Jon F. Davis

Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat

Recent studies indicate that decreased central dopamine is associated with diet-induced obesity in humans and in animal models. In the current study, the authors assessed the hypothesis that diet-induced obesity reduces mesolimbic dopamine function. Specifically, the authors compared dopamine turnover in this region between rats fed a high-fat diet and those consuming a standard low-fat diet. The authors also assessed behavioral consequences of diet-induced obesity by testing the response of these animals in a conditioned place paradigm using amphetamine as a reinforcer and in an operant conditioning paradigm using sucrose reinforcement. Results demonstrate that animals consuming a high-fat diet, independent of the development of obesity, exhibit decreased dopamine turnover in the mesolimbic system, reduced preference for an amphetamine cue, and attenuated operant responding for sucrose. The authors also observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens. These data are consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation, which may have implications for the treatment of obesity and/or addiction.

The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats.

Consumption beyond homeostatic needs, referred to here as reward-based feeding behavior, is a central contributor to the current obesity epidemic worldwide. Importantly, reward-based feeding can be driven by palatability, the taste and texture of the food, as well as cues associated with the consumption of palatable foods. The hypothalamic orexin system regulates both diet preference and anticipation of food rewards making it a likely target to modulate reward-based feeding behavior. In the current manuscript we hypothesized that orexin signaling mediates food-motivated behaviors and reward-based feeding behavior. We further hypothesized that orexin neurons and targets of the orexin system become activated in response to cues associated with the consumption of palatable food. Data from these studies suggest that orexin signaling promotes progressive ratio responding for palatable foods while blockade of orexin signaling attenuates reward-based feeding of a high fat diet. In addition, cues linked to the consumption of chocolate, or the receipt of a daily meal, activate the orexin system and its target regions differentially. Collectively, these data suggest that orexin signaling mediates reward-based feeding behavior and, within specific target regions, may regulate cue-induced overconsumption of palatable foods.

Leptin Regulates Energy Balance and Motivation Through Action at Distinct Neural Circuits

BACKGROUND Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine. METHODS The contribution of endogenous leptin signaling for food motivation and mesolimbic dopamine tone was examined after viral-mediated reduction of the leptin receptor within LH and midbrain neurons in male rats. RESULTS Knockdown of leptin receptors selectively in the LH caused increased body weight, caloric consumption, and body fat in rats maintained on a calorically dense diet. Knockdown of leptin receptors selectively in midbrain augmented progressive ratio responding for sucrose and restored high-fat, diet-induced suppression of dopamine content in the nucleus accumbens. CONCLUSIONS In summary, endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods and the consequent increase in body mass, whereas leptin action in the midbrain regulates effort-based responding for food rewards and mesolimbic dopamine tone. These data highlight the ability of leptin to regulate overconsumption of palatable foods and food motivation through pathways that mediate energy homeostasis and reward, respectively.

Pleasurable behaviors reduce stress via brain reward pathways

Individuals often eat calorically dense, highly palatable “comfort” foods during stress for stress relief. This article demonstrates that palatable food intake (limited intake of sucrose drink) reduces neuroendocrine, cardiovascular, and behavioral responses to stress in rats. Artificially sweetened (saccharin) drink reproduces the stress dampening, whereas oral intragastric gavage of sucrose is without effect. Together, these results suggest that the palatable/rewarding properties of sucrose are necessary and sufficient for stress dampening. In support of this finding, another type of natural reward (sexual activity) similarly reduces stress responses. Ibotenate lesions of the basolateral amygdala (BLA) prevent stress dampening by sucrose, suggesting that neural activity in the BLA is necessary for the effect. Moreover, sucrose intake increases mRNA and protein expression in the BLA for numerous genes linked with functional and/or structural plasticity. Lastly, stress dampening by sucrose is persistent, which is consistent with long-term changes in neural activity after synaptic remodeling. Thus, natural rewards, such as palatable foods, provide a general means of stress reduction, likely via structural and/or functional plasticity in the BLA. These findings provide a clearer understanding of the motivation for consuming palatable foods during times of stress and influence therapeutic strategies for the prevention and/or treatment of obesity and other stress-related disorders.

Signaling through the ghrelin receptor modulates hippocampal function and meal anticipation in mice.

The ability to predict a particular meal is achieved in part by learned associations with stimuli that predict nutrient availability. Ghrelin is an orexigenic peptide produced by both the gut and brain that rises before anticipated meals and it has been suggested that pre-prandial ghrelin increases may act as a signal to predict meal delivery. Here, we used wild type and ghrelin receptor deficient mice to test the hypothesis that ghrelin signaling is necessary for the processing of emotionally relevant stimuli, spatial learning and habituated feeding responses. We tested spatial and fear-related memory with the Morris water maze and step through passive avoidance tests, respectively and utilized food anticipatory activity to monitor habituated feeding responses following two weeks of a meal feeding paradigm. Our results indicate that ghrelin signaling modulates spatial memory performance and is necessary for the development of food anticipatory activity. Collectively, these results suggest that ghrelin receptor signaling is necessary for adaptations in the anticipatory responses that accompany restricted feeding.

Dominant rats are natural risk takers and display increased motivation for food reward.

Risk-taking behavior is a vital aspect mediating the formation of social structure in animals. Here, we utilized the visible burrow system (VBS), a model in which rats form dominance hierarchies, to test the hypothesis that dominant rats in the VBS are natural risk takers and display an increased motivational state after VBS exposure. In particular, we predicted that dominant rats would have attenuated anxiety-like behavior and augmented acquisition of operant responding for food reward relative to subordinate and controls. We further hypothesized that these behaviors would correlate with elevated mesocortical orexin signaling. Prior to burrow exposure, male Long-Evans rats were tested on the elevated plus maze (EPM), and subsequently exposed to the VBS for seven consecutive days. At the conclusion of burrow exposure body weight and plasma corticosterone were used to confirm social rank within each colony. Interestingly, rats that went on to become dominant in the VBS spent significantly more time in the open arms of the EPM prior to burrow exposure and displayed increased operant responding for food reward. This effect was present over a range of reinforcement schedules and also persisted for up to 1 month following VBS exposure. Moreover, dominant rats displayed increased orexin receptor mRNA in the medial prefrontal cortex (mPFC) relative to subordinate and control rats. These data support previous findings from our group and are consistent with the hypothesis that risk-taking behavior may precede dominance formation in social hierarchies.

Orexin signaling in the paraventricular thalamic nucleus modulates mesolimbic dopamine and hedonic feeding in the rat

Data from our laboratory indicate that the orexin system is involved in the regulation of both conditioned and unconditioned responding for palatable foods. Anticipation of food rewards activates orexin receptor containing neurons within the paraventricular nucleus of the thalamus (PVT). The PVT regulates mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens and modulates the processing of cognitive-emotional information, suggesting that the PVT may represent a unique brain region with the capacity to mediate orexinergic effects on brain dopamine and behavior. Here, we tested the hypothesis that PVT orexin signaling mediates mesolimbic dopamine and reward-based feeding. To do this we used a behavioral pharmacological approach in tandem with central genetic manipulation of the orexin-1 receptor in the PVT. Data from these studies indicate that orexin-A action in the PVT increases dopamine levels in the nucleus accumbens. In addition, endogenous orexin signaling in the PVT mediates locomotor activity and hedonic feeding responses. Together these data highlight the PVT as a critical site capable of mediating orexin action on brain dopamine and reward-based feeding.

Angiotensin Type 1 Receptors in the Subfornical Organ Mediate the Drinking and Hypothalamic-Pituitary-Adrenal Response to Systemic Isoproterenol

Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT1R [AT1R antisense (AT1R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT1R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT1R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a beta-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT1R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT1R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT1R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.

Gastric Bypass Surgery Attenuates Ethanol Consumption in Ethanol-Preferring Rats

BACKGROUND Roux-en-Y gastric bypass (RYGB) surgery is an effective weight loss strategy employed to treat obesity and associated complications. Importantly, the RYGB procedure has been reported to attenuate reward-related consummatory behaviors. The present work examined the hypothesis that RYGB surgery attenuates ethanol intake and reward in the context of frequent ethanol consumption. METHODS To do this, self-report of ethanol intake was examined in human bariatric patients (n = 6165) before and following the RYGB procedure. In addition, we utilized a rodent model of RYGB and examined ethanol consumption and ethanol reward in male ethanol-preferring (P) rats, which are selectively bred to consume large volumes of ethanol. RESULTS Patients that reported frequent consumption of ethanol before RYGB reported decreased consumption following RYGB surgery. Moreover, the RYGB procedure decreased ethanol intake and the reinforcing properties of ethanol in P rats. Notably, the attenuating effect of RYGB surgery on ethanol consumption was associated with ethanol-induced increases in the gut hormone glucagon-like peptide-1 (GLP-1). Pharmacologic administration of GLP-1 agonists attenuated ethanol consumption in sham P rats. In addition, pharmacologic replacement of the gut hormone ghrelin restored drinking behavior in P rats following RYGB. CONCLUSIONS Collectively, these findings unveil the potential of RYGB surgery to attenuate ethanol consumption in some humans and rats. Furthermore, our data indicate that this regulation is achieved, in part, through reduction of reward and is modified by the gut hormones GLP-1 and ghrelin.

Learned and cognitive controls of food intake.

While much has been elucidated about the hypothalamic controls of energy balance, the epidemic of obesity continues to escalate. Recent work has suggested that extra-hypothalamic central nervous system structures may play a previously un-appreciated role in the control of ingestive behavior and body weight regulation. Because animals can and do learn about food and food-related stimuli, as well as the consequences of eating, we and others have sought to understand the cognitive process that underlies that learning. Additionally, we have begun to investigate the neuro-anatomical bases for complex learning about food and food cues. Here we review some evidence for learning about food as well as evidence that the hippocampus may play a critical role in the brains ability to regulate body weight through such learning processes.