Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin

Abstract

Background/objectives:The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin.Subjects/methods:We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling.Results:Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353).Conclusions:Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling.

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

“…S4E). Together, these data provide evidence that enhanced LHA Nts neuronal activity counteracts the drive to consume palatable food in an energy-restricted state, similar to what occurs after diet-induced weight loss (Sumithran et al, 2011; van der Plasse et al, 2015). …”

Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior

“…Given that insulin also acts in the hypothalamus to promote satiety [38], this suggests a potential mechanism by which diet may influence circuits important for reward learning and homeostasis. Indeed, a number of nutritionally-regulated hormones involved in hypothalamic control of feeding and glucose homeostasis—including glucagon-like peptide 1 [39], amylin [40], leptin [41], and ghrelin [42]—also modulate mesocorticolimbic dopamine signaling. Accordingly, recent data suggest that hypothalamic feeding circuits are regulated by sensory input [9], and may integrate information from reward circuits about nutritional and hedonic properties of food to direct metabolic learning and memory [43].…”

Integration of homeostatic signaling and food reward processing in the human brain

“…Furthermore, both dopaminergic as well as opioid signaling, which are crucial during the processing of the anticipation or receipt of rewards, respectively (23), have been found to be affected by homeostatic satiety signaling (5,(24)(25)(26). However, studies investigating neural reactivity to food stimuli found both baseline as well as reward-level-dependent homeostasis-induced increases in dopamine (27)(28)(29) and opioid signaling (30,31). Therefore, it still remains unclear whether mesolimbic reward signaling during a fasted state is generally increased irrespective of reward modality or if it is only increased for food reward.…”