Ghrelin directly targets the ventral tegmental area to increase food motivation

doi:10.1016/j.neuroscience.2011.02.016

Neuroscience

Volume 180, 28 April 2011, Pages 129-137

https://doi.org/10.1016/j.neuroscience.2011.02.016 Get rights and content

Abstract

Ghrelin, a circulating orexigenic stomach-derived hormone, has recently been implicated in extra-homeostatic feeding, increasing food reward and food-motivated behavior. The precise target site(s) for ghrelin's effects on food reward have yet to be elucidated. The neurocircuitry underpinning food-motivated behavior involves, in particular, the dopamine cells of the ventral tegmental area (VTA) that project to the nucleus accumbens (NAcc). Ghrelin stimulation in both of these mesolimbic reward areas increases chow intake. Here we sought to determine if ghrelin acts directly within these mesolimbic reward areas to increase food reward/motivation in studies that combine feeding behavior, pharmacology, and neuroanatomy. We found that motivated behavior for a sucrose reward, assessed in an operant conditioning paradigm in rats, was increased when ghrelin was microinjected directly into the VTA but not into the NAcc. By contrast, ghrelin administration to both areas increased the free feeding of chow. Importantly, in a state of overnight food restriction, where endogenous levels of ghrelin are increased, ghrelin receptor (GHS-R1A) blockade in the VTA was sufficient to decrease the motivation to work for a sugar reward. Blockade of the GHS-R1A in VTA or NAcc was not sufficient to reduce fasting-induced chow hyperphagia. Taken together our data identify the VTA but not the NAcc as a direct, necessary, and sufficient target site for ghrelin's action on food motivation.

Highlights

▶Motivation for food increased after VTA, but not the NAcc, ghrelin stimulation. ▶Ghrelin administration to both areas increased the free feeding of chow. ▶GHS-R1A blockade in only the VTA was sufficient to decrease food motivation. ▶VTA is a direct, necessary and sufficient target for ghrelin's food motivation action.

Section snippets

Animals

Adult male Sprague-Dawley rats (200–250 g, Charles River, Germany) were housed in a 12-h light/dark cycle with regular chow and water available ad libitum, except when indicated otherwise. All animal procedures were carried out with ethical permission and in accordance with the University of Gothenburg Institutional Animal Care and Use Committee guidelines.

Surgery

All rats in the behavioral studies were implanted with a guide cannula targeting the VTA or the NAcc shell, (26 gauge; Plastics One,

VTA ghrelin microinjection

To determine whether ghrelin receptors in the VTA are relevant and directly engaged in changing the motivational value of palatable food, specifically sucrose, we examined sucrose self-administration in a progressive ratio response schedule in rats 10 min after VTA vehicle or ghrelin microinjection. Operant behavior (expressed as number of sugar rewards earned) was significantly increased in rats after ghrelin microinjection into the VTA (Fig. 1A), with nearly a 50% increase in rewards earned

Discussion

In the present study, we identify the VTA, a key structure in the mesolimbic reward system, as a primary target for ghrelin's effects to increase incentive motivated behavior for a sweet food reward. Specifically, we used an operant responding paradigm to show that motivated behavior for a sucrose reward (reflected by increased performance in a progressive ratio operant conditioning paradigm) was increased by direct VTA microinjection of ghrelin and, conversely, was decreased by direct VTA

Acknowledgments

The research was supported by the EU (FP7-HEALTH- 2009–241592, FP7-KBBE-2009-3-245009 and FP7-KBBE-2010-4-266408), Swedish Medical Research Council (K2007-54X-20328–013), ALF Göteborg (138741), the Swedish Foundation for Strategic Research to Sahlgrenska Center for Cardiovascular and Metabolic Research (A305-188) and the Swedish Institute. We would also like to thank Maria Fedchenko for help with data analysis.

References (36)

A.M. Cason et al.
Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity
Physiol Behav
(2010)
M.A. Cowley et al.
The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis
Neuron
(2003)
S.L. Dickson et al.
Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons
Neuroscience
(1993)
X.M. Guan et al.
Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues
Brain Res Mol Brain Res
(1997)
J.A. Harrold et al.
Autoradiographic analysis of ghrelin receptors in the rat hypothalamus
Brain Res
(2008)
K.J. Livak et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method
Methods
(2001)
S. Malik et al.
Ghrelin modulates brain activity in areas that control appetitive behavior
Cell Metab
(2008)
A.M. Naleid et al.
Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens
Peptides
(2005)
M. Perello et al.
Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner
Biol Psychiatry
(2010)
D. Quarta et al.
Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens
Neurochem Int
(2009)

N. Salomé et al.

Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats

Eur J Pharmacol

(2009)

C.B. Saper et al.

The need to feed: homeostatic and hedonic control of eating

Neuron

(2002)

A.L. Tracy et al.

The melanocortin antagonist AgRP (83-132) increases appetitive responding for a fat, but not a carbohydrate, reinforcer

Pharmacol Biochem Behav

(2008)

R.A. Wise

Brain reward circuitry: insights from unsensed incentives

Neuron

(2002)

A. Abizaid et al.

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

J Clin Invest

(2006)

D.E. Cummings et al.

A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

Diabetes

(2001)

Y. Date et al.

Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

Endocrinology

(2000)

S. Diano et al.

Ghrelin controls hippocampal spine synapse density and memory performance

Nat Neurosci

(2006)

Cited by (275)

Ghrelin receptor antagonism and satiety attenuate Pavlovian-instrumental transfer
2024, Neurobiology of Learning and Memory
Animals rely on learned cues to guide their behaviour for rewards such as food. The Pavlovian-instrumental transfer (PIT) task can be used to investigate the influence of Pavlovian stimuli on instrumental responding. Ghrelin, an orexigenic peptide, and its receptor, growth hormone secretagogue receptor 1A (GHS-R1A), has received growing interest for its role in reward-motivated learning and behaviours. A significant population of GHS-R1A have been identified within the ventral tegmental area (VTA), a critical node in the mesolimbic reward circuit that is necessary for the expression of PIT. As ghrelin has been found to increase dopaminergic activity in the VTA, we predicted that GHS-R1A antagonism with JMV-2959 would attenuate PIT. Further, given the relationship between hunger levels and changes in ghrelin signalling, we sought to compare the effects GHS-R1A antagonism with those of satiety, hypothesizing parallel effects, with each attenuating PIT. Rats received daily sessions of Pavlovian and then instrumental training over 3 weeks. Across three experiments, we examined the effects of a shift to satiety, or treatment with the GHS-R1A antagonist JMV-2959, either peripherally or directly into the VTA. We found that presentations of a stimulus paired with food reward enhanced responding for food across all conditions, thus demonstrating the expected PIT effect. Further, GHS-R1A antagonism, both peripherally and within the VTA, as well as satiety significantly reduced the magnitude of the PIT effect compared to control conditions. These results clarify our understanding of ghrelin signalling in PIT and begin to elucidate the role of feeding-related peptides in the modulation of reward-related responding.
Ghrelin signalling in AgRP neurons links metabolic state to the sensory regulation of AgRP neural activity
2023, Molecular Metabolism
The sensory detection of food and food cues suppresses Agouti related peptide (AgRP) neuronal activity prior to consumption with greatest suppression occurring in response to highly caloric food or interoceptive energy need. However, the interoceptive mechanisms priming an appropriate AgRP neural response to external sensory information of food availability remain unexplored. Since hunger increases plasma ghrelin, we hypothesized that ghrelin receptor (GHSR) signalling on AgRP neurons is a key interoceptive mechanism integrating energy need with external sensory cues predicting caloric availability.
We used in vivo photometry to measure the effects of ghrelin administration or fasting on AgRP neural activity with GCaMP6s and dopamine release in the nucleus accumbens with GRAB-DA in mice lacking ghrelin receptors in AgRP neurons.
The deletion of GHSR on AgRP neurons prevented ghrelin-induced food intake, motivation and AgRP activity. The presentation of food (peanut butter pellet) or a wooden dowel suppressed AgRP activity in fasted WT but not mice lacking GHSRs in AgRP neurons. Similarly, peanut butter and a wooden dowel increased dopamine release in the nucleus accumbens after ip ghrelin injection in WT but not mice lacking GHSRs in AgRP neurons. No difference in dopamine release was observed in fasted mice. Finally, ip ghrelin administration did not directly increase dopamine neural activity in the ventral tegmental area.
Our results suggest that AgRP GHSRs integrate an interoceptive state of energy need with external sensory information to produce an optimal change in AgRP neural activity. Thus, ghrelin signalling on AgRP neurons is more than just a feedback signal to increase AgRP activity during hunger.
The role of dysregulated ghrelin/LEAP-2 balance in anorexia nervosa
2023, iScience
LEAP-2 is a ghrelin antagonist with an anorexigenic drive. This study investigates the evolution of plasma ghrelin and LEAP-2 concentrations in 29 patients with anorexia nervosa (AN) before and after refeeding and compares it to physiological adaptations during fasting in healthy controls or to mouse model of chronic food restriction and refeeding. Acute and chronic food restriction decrease LEAP-2 and increase ghrelin concentrations in both humans and mice, while patients with AN displayed higher ghrelin and LEAP-2 concentrations before than after refeeding (p = 0.043). After 6 months follow-up, patients with unstable weight gain (n = 17) had significantly decreased LEAP-2 concentrations after refeeding (p = 0.044), in contrast to patients with stable weight gain (n = 12). We provide evidence that the ghrelin/LEAP-2 system is not regulated according to the nutritional status in AN, in contrast to what is physiologically expected when coping with food restriction.
Chronic food restriction in mice and increased systemic ghrelin induce preference for running wheel activity
2023, Psychoneuroendocrinology
In eating disorders, particularly anorexia nervosa (AN), patients exhibit intense physical activity which is inappropriate regarding food restriction and chronic undernutrition, and exacerbates weight loss and energy deprivation. Rodent models of food restriction exhibit increased running wheel activity in the food anticipation period, also known as Food Anticipatory Activity (FAA). FAA probably has various physiological and/or neurobiological origins. Plasma concentrations of the orexigenic hormone ghrelin are, for example, increased during FAA. We hypothesize that the drive for physical activity in chronic food restriction is triggered by metabolic factors but also relies on motivational aspects that we aim to decipher in this study.
Young female C57Bl6/J mice were exposed to a paradigm based on a progressive 50% quantitative food restriction alone (FR) or associated with running wheel activity (Food Restriction Wheel: FRW) in their home-cage during 15 days. We measured preference for running wheel in a three-chamber apparatus in which animals could choose to explore either a known running wheel or a novel object. Testing took place either during resting or during FAA. We calculated the time spent in each compartment and the activity in running wheels. After progressive refeeding over 10 days, mice were tested again when refed. Plasma levels of both ghrelin isoforms were measured with selective immunoassays.
When tested during FAA period, food restricted mice displayed increased preference for the running wheel compared to ad libitum fed controls. Both FR and FRW mice exhibited increased running time and distance in the wheel and running distance was correlated with ghrelin levels. Similar preference and behavior were found when testing took place during the resting period. Animals housed without an active wheel also exhibited active running. Progressive refeeding resulted in body weight restoration, a decrease in FAA and completely abolished preference for the running wheel. Refed animals displayed similar behavior as ad libitum fed controls.
These data provide evidence that food restriction-induced physical activity is closely correlated with metabolic adaptations to nutritional status implicating ghrelin in the quantity of physical activity.
Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights
2023, Physiology and Behavior
Dysfunctional signaling in midbrain reward circuits perpetuates diseases characterized by compulsive overconsumption of rewarding substances such as substance abuse, binge eating disorder, and obesity. Ventral tegmental area (VTA) dopaminergic activity serves as an index for how rewarding stimuli are perceived and triggers behaviors necessary to obtain future rewards. The evolutionary linking of reward with seeking and consuming palatable foods ensured an organism's survival, and hormone systems that regulate appetite concomitantly developed to regulate motivated behaviors. Today, these same mechanisms serve to regulate reward-directed behavior around food, drugs, alcohol, and social interactions. Understanding how hormonal regulation of VTA dopaminergic output alters motivated behaviors is essential to leveraging therapeutics that target these hormone systems to treat addiction and disordered eating. This review will outline our current understanding of the mechanisms underlying VTA action of the metabolic hormones ghrelin, glucagon-like peptide-1, amylin, leptin, and insulin to regulate behavior around food and drugs of abuse, highlighting commonalities and differences in how these five hormones ultimately modulate VTA dopamine signaling.
Effect of feed modification on the behavior, blood profile, and telomere in horses exhibiting abnormal oral behaviors
2023, Journal of Veterinary Behavior
The physiological mechanism underlying the relationship between diet and abnormal oral behaviors (AOB) such as oral stereotypic (OS) and redirected behaviors (RB) in horses is relatively uncertain. Therefore, this study aims to elucidate the effect of diet modification on the behavioral changes, blood profile, hormonal concentrations, and relative telomere length in patrolling horses exhibiting AOB. A total of 12 patrolling horses were divided equally into the low AOB (n = 6; control) and the high AOB (n = 6; treatment) groups based on the mean time spent demonstrating OS and RB. Throughout the 30-day study, the high AOB horses were fed with a high forage high fiber (HFHF) diet, whereas the low AOB horses were fed with their normal allowance of high concentrate low fiber (HCLF) diet. The horses’ behaviors were recorded 3 days before the experiment commenced and was re-observed in the last 3 days of the experiment. Blood samples were collected before the feeding trial and post-feeding for the determination of hemato-biochemistry, plasma ghrelin, leptin and corticosterone concentrations, as well as the relative telomere length. Generally, High AOB horses fed with the HFHF diet exhibited a significant increase in bodyweight gain, whereas the mean proportion of time spent on OS and RB was significantly reduced. The feeding of the HFHF diet also significantly altered the hemato-biochemistry parameters of high AOB horses as compared to the pre-treatment and the control group fed with the HCLF diet. Post-treatment horses also revealed significantly lower plasma cortisol and ghrelin levels, but significantly higher plasma leptin levels. No significant association was found in the telomere length expression between AOB and type of diet. Conclusively, simple feed modification such as HFHF was able to influence the AOB, blood profile, and hormonal concentrations, which could ultimately improve the overall health and well-being of horses.

View all citing articles on Scopus

View full text

Cognitive, Behavioral, and Systems NeuroscienceResearch PaperGhrelin directly targets the ventral tegmental area to increase food motivation

Abstract

Highlights

Section snippets

Animals

Surgery

VTA ghrelin microinjection

Discussion

Acknowledgments

Physiol Behav

Neuron

Neuroscience

Brain Res Mol Brain Res

Brain Res

Methods

Cell Metab

Peptides

Biol Psychiatry

Neurochem Int

Eur J Pharmacol

Neuron

Pharmacol Biochem Behav

Neuron

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

J Clin Invest

A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

Diabetes

Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

Endocrinology

Ghrelin controls hippocampal spine synapse density and memory performance

Nat Neurosci

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Ghrelin directly targets the ventral tegmental area to increase food motivation