Thesis defense – Zhe Zhao

Venue: Neurocentre Magendie (conference room)

Role of the type-1 cannabinoid receptor in the control of water intake

Zhe Zhao
Team Marsicano
Neurocentre Magendie

Thesis supervisor: Giovanni Marsicano

Thesis defended in english

Abstract

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.

Keywords: thirst, CB₁ receptor, water intake, brain, cell type, the anterior cingulate cortex, the insular cortex, the basolateral amygdala, neural circuit.

Publications

Zhao Z., Soria-Gómez E., Varilh M., Julio-Kalajzic F., Cannich A., Castiglione A., Vanhoutte L., Duveau A., Zizzari F., Beyeler A., Cota D., Bellocchio L., Busquets-Garcia A., Marsicano G.
Top-down control of water intake by the endocannabinoid system.
(In preparation)

Martin-Fernandez M., Jamison S., Robin L., Zhao Z., Martin D., Aguilar J., Benneyworth M., Marsicano G., Araque A.
Synapse-specific astrocyte gating of amygdala-related behavior.
Nature Neuroscience, 2017 (IF:17.839)

Zhao Z., Wang L., Gao W., Hu F., Zhang J., Ren Y., Lin R., Feng Q., Cheng M., Ju D., Chi Q., Wang D., Song S., Luo M., Zhan C.
A central catecholaminergic circuit controls blood glucose levels during stress.
Neuron, Volume 95, Issue 1, p138–152.e5, 5 July 2017 (IF: 14.024, Featured article)

Wang D., He X., Zhao Z., Feng Q., Lin R., Sun Y., Ding T., Xu F., Luo M., Zhan C.
Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons.
Frontiers in Neuroanatomy 9:40, 2015 (IF: 3.26)

Jury

M. FERREIRA Guillaume, Dr., Université de Bordeaux, France – Président
M. WOTJAK Carsten, Dr. Max Planck Institute of Psychiatry Munich, Allemagne – Rapporteur
M. GUZMAN Manuel, Pr., Universidad Complutense de Madrid, Espagne – Rapporteur
Mme LORENS-CORTES, Catherine, Dr., Collège de France, France – Examinateur
M. FRICK Andreas, Dr., Université de Bordeaux, France – Examinateur
M. MARSICANO Giovanni, Dr., Université de Bordeaux, France – Directeur de thèse