Does activation of midbrain dopamine neurons promote or reduce feeding?

BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. METHODS: Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. RESULTS: Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour. CONCLUSIONS: Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviour.

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

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.

The neuroanatomical function of leptin in the hypothalamus.

The anorexigenic hormone leptin plays an important role in the control of food intake and feeding-related behavior, for an important part through its action in the hypothalamus. The adipose-derived hormone modulates a complex network of several intercommunicating orexigenic and anorexigenic neuropeptides in the hypothalamus to reduce food intake and increase energy expenditure. In this review we present an updated overview of the functional role of leptin in respect to feeding and feeding-related behavior per distinct hypothalamic nuclei. In addition to the arcuate nucleus, which is a major leptin sensitive hub, leptin-responsive neurons in other hypothalamic nuclei, including the, dorsomedial-, ventromedial- and paraventricular nucleus and the lateral hypothalamic area, are direct targets of leptin. However, leptin also modulates hypothalamic neurons in an indirect manner, such as via the melanocortin system. The dissection of the complexity of leptin's action on the networks involved in energy balance is subject of recent and future studies. A full understanding of the role of hypothalamic leptin in the regulation of energy balance requires cell-specific manipulation using of conditional deletion and expression of leptin receptors. In addition, optogenetic and pharmacogenetic tools in combination with other pharmacological (such as the recent discovery of a leptin receptor antagonist) and neuronal tracing techniques to map the circuit, will be helpful to understand the role of leptin receptor expressing neurons. Better understanding of these circuits and the involvement of leptin could provide potential sites for therapeutic interventions in obesity and metabolic diseases characterized by dysregulation of energy balance.

Food cues and ghrelin recruit the same neuronal circuitry.

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.

Contribution of the mesolimbic dopamine system in mediating the effects of leptin and ghrelin on feeding.

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.

Pharmacological manipulation of neuronal ensemble activity by reverse microdialysis in freely moving rats: a comparative study of the effects of tetrodotoxin, lidocaine, and muscimol.

To be able to address the question how neurotransmitters or pharmacological agents influence activity of neuronal populations in freely moving animals, the combidrive was developed. The combidrive combines an array of 12 tetrodes to perform ensemble recordings with a moveable and replaceable microdialysis probe to locally administer pharmacological agents. In this study, the effects of cumulative concentrations of tetrodotoxin, lidocaine, and muscimol on neuronal firing activity in the prefrontal cortex were examined and compared. These drugs are widely used in behavioral studies to transiently inactivate brain areas, but little is known about their effects on ensemble activity and the possible differences between them. The results show that the combidrive allows ensemble recordings simultaneously with reverse microdialysis in freely moving rats for periods at least up to 2 wk. All drugs reduced neuronal firing in a concentration dependent manner, but they differed in the extent to which firing activity of the population was decreased and the in speed and extent of recovery. At the highest concentration used, both muscimol and tetrodotoxin (TTX) caused an almost complete reduction of firing activity. Lidocaine showed the fastest recovery, but it resulted in a smaller reduction of firing activity of the population. From these results, it can be concluded that whenever during a behavioral experiment a longer lasting, reversible inactivation is required, muscimol is the drug of choice, because it inactivates neurons to a similar degree as TTX, but it does not, in contrast to TTX, affect fibers of passage. For a short-lasting but partial inactivation, lidocaine would be most suitable.