Direct and indirect Innervation and Modulation of the Mesolimbic Dopamine System by Leptin Responsive Neurons

Obesity is a burgeoning problem and a major risk factor for the development of Type-2 diabetes, cardiovascular disease, and cancer. This is likely caused by coupling of environments promoting an obesogenic lifestyle with biological systems that evolved to maintain body weight by responding to rewarding properties of food. It is crucial to understand systems that link energy balance and reward as we seek to define mechanisms that drive overeating and obesity.;A major breakthrough in our understanding of energy homeostasis came with the discovery of the adipose-derived satiety factor, leptin. Leptin's primary action in the brain is in the mediobasal hypothalamus where much of its anorectic effects are mediated. Recent research has shown that hypothalamic leptin signaling is inadequate to account for all of leptin's actions in the brain. There are several leptin receptor-expressing neural populations that are may mediate reward sensation as they interact with elements of the mesolimbic dopamine system.;Our goals were to interrogate leptin-responsive neural populations that interact with the mesolimbic dopamine reward system (MLDA) in an attempt to better understand the relationship between energy status and reward. We used novel leptin receptor (LepRb) specific tract tracing system to identify the circumscribed projection pattern of ventral tegmental area (VTA) LepRb neurons and their downstream targets. Additionally we investigated LepRb neurons in the lateral hypothalamic area (LHA) which are known to project locally to orexin neurons and indirectly to VTA dopamine (DA) neurons. Using molecular mouse models with deficient LepRb expression in LHA neurons we assessed how leptin acts through the LHA to modulate reward sensitivity. We also studied the role of the neuropeptide neurotensin in mediating LHA LepRb neural. We found that VTA LepRb neurons project to and regulate GABAergic CART neurons in the central amygdala where they presumably regulate limbic function while LHA LepRb neurons modulate striatal behaviors. These findings confirm the supposition that individual LepRb neural populations regulate distinct aspects of central leptin signaling as a whole.;Advancing our knowledge of how systems that maintain energy balance interact with reward processing brain regions is an important step to our combating the development of obesity.