Activité physique et récompense : impact de la leptine et de la signalisation STAT3 dans les neurones dopaminergiques
Endurance running is rewarding and related to food seeking behaviors. Influence of leptin on voluntary physical activity is well documented from a physiological point of view, but little is known about its hedonic impact. Leptin inhibits the rewarding aspects of food consumption and plays a similar role for other types of stimuli. Leptin binds to the long form of the leptin receptor, situated on dopamine (DA) and GABA neurons of the ventral tegmental area (VTA) in the midbrain. Signal Transducer and Activator of Transcription 3 (STAT3) is an important transcription factor of the leptin signalling cascade.  Phosphorylation of STAT3 is detected only in a subset of neurons that are positive for the leptin receptor, conferring unique properties to DA STAT3 neurons. We generated a mouse model invalidated for STAT3 selectively in dopamine neurons (STAT3DAT-KO).  We first assessed basic metabolic parameters of our model using CLAMS metabolic chambers, including ambulatory acitivity, respiratory exchange ratio (RER) and heat production. STAT3DAT-KO are hyperactive as seen by a higher locomotor activity, but there is no inter-group variation of RER and heat production, and the weight gain is the same.  A rescue strategy targeting the reinsertion of STAT3 in DA neurons of the mesolimbic system normalizes physical activity of the STAT3DAT-KO - which was previously much higher - to that of the control mice, following free access to a running wheel for a period of 4 weeks. The injection of a psychostimulant (agonist of the type1 DA receptor (D1R), Chloro-APB-Hydrobromide (SKF 82958)) reflects a reduced DA signalling STAT3DAT-KO. A compulsive food seeking test reveals a suppression of sucrose intake in both experimental groups. We demonstrate for the first time that the motivation allied to endurance running, independently of food intake regulation by leptin, is dependent upon a diminished leptin-STAT3 signalling in DA neurons of the midbrain, revealing STAT3 as a key player in the regulation of DA tone and the rewarding properties of physical activity.
Dopamine Leptin and STAT3 Physical activity Running Reward Ventral tegmental area