Leptin modulation of locomotor and emotional behaviors : the role of STAT3 signaling in dopamine neurons

The adipocyte-derived hormone leptin circulates in proportion to the body fat content and transduces its signal through the long form of its receptor via a number of neural pathways, including MAPK, PI3-K, AMPK and JAK2-STAT3. Of note, STAT3 constitutes a key pathway downstream to the leptin receptor by which leptin modulates the expression of genes involved in energy balance. Most research has focused on leptin receptor function within the hypothalamus, in particular leptin receptor function within the arcuate nucleus. However, leptin receptors are also expressed on dopaminergic neurons of the ventral tegmental area, and leptin has been shown to target this brain region to influence feeding, motivation, locomotion, anxiety and dopamine tone. Moreover, leptin activates STAT3 in both dopaminergic and GABAergic neuronal populations. Although these findings contribute to our understanding of the multiple actions of leptin in the central nervous system, it remains to be resolved which cells and leptin receptor signaling pathway mediates the neurobehavioral effects of leptin in the midbrain. Aiming at determining the contribution of STAT3 signaling in midbrain DA neurons, we generated a line of conditional knockout mice in which the main activation site of STAT3 gene (tyr 705) is absent specifically in dopaminergic neurons (STAT3DAT-KO mice). Using this genetic mouse model, we assessed the impact of ablation of STAT3 signaling in dopaminergic neurons on a number of dopamine-related functions, including feeding, locomotion, reward-related behaviors, emotion and nucleus accumbens dopamine release. Interestingly, we observed a sexual dimorphism in the phenotype of STAT3DAT-KO mice. STAT3 signaling in DA neurons mediates the actions of leptin in the midbrain to decrease locomotion and running reward, and to increase dopamine release and availability in male mice. However, it does not modulate emotional behavior. On the other hand, STAT3DAT-KO female mice exhibited increased anxiety-like behavior accompanied by increased plasma corticosterone levels, without changes in behavioral despair relative to littermate controls. However, loss of STAT3 activation in dopaminergic neurons does not modulate locomotor behavior in female mice. Notably, the actions of leptin in the midbrain to influence feeding behavior are not mediated by STAT3 signaling in dopaminergic neurons, as both male and female STAT3DAT-KO mice have normal feeding behavior as compared to littermate controls. Our results demonstrate that STAT3 signaling in dopaminergic neurons mediates the anxiolytic actions of leptin, and support the hypothesis that leptin communicates body energy status (defined as a relationship between energy intake and energy expenditure) to mesolimbic regions to adjust the motivational and rewarding effects of multiple behaviors that serve to either restore or deplete energy stores. In addition, this work highlight the importance of studying cell-type specific modulation of leptin signaling molecules to tease apart pathways and the mechanisms involved in the different neurobehavioral functions of this adipocyte-derived hormone.

Keyphrases: STAT3, dopamine, leptin, dopamine, midbrain, running reward, anxiety, behavior