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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






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





Ignacio Fernandez Moncada was born far away, in the colorful city of Valparaiso (Chili), that faces the Pacific Ocean. He is now a post-doc researcher at the Neurocentre Magendie, in Giovanni Marsicano’s team. Let’s meet him!




Hottopic
27/05/2020 10h30
Paula Gomez from Marsicano's lab will give a presentation entitled 'CB1 receptor control of social affective behaviors'

Hottopic
26/02/2020 10h00
Gianluca LAVANCO from Marsicano's lab will give a presentation entitled “What is the role of the mitochondrial CB1 receptor in the cannabinoid-induced modulation of learning and memory and synaptic plasticity?”

Hottopic
29/01/2020 10h00
Imane HUREL from Marsicano's lab will give a presentation entitled 'Choosing between exercise and food in a closed economy setting: role of CB1 receptors'

Seminars
24/01/2020 11h30
Francisco Papaleo

Meeting room: Centre Broca Nouvelle-Aquitaine

from IIT Central Research Labs Genova's lab will give a presentation entitled 'Bottom-Up and Top-Down Control of Emotion Recognition'

Francisco Papaleo
Senior Researcher Tenure Track – Principal Investigator
IIT Central Research Labs Genova
https://www.iit.it/people/francesco-papaleo

Invited by Giovanni Marsicano (Neurocentre Magendie)

Summary:

The prefrontal cortex (PFC) has been implicated in processing of the emotional state of others through nonverbal communication. This social cognitive function is altered in psychiatric disorders such as autism and schizophrenia and is hypothesized to rely on an intact cortical neuronal excitatory and inhibitory balance. Here, by combining in vivo electrophysiology with a behavioral task for emotion recognition in mice, we show that neurons in the medial prefrontal cortex (mPFC) are differentially activated during exploration of conspecifics depending on their affective state. Optogenetic manipulations revealed a double dissociation of interneuron roles in emotion recognition; specifically, inhibition of mPFC somatostatin (SOM+) but not of parvalbumin (PV+) interneurons abolishes emotion discrimination. Conversely, activation of mPFC SOM+ interneurons induces social discrimination in this task. Our findings provide new insights into the neurobiological mechanisms of emotion recognition.



PhD/HDR defense
09/12/2019 14h00
Zhe ZHAO from Marsicano's lab will give a presentation entitled 'Role of the type-1 cannabinoid receptor in the control of water intake.' Role of the type-1 cannabinoid receptor in the control of water intake

Role of the type-1 cannabinoid receptor in the control of water intake
Thesis supervisor: Giovanni MARSICANO PhD

Water intake is crucial for maintaining body fluid homeostasis and animals’ survival. Complex brain processes trigger thirst, which arises upon losing blood volume (i.e. extracellular dehydration) or increasing blood osmolality (i.e. intracellular dehydration), to replenish water for fluid balance. The brain plays a key role in modulating these processes, but the central mechanisms regulating water intake are not fully understood. Type-1 cannabinoid receptors (CB1) are widely and abundantly expressed in the central nervous system where they modulate a variety of functions, such as memory, anxiety and feeding behavior. However, the role of CB1 receptors in the control of water intake is still a matter of debate, since pharmacological activation or blockade of CB1 receptors produced contradictory results in drinking behavior experiments.
My thesis work focuses on the role of CB1 receptors in the control of water intake. By using genetic, pharmacological, anatomical, imaging, and behavioral approaches, I examined the involvement of CB1 receptors in the control of water intake induced by different physiological conditions of extracellular or intracellular dehydration. The results showed that CB1 receptor signaling is required to promote water intake. In particular, global deletion of CB1 receptors does not change plasma osmolality and body water composition, but it decreases water intake induced by water deprivation, systemic or intracerebroventricular (ICV) administration of sodium chloride, or ICV injection of the peptide hormone angiotensin II. In the attempt to better detail the neuronal mechanisms of this function, I discovered that the presence of CB1 receptors in cortical glutamatergic neurons, particularly the ones located in the anterior cingulate cortex (ACC) glutamatergic neurons promote drinking behavior. CB1 receptors are abundantly expressed in axon terminal of ACC glutamatergic neurons projecting to the basolateral amygdala (BLA) and selective expression of CB1 receptors in this circuit is sufficient to guarantee proper drinking behavior in mice. Altogether, these data reveal that CB1 receptors are necessary to promote water intake, and that their presence in the ACC-BLA circuit is sufficient for the top-down control of drinking behavior.
Furthermore, I also provided evidence that CB1 controls water intake in different conditions at other levels, e.g. insular cortex, cholinergic cells, and mitochondria.
In summary, my thesis work analyzed the role of CB1 receptors in distinct cell populations/neuronal circuits for the control of water intake. These results will help further understanding the functions of the ECS and the brain regulation of thirst.

Date de la soutenance: 09/12/2019 - 14h00
Lieu: NeuroCentre Magendie conference room 


Hottopic
30/10/2019 10h00
Antonio PAGANO-ZOTTOLA from Marsicano's lab will give a presentation entitled ' Melatonin Receptor 1, a new partner for CB1 receptor in mitochondria.'


mTORC1 and CB1 receptor signaling regulate excitatory glutamatergic inputs onto the hypothalamic paraventricular nucleus in response to energy availability

Wilfrid Mazier, Nicolas Saucisse, Vincent Simon, Astrid Cannich, Giovanni Marsicano, Federico Massa & Daniela Cota