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: Centre Broca Nouvelle-Aquitaine Conference Room

Dynamics of interactions between excitation and perisomatic inhibition in the normal and epileptic hippocampal circuit in vivo.
Directeur de thèse : Xavier Leinekugel
Date de la soutenance: 21/11/2019 - 14h00
Lieu: Magendie Salle de conference

Bile acids signaling as a novel mechanism in the hypothalamic control of energy balance

Thesis supervisor:
Daniela Cota, MD, HDR

Summary: Bile acids (BA) are cholesterol-derived molecules mostly known for participating in the digestion of lipids. By activating the Takeda G protein coupled receptor 5 (TGR5) in peripheral organs, BA can also act as signaling molecules to reduce body weight, increase energy expenditure and improve glycaemia. These outcomes imply an anti-obesity function for TGR5. Since the major center of convergence of nutrient, hormonal, and environmental cues is the brain, particularly the hypothalamus, we hypothesized a role for TGR5 in this brain structure, specifically under diet-induced obesity.

Our results show that TGR5 and BAs transporters are expressed in the mediobasal hypothalamus (MBH), and that obese mice have decreased circulating and hypothalamic BA levels. Acute intracerebroventricular (ICV) or intra-MBH administration of TGR5 agonists reduced food intake and body weight in obese mice only, and improved insulin sensitivity. Accordingly, chronic ICV administration of the TGR5 agonist in obese mice reduced their body weight and adiposity, while increasing energy expenditure and markers of sympathetic activity in the adipose tissue. Indeed, experiments conducted at thermoneutrality (30°C) or chemical sympathectomy blunted these effects, demonstrating that central TGR5 effects require the engagement of the sympathetic nervous system. Conversely, by using genetic animal models, we observed that the deletion of TGR5 in the MBH rapidly increased food intake, body weight and adiposity, while blunting the sympathetic response to a cold challenge (4h at 4°C), hence worsening obesity.

Our work proves the existence of a functional hypothalamic BA – TGR5 receptor system. We show for the first time that the activation of TGR5 in the MBH decreases body weight and adiposity, while increasing energy expenditure through recruitment of the sympathetic nervous system. These results expose a new mechanism of action for potential anti-obesity therapies.

Keywords: Bile acids, TGR5, diet-induced obesity, mediobasal hypothalamus, energy balance, sympathetic activity, thermogenesis.
Date de la soutenance: 14/11/2019 - 14h00
Lieu: Neurocentre Magendie Seminar room

Lieu: Auditorium Médiathèque Jacques Ellul – Pessac

from Marsicano's lab will give a presentation entitled 'Sport : quand la motivation dépasse la raison'


Pour plus de détails: https://www.bordeaux-neurocampus.fr/event/conference-a-pessac/