Venue: Neurocentre Magendie – Conference room
Defense in english
Role of the endocannabinoid system in the motivational balance between feeding and physical exercise in mice
Physical inactivity, a major public health problem, is mainly caused by a lack of motivation for physical activity which can be associated, as in obesity, with hyper-motivation for palatable food. Conversely, an exacerbated motivation for physical exercise can lead to addiction, whether intrinsic or associated with e.g. voluntary dietary restriction as in restrictive anorexia (RA) in adolescents. These data illustrate the need to identify the neurobiological mechanisms responsible for the motivational balance between physical activity and food intake, before attempting to characterise the processes deregulated in these pathologies. Taking into account the fact that studies aiming to identify these bases use models of forced (treadmill) or volitional (wheel) exercise that do not allow for a selective measurement of motivation for physical activity, this Thesis relied on the development of paradigms using operant conditioning to confront them with classical models of physical exercise before then dissecting the role of the endocannabinoid system in the motivational balance between physical activity and food intake in the mouse.
The first experimental part of my Thesis aimed to dissect the different dimensions (motivation, performance) associated with physical activity in the most widely used rodent model of RA, i.e. the “activity-based anorexia” (ABA) model. The latter is based on limited access to food (by the experimenter) combined with free and permanent access to an activity wheel. The use of an operant conditioning protocol to measure motivation for each reward (i.e. food and exercise), including in a choice protocol, revealed a dichotomy between physical activity performance – as measured in ABA – and motivation for this activity in adolescent females subjected to early stress (an etiological factor in RA).
In view of the addictive power of exercise, the second objective of my Thesis was to analyse the hypothesis that exercise shares with drugs of abuse the ability to enhance the excitatory tone on ventral tegmental area (VTA) dopaminergic neurons. Using ex vivo electrophysiological approaches combined with a reinstatement/recovery conditioning protocol for the wheel, we showed that (i) physical activity, as do cocaine or amphetamine, increases the excitatory tone on VTA dopaminergic neurons, and (ii) this increase correlates with the degree of motivation of the animal.
Using constitutive and conditional mutants for the CB1 receptor, we recently revealed that CB1 receptors on GABAergic neurons positively control motivation to run without affecting that for palatable food. However, these findings were based on temporary conditioning sessions, raising the question of the importance of this GABAergic control when choosing between these rewards on a permanent basis. The third objective of my Thesis was therefore to develop a “closed economy” choice protocol, in which animals, housed individually in operating chambers, have a permanent choice between standard food and exercise in a wheel. In addition, in order to estimate the so-called “essential values” of each of the two rewards, the effort demand (i.e. the price to be paid) to access each reward was progressively increased. The combined use of this new paradigm with viral approaches allowed us to reveal that CB1 receptors on GABAergic neurons in the ventromedial part of the striatum have a necessary and sufficient role in controlling the “essential value” of physical activity.
Keywords: CB1 receptors, Motivation, Physical activity, Feeding, Operant conditioning, Reward
Muguruza C*, Redon B*, Fois GR, Hurel I, Scocard A, Nguyen C, Stevens C, Soria-Gomez E, Varilh M, Cannich A, Daniault J, Busquets-Garcia A, Pelliccia T, Caillé S, Georges F, Marsicano G, Chaouloff F. 2019. The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors. JCI Insight 4: e126190.
Redon B, Hurel I, Marsicano G, Chaouloff F. 2019. An Operant Conditioning Task to Assess the Choice between Wheel Running and Palatable Food in Mice. BIO-PROTOCOL 9.
Hurel I*, Redon B*, Scocard A, Malezieux M, Marsicano G, Chaouloff F. 2019. Beyond the Activity-Based Anorexia Model: Reinforcing Values of Exercise and Feeding Examined in Stressed Adolescent Male and Female Mice. Frontiers in Pharmacology 10: 587.
Medrano M*, Hurel I*, Mesguich E, Redon B, Stevens C, Georges F, Melis M, Marsicano G, Chaouloff F. 2021. Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons. Addiction Biology 26.
Hurel I*, Muguruza C*, Redon B, Marsicano G, Chaouloff F. 2021. Cannabis and exercise: Effects of Δ9-tetrahydrocannabinol on preference and motivation for wheel-running in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 105: 110117.
*Share first authorship
VILTART Odile, Pr – Université de Lille, France – Présidente
CABOCHE Jocelyne, Dr – Université de la Sorbonne, France – Rapporteure
VALJENT Emmanuel, Dr – Université de Montpellier, France – Rapporteur
TRIFILIEFF Pierre, Dr – Université de Bordeaux, France – Examinateur
GANGAROSSA Giuseppe, Pr – Université Paris Cité, France – Examinateur
CHAOULOFF Francis, Dr – Université de Bordeaux, France – Invité (Directeur de thèse)
MARSICANO Giovanni, Dr – Université de Bordeaux, France – Invité (Chef d’équipe)