Lieu : Centre Broca Nouvelle-Aquitaine
Defense in english
Title
Cannabinoid modulation of behavorial processes: From Adolescence to Adulthood
Summary
The endocannabinoid system (ECS) is a crucial modulatory system involved in the regulation of diverse brain functions and behavior. The ECS is the target of the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), which exerts many of its psychotomimetic effects by binding to brain cannabinoid type-1 (CB1) receptors. Cannabis is currently the most widely used psychoactive substance worldwide, with a highest consumption rate observed among adolescents and young adults. Adolescence comprises a sensitive developmental period, during which cannabinoid drugs can easily disrupt the normative trajectory of brain maturation, giving rise to long-term consequences. Indeed, the association between adolescent cannabis use and persistent negative outcomes has long been the focus of neuroscience research, with numerous studies associating these outcomes with a range of neuropsychiatric disorders—psychotic disorders being some the most prominent. However, the mechanisms linking cannabinoid exposure to long-term behavioral effects are complex, and results in the field remain inconclusive.
Animal models exposed to THC during developmental periods (e.g. adolescence) are therefore critical to assess the impact of cannabis use. By using a model of adolescent THC in mice, the first aim of this study was to characterize the specific adult behavioral profile of male and female mice. To this end, a set of psychotic-like behavioral processes related to motor, social and cognitive functions were evaluated in adulthood. Moreover, in order to assess possible alterations in mental sensory representations, which more accurately represent the distinctive features of the core psychotic symptoms (i.e. hallucinations and delusions), we investigated the effect of adolescent THC in a representation-mediated learning protocol. Resembling cannabis-induced psychotic states in humans, impairments in this protocol have been described after acute administration of THC, however the effect of adolescent THC has never been investigated. Altogether, our findings reveal sex-dependent effects, with adolescent THC mainly disrupting motor, social and short-term memory functions in male mice, and associative learning and memory in female mice.
The second aim of this study was to explore potential neurobiological mechanisms underlying the effects of adolescent THC. Therefore, we performed analysis of the CB1 receptor status and signaling targets (such as the ERK and CREB proteins), observing sex- and region-dependent changes. Our recent findings have shown that mitochondrial Complex I (CI) instability through the specific de-phosphorylation of its NDUFS4 subunit in astrocytes is the mechanism leading to persistent THC-
induced social deficits. Here, we demonstrated that NDUFS4 phosphorylation is specifically decreased by adolescent THC in male, but not in female mice, suggesting that the phosphorylation status of this CI subunit might be responsible for the sex-specific behavioral effects. Notably, astroglial expression of a phosphomimetic mutant form of NDUFS4 was able to prevent the adolescent THC-induced behavioral effects on locomotion and social interaction in adult male mice. These results strongly support the idea that mitochondrial alterations in astrocytes are causally involved in the enduring behavioral effects of adolescent THC, highlighting the emerging role of cellular bioenergetics in the regulation of behavior.
Finally, an additional objective of my work was dedicated to the exploration of the physiological role of CB1 receptors in representation-mediated learning processes. These processes may be uniquely suited for preclinical investigations of psychosis, and associative learning theories have provided the framework, through which representation-mediated phenomena can be studied in animals, using higher-order conditioning behavioral tasks. Earlier findings have already established the importance of the CB1-dependent control of sensory representations in the brain. Here, we have investigated the role of different CB1 receptor populations in representation-mediated learning, as well as in direct reinforcement learning, using specific conditional mutant mouse lines that target the CB1 receptors in dopamine D1-positive cells, and also in mitochondria.
Overall, the present work adds important findings to the existent literature of adolescent cannabinoid effects, and describes a novel molecular mechanism causally mediating some of them, while also contributing in advancing the understanding of CB1 receptors’ role in higher-order associative learning processes.
Keywords: adolescence, CB1 receptors, behavior, psychosis, THC, mitochondria, associative learning, representation-mediated learning
Publications
- Ioannidou, C., Busquets-Garcia, A., Ferreira, G. and Marsicano, G. (2021). Neural Substrates of Incidental Associations and Mediated Learning: The Role of Cannabinoid Receptors. Front. Behav. Neurosci. 15:722796
- Oliveira da Cruz, J.F.*, Ioannidou, C.*, Pagano Zottola, A.C.*, Muguruza, C.* et al. (2020). Sex‐dependent pharmacological profiles of the synthetic cannabinoid MMB‐Fubinaca. Addiction Biology. e12940
- Jimenez-Blasco, D.*, Busquets-Garcia, A.*, Hebert-Chatelain, E.*, Serrat, R., Vicente-Gutierrez, C., Ioannidou, C. et al. (2020). Glucose metabolism links astroglial mitochondria to cannabinoid effects. Nature. 583, 603–608
- Ioannidou, C., Marsicano, G. and Busquets-Garcia, A. (2018). Assessing Prepulse Inhibition of Startle in Mice. Bio-protocol. 8(7): e2789
- Busquets-Garcia, A., Oliveira da Cruz, J.F, Terral, G., Pagano Zottola A.C., Soria-Gomez, E., Contini, A., Martin, H., Redon, B., Varilh, M., Ioannidou, C. et al (2018). Hippocampal CB1 Receptors Control Incidental Associations. Neuron. 99(6): 1247-1259.e1247
Jury
M. COUTUREAU, Etienne, Université de Bordeaux, France (Président)
M. HIGUERA MATAS, Alejandro, Universidad Nacional de Educación a Distancia, Espagne (Rapporteur)
Mme. MELIS, Miriam, Université de Cagliari, Italie (Rapporteur)
Mme. PARKES, Shauna, Université de Bordeaux, France (Examinateur)
M. BUSQUETS GARCIA, Arnau, Institut Hospital del Mar d’Investigacions Mèdiques, Espagne (Invité)
M. MARSICANO, Giovanni, Université de Bordeaux, France (Invité)(Thesis Supervisor)
Christina Ioannidou
Team “Endocannabinoids and neuroadaptation”
Neurocentre Magendie
thesis supervisor: Giovanni Marsicano