Disruption of cue-potentiated feeding in mice with blocked ghrelin signaling
ABSTRACT The peptide hormone ghrelin regulates a variety of eating behaviors. Not only does it potently increase intake of freely-available food, but also shifts food preference toward diets rich in fat, enhances operant responding for food rewards, and induces conditioned place preference for food rewards. Here, we postulated that ghrelin also enables cue-potentiated feeding, in which eating is enhanced upon presentation of a food-conditioned stimulus. To test this hypothesis, a novel cue-potentiated feeding protocol adapted for use in mice was designed and validated, and then the effects of pharmacologic ghrelin receptor (GHSR) antagonism and GHSR transcriptional blockade (as occurs in GHSR-null mice) were assessed. Sated C57BL/6J mice indeed demonstrated cue-potentiated intake of grain-based pellets specifically upon presentation of a positive conditioned stimulus (CS+) but not a negative conditioned stimulus (CS-). Treatment with a GHSR antagonist blocked potentiated feeding in sated C57BL/6J mice in response to the CS+. In contrast, while GHSR-null mice also lacked a potentiation of feeding specifically in response to the CS+, they displayed an enhanced intake of pellets in response to both the positive and negative conditioned stimuli. The pattern of immediate early gene expression within the basolateral amygdala - a brain region previously linked to cue-potentiated feeding - paralleled the observed behavior of these mice, suggesting uncharacteristic activation of the amygdala in response to negative conditioned stimuli in GHSR-null mice as compared to wild-type littermates. Thus, although the observed disruptions in cue-potentiated feeding are different depending upon whether GHSR activity or GHSR expression is blocked, a key role for GHSRs in establishing a specific positive cue-food association has now been established.
SourceAvailable from: Reginald Frederick Westbrook[Show abstract] [Hide abstract]
ABSTRACT: Changes in food composition and availability have contributed to the dramatic increase in obesity over the past 30-40 years in developed and, increasingly, in developing countries. The brain plays a critical role in regulating energy balance. Some human studies have demonstrated increased preference for high fat and high sugar foods in people reporting greater stress exposure. We have examined neurochemical changes in the brain in rodent models during the development of obesity, including the impact of obesity on cognition, reward neurocircuitry and stress responsiveness. Using supermarket foods high in fat and sugar, we showed that such a diet leads to changes in neurotransmitters involved in the hedonic appraisal of foods, indicative of an addiction-like capacity of foods high in fat and/or sugar. Importantly, withdrawal of the palatable diet led to a stress-like response. Furthermore, access to this palatable diet attenuated the physiological effects of acute stress (restraint), indicating that it could act as a comfort food. In more chronic studies, the diet also attenuated anxiety-like behavior in rats exposed to stress (maternal separation) early in life, but these rats may suffer greater metabolic harm than rats exposed to the early life stressor but not provided with the palatable diet. Impairments in cognitive function have been associated with obesity in both people and rodents. However, as little as 1 week of exposure to a high fat, high sugar diet selectively impaired place but not object recognition memory in the rat. Excess sugar alone had similar effects, and both diets were linked to increased inflammatory markers in the hippocampus, a critical region involved in memory. Obesity-related inflammatory changes have been found in the human brain. Ongoing work examines interventions to prevent or reverse diet-induced cognitive impairments. These data have implications for minimizing harm caused by unhealthy eating. Copyright © 2014. Published by Elsevier Ltd.Neuroscience & Biobehavioral Reviews 12/2014; DOI:10.1016/j.neubiorev.2014.12.002 · 10.28 Impact Factor
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ABSTRACT: Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e. hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS-). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS-, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 02/2015; DOI:10.1111/jnc.13080 · 4.24 Impact Factor
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ABSTRACT: “Hunger is the best spice” is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry. The neurobiological underpinnings of this lore include activation of the brain's reward system and the stimulation of this system by the hunger-promoting hormone, ghrelin. Ghrelin is produced largely from the stomach and levels are higher preprandially. The ghrelin receptor is expressed in many brain areas important for feeding control, not only hypothalamic nuclei involved in energy balance regulation but also reward-linked areas such as the ventral tegmental area (VTA). By targeting the mesoaccumbal dopamine neurons of the VTA, ghrelin recruits pathways important for food reward-related behaviors that show overlap with but are also distinct from those important for food intake. Here, we review a variety of studies that support the notion that ghrelin signaling at the level of the mesolimbic system is one of the key molecular substrates that provides a physiological signal connecting gut and reward pathways.This article is protected by copyright. All rights reserved.Journal of Neuroendocrinology 11/2014; DOI:10.1111/jne.12236 · 3.51 Impact Factor