ABSTRACT
A complex set of brain based systems modulate feeding to maintain constant body weight. The adipose derived-hormone, leptin, plays a crucial role in this control by acting on diverse leptin receptor (LepRb)-expressing neurons in the hypothalamus and brainstem to modify behavior and metabolism. In addition to controlling energy expenditure and satiety, leptin controls motivation and the reward value of food by regulating two interconnected systems: hypocretin (HCRT) neurons and the mesolimbic dopamine (MLDA) system. Modest/acute decreases in leptin levels, as associated with mild caloric restriction, increase MLDA activity and overall food-seeking behavior; in contrast, severe starvation or complete leptin deficiency blunt MLDA activity, along with motivation and associated behaviors. Lateral hypothalamic (LHA) LepRb neurons project to dopamine (DA) neurons in the ventral tegmental area, where neurotensin (NT) release augments MLDA function; these LepRb(NT) cells also innervate HCRT neurons to control Hcrt expression and inhibit HCRT neurons. Ablation of LepRb in these cells abrogates the control of HCRT cells by leptin and decreases activity and MLDA function. We propose that this neural pathway regulates the MLDA, activity, and motivation in response to leptin and nutritional status.