Search

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.

Background: Rats that have restricted access to food at a fixed time point of the circadian phase display high levels of food anticipatory activity (FAA). The orexigenic hormone ghrelin has been implicated in the regulation of FAA. However, it is not known via which brain area ghrelin exerts this effect. Growth hormone secretagogue receptor 1a (GHS-R1a) is highly expressed in the hypothalamus, including the dorsomedial hypothalamus (DMH) and the ventromedial hypothalamus (VMH). These two hypothalamic areas have been reported to play a role in FAA., Aim of the Study: To examine the role of GHS-R1a signaling in the DMH and VMH in FAA., Design: Adeno-associated virus expressing a shRNA directed against GHS-R1a was used to establish local knockdown of GHS-R1a in the DMH and VMH in rats. Rats were subsequently subjected to a restricted feeding schedule (RFS)., Results: Under ad libitum conditions, knockdown of GHS-R1a in the VMH increased food intake and body weight gain. In addition, GHS-R1a knockdown in VMH and DMH reduced body temperature and running wheel activity (RWA). When rats were subjected to a RFS, the main effect of GHS-R1a knockdown in both DMH and VMH was a decrease in RWA and an attenuation of body weight loss. Rats with knockdown of GHS-R1a in DMH and VMH showed a delay in onset of FAA. In addition, GHS-R1a knockdown in DMH resulted in a reduction of FAA amplitude., Conclusion: This is the first study to investigate the effect of local hypothalamic knockdown of GHS-R1a on FAA. Our results implicate hypothalamic GHS-R1a signaling in the regulation of FAA. Nevertheless, some FAA remained, suggesting that a distributed network of brain areas and signaling pathways is involved in the development of FAA.

Background: Cues that are associated with the availability of food are known to trigger food anticipatory activity (FAA). This activity is expressed as increased locomotor activity and enables an animal to prepare for maximal utilization of nutritional resources. Although the exact neural network that mediates FAA is still unknown, several studies have revealed that the medial hypothalamus is involved. Interestingly, this area is responsive to the anorexigenic hormone leptin and the orexigenic hormone ghrelin that have been shown to modulate FAA. However, how FAA is regulated by neuronal activity and how leptin and ghrelin modulate this activity is still poorly understood., Objective: We aimed to examine how the total neuronal population and individual neurons in the medial hypothalamus respond to cue-signaled food availability in awake, behaving rats. In addition, ghrelin and leptin were injected to investigate whether these hormones could have a modulatory role in the regulation of FAA., Design: Using in vivo electrophysiology, neuronal activity was recorded in the medial hypothalamus in freely moving rats kept on a random feeding schedule, in which a light cue signaled upcoming food delivery. Ghrelin and leptin were administered systemically following the behavioral paradigm., Results: The food-predictive cue induced FAA as well as a significant increase in neural activity on a population level. More importantly, a sub-population of medial hypothalamic neurons displayed highly correlated identical responses to both ghrelin and FAA, suggesting that these neurons are part of the network that regulates FAA., Conclusion: This study reveals a role for ghrelin, but not leptin, signaling within medial hypothalamus in FAA on both a population level and in single cells, identifying a subset of neurons onto which cue information and ghrelin signaling converge, possibly to drive FAA.

Feeding behaviour is crucial for the survival of an organism and is regulated by different brain circuits. Among these circuits the mesolimbic dopamine (DA) system is implicated in the anticipation and motivation for food rewards. This system consists of the dopaminergic neurons in the ventral tegmental area (VTA), and their projections to different cortico-limbic structures such as the nucleus accumbens and medial prefrontal cortex. While the importance of this system in motivational drive for different rewards, including drugs of abuse, has been clearly established, its role in energy balance remains largely unexplored. Evidence suggests that peripheral hormones such as leptin and ghrelin are involved in the anticipation and motivation for food and this might be partially mediated through their effects on the VTA. Yet, it remains to be determined whether these effects are direct effects of ghrelin and leptin onto VTA DA neurons, and to what extent indirect effects through other brain areas contribute. Elucidation of the role of leptin and ghrelin signalling on VTA DA neurons in relation to disruptions of energy balance might provide important insights into the role of this neural circuit in obesity and anorexia nervosa.

Objective: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear., Methods and Results: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature., Conclusion: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.

The hunger hormone ghrelin is secreted from the stomach and binds to the growth hormone secretagogue receptor (GHSR)-1a. Ghrelin activates the ventral tegmental area (VTA) dopamine system to increases food reward-seeking behaviour [1],[2]. Although dopamine neuronal activity and licking behavior were proportional to the amount of sucrose reward, ghrelin did not modulate the licks and calcium signal during the reward consumption (FGCamp(1,12) = 0.01 p=0.91; Flicks F(1,9)=0.651, p=0.44). In summary, ghrelin enhances the activity of dopaminergic neurons in the VTA during a predictive cue but did not affect dopamine response to sucrose reward value. [Extracted from the article]