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

G Van Der Plasse,R Van Zessen,H Erkan,M C M Luijendijk,G M J Ramakers,R A H Adan,G D Stuber

doi:10.1038/ijo.2015.131

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.

Highlights

The worldwide prevalence of obesity and the ongoing debate with respect to the existence of eating-addiction illustrates the importance of a precise understanding of the neurobiology of feeding behavior.[1]
We show that a cue that predicts the availability of a food reward induces DA firing, but only in conditions of food restriction
Neuronal activity measured in mildly fasted rats revealed that while midbrain DA neurons strongly increase their activity to reward-predicting cues, both leptin pre-treatment and free access to chow before task execution abolished this cue-induced firing

Summary

Introduction

The worldwide prevalence of obesity and the ongoing debate with respect to the existence of eating-addiction illustrates the importance of a precise understanding of the neurobiology of feeding behavior.[1]. In addition to metabolic centers located in the hypothalamus that sense and regulate energy homeostasis,[2] dopaminergic (DA) neurons in the midbrain (ventral tegmental area (VTA) and substantia nigra) have a crucial role in reinforcing food seeking behavior.[3,4]. Activity of VTA DA neurons that project to the ventral striatum, which is important for feeding behavior,[5,6] is necessary for the formation of cue-reward associations and effort-related food seeking.[7] Previous experiments in monkeys show that these DA neurons have an important role in signaling the value of foodpredicting cues that drive motivated behavior.[8] Importantly, this

Methods

Results

Conclusion