comes after the team has identified cannabinoid receptors located on the membrane of the mitochondria within astrocytes. Among other functions, these cells play a very important role in energy metabolism of the brain. They capture glucose from the blood and metabolize it into lactate, which acts as “food” for neurons. “Given the importance of astrocytes and energy use for brain function, we wanted to understand the role of these specific cannabinoid receptors and the consequences for the brain and behavior when exposed to cannabis,” explains Marsicano.

Researchers then exposed mice to the cannabinoid THC, the main psychoactive compound in cannabis. They observed that persistent activation of mitochondrial cannabinoid receptors located in astrocytes resulted in a cascade of molecular processes leading to dysfunction of glucose metabolism in astrocytes.

As a result, the ability of astrocytes to transform glucose into “food” for neurons was reduced. In the absence of the necessary energy intake, the functioning of neurons was compromised in the animals, with a harmful impact on behavior. In particular, social interactions were decreased for up to 24 hours after exposure to THC.

“Our study is the first to show that the decline in sociability sometimes associated with cannabis use is the result of altered glucose metabolism in the brain. It also opens up new avenues of research to find therapeutic solutions to alleviate some of the behavioral problems resulting from exposure to cannabis. In addition, it reveals the direct impact of astrocyte energy metabolism on behavior,” says Marsicano.

At a time when the debate over therapeutic cannabis is returning to the forefront, the researchers also believe that this type of work is needed to better understand how the body’s various cannabinoid receptors interact with the drug, and whether any of them are particularly associated with harmful effects. Such research would make it possible to ensure the optimal management of patients who might need this type of therapy.

[1] With Arnau Busquets-Garcia (now in Barcelona, Spain) and Etienne Hebert-Chatelain (now in Moncton, Canada)

[2] With Daniel Jimenez-Blasco






Hottopic
24/06/2020 10h00
Pierre Louis Raux from Revest's lab will give a presentation entitled "Physiological regulation of the cannabinoid type-1 receptor by the neurosteroid pregnenolone: study in mutant CB1-E134G mice"

Hottopic
24/06/2020 10h30
Rafael De Sa from Frick's lab will give a presentation entitled "Single-cell RNA and electrophysiological profiling of D1+ and D2+ principal neurons of the prefrontal cortex"