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The paraventricular nucleus of the thalamus (PVT) is a key node integrating information about emotion and relaying output to other limbic structures influencing motor behavior. With recent studies showing the anterior (aPVT) and posterior (pPVT) subregions of this nucleus to have different anatomical connections and functions in ingestive behavior, the present study investigated whether they also make different contributions to emotional behaviors. Rats were microinjected in the aPVT or pPVT with saline vehicle or the GABAB+GABAA agonists, baclofen+muscimol (bac+mus; 0.3+0.03nmol), to inhibit neural activity and were then tested between-subject for differences in emotional behavior. In a novel activity chamber, bac+mus significantly reduced locomotor activity, with this change somewhat larger after injection in the pPVT than the aPVT. In a familiar activity chamber, bac+mus again reduced locomotor activity but induced similar changes after injection in the aPVT and pPVT. In an elevated plus maze, bac+mus significantly decreased open arm time and entries, although this was observed only after injection in the pPVT. Thus, while both PVT subregions are necessary for general locomotor activity, the pPVT appears to have a greater function in both novelty-induced activity and anxiety-like behavior, indicating that this subregion makes a greater contribution than the aPVT to reactions to stressful stimuli., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Consummatory behavior is driven by both caloric and emotional need, and a wide variety of animal models have been useful in research on the systems that drive consumption of food and drugs. Models have included selective breeding for a specific trait, manipulation of gene expression, forced or voluntary exposure to a substance, and identification of biomarkers that predict which animals are prone to overconsuming specific substances. This research has elucidated numerous brain areas and neurochemicals that drive consummatory behavior. Although energy homeostasis is primarily mediated by the hypothalamus, reinforcement is more strongly mediated by nuclei outside the hypothalamus, in mesocorticolimbic regions. Orexigenic neurochemicals that control food intake can provide a general signal for promoting caloric intake or a more specific signal for stimulating consumption of a particular macronutrient, fat, carbohydrate, or protein. The neurochemicals involved in controlling fat ingestion--galanin, enkephalin, orexin, melanin-concentrating hormone, and the endocannabinoids--show positive feedback with this macronutrient, as these peptides both increase fat intake and are further stimulated by its intake. This positive association offers some explanation for why foods high in fat are so often overconsumed. Consumption of ethanol, a drug of abuse that also contains calories, is similarly driven by the neurochemical systems involved in fat intake, according to evidence that closely relates fat and ethanol consumption. Further understanding of the systems involved in consummatory behavior will enable the development of effective therapies for the treatment of both overeating and drug abuse.

This review is aimed at understanding some of the common neurochemical, behavioral and physiological determinants of drug and food overconsumption. Much current work has been devoted to determining the similarities between the brain circuits controlling excessive use of addictive drugs and the overconsumption of palatable foods. The brain systems involved likely include peptides of both mesolimbic and hypothalamic origin. Evidence gathered from expression and injection studies suggests that the consumption of drugs, such as ethanol and nicotine, and also of palatable foods rich in fat is stimulated by different orexigenic peptides, such as enkephalin, galanin, orexin, and melaninconcentrating hormone, acting within the hypothalamus or various limbic structures, while another peptide, neuropeptide Y, is closely related to carbohydrate consumption and shows an inverse relationship with ethanol and nicotine consumption. Moreover, studies in animal models suggest that a propensity to overconsume these reinforcing substances may result from preexisting disturbances in these same peptide systems. These neurochemical disturbances, in turn, may also be closely linked to specific behaviors associated with excessive consummatory behavior, such as hyperactivity or novelty-seeking, palatable food preference, and also fluctuations in circulating lipid levels. Clear understanding of the relationship between these various determinants of consummatory behavior will allow researchers to effectively predict and examine at early stages of exposure animals that are prone to drug and food overconsumption. This work may ultimately aid in the identification of inherent traits that increase the risk for drug abuse and palatable food overconsumption.

Galanin (GAL) plays an integral role in consummatory behavior. In particular, hypothalamic GAL has a positive, reciprocal relationship with dietary fat and alcohol. In this relationship, GAL increases the consumption of fat or alcohol which, in turn, stimulates the expression of GAL, ultimately leading to overconsumption. Through actions in the amygdala, this relationship may become especially important in stress-induced food or drug intake. These effects of GAL in promoting overconsumption may involve various neurotransmitters, with GAL facilitating intake by stimulating norepinephrine and dopamine and reducing satiety by decreasing serotonin and acetylcholine. In addition, GAL in the hypothalamus stimulates the opioid, enkephalin, throughout the brain, which also promotes overconsumption. The relationship between GAL, fat, and alcohol may involve triglycerides, circulating lipids that are released by fat or alcohol and that correlate positively with hypothalamic GAL expression. In females, levels of endogenous GAL also fluctuate across the reproductive cycle, driven by a rise in the ovarian steroids, estrogen, and progesterone. They peak during the proestrous phase and also at puberty, simultaneous to a sharp increase in preference for fat to meet energy demands. Prenatal exposure to a high-fat diet also enhances hypothalamic expression of GAL into adulthood because of an increase in neurogenesis and proliferation of GAL-expressing neurons in this region. This organizational change may reflect the role of GAL in neuronal development, including neurite growth in adulthood, cell survival in aging, and cell stability in the disease state. By responding positively to fat and alcohol and guiding further neuronal development, GAL potentiates a long-term propensity to overconsume fat and alcohol.

The studies described in this report provide interesting animal models for exploring some of the metabolic and neural antecedents to the over-consumption of fat and alcohol. The results provide strong support for the existence of positive feedback loops that involve a close relation between circulating lipids and orexigenic peptides in dorsal regions of the hypothalamus. The peptides involved in these circuits include galanin, enkephalin, dynorphin and orexin. These peptides are expressed in the paraventricular nucleus and perifornical lateral hypothalamus, and they have very different functions from peptides expressed in the arcuate nucleus. Through mechanisms involving circulating lipids that rise on energy-dense diets, these peptides in the dorsal hypothalamus are each increased by the consumption of fat and ethanol; these nutrients, in turn, stimulate further production of these same peptides that promote overeating and excess drinking. These mechanisms involving non-homeostatic, positive feedback circuits may be required under conditions when food supplies are scarce and periods of gorging are essential to survival. However, they have pathological and sometimes life-threatening consequences in modern society, where fat-rich foods and alcoholic drinks are abundantly available and are contributing to the marked rise over the past 25 years in obesity and diabetes in both children and adults.

To understand mechanisms underlying a resistance to obesity, two obesity-resistant inbred mouse strains, SWR/J and A/J, were compared to 3 inbred "control" strains, C3H/HeJ, BALB/cByJ and C57L/J. These 5 strains, studied at 5 weeks of age when similar in body weight, were maintained for 3 weeks on a 3-diet feeding paradigm, with separate jars of carbohydrate, protein and fat, or for 1 week on a single high-fat or low-fat diet. The control strains each chose a balanced diet, with 50% carbohydrate and 15-25% fat, and they had a similar, normal range of scores for measures of body weight, adiposity, endocrine parameters and metabolic enzyme activity. Compared to these control strains, the obesity-resistant SWR/J and A/J strains consumed more total calories and selected a diet with significantly more fat (35-45%) and less carbohydrate (35%). Despite overeating, they weighed less and had significantly reduced adiposity. They also had lower levels of insulin and exhibited increased capacity of skeletal muscle to metabolize fat, as indicated by measures beta-hydroxyacyl-CoA dehydrogenase activity or its ratio to citrate synthase. Measurements of hypothalamic peptides via radioimmunoassay or real-time quantitative PCR revealed markedly enhanced galanin (GAL) in the paraventricular nucleus and reduced neuropeptide Y (NPY) expression in the arcuate nucleus of obesity-resistant mice. These patterns in SWR/J and A/J strains, seen on a low-fat as well as high-fat diet, may reflect mechanisms involving excess GAL and reduced NPY that contribute early, respectively, to the over-consumption of a high-fat diet and a resistance to the obesity-promoting effects of this diet.

Galanin (GAL) is known to stimulate feeding behavior. This peptide has different properties and functions from other feeding stimulants, e.g., neuropeptide Y and agouti-related protein. Hypothalamic GAL is relatively unresponsive to food deprivation and to changes in corticosterone, glucose utilization, dietary carbohydrate and leptin. This indicates that this peptide is not essential under conditions when food is scarce or low-energy, high-carbohydrate diets are being consumed. In contrast, recent evidence suggests that GAL in the paraventricular nucleus (PVN) functions in close relation to dietary fat and alcohol. In particular, it mediates functions that allow animals to adapt to conditions of positive energy balance involving excess consumption of these nutrients. This peptide in the PVN is stimulated by a high-fat diet and also by alcohol. It is stimulated by an increase in circulating lipids caused by a fat-rich meal or alcohol consumption, and it rises during the middle of the active feeding cycle, when fat consumption and triglycerides naturally rise. When centrally injected, GAL in the PVN increases the consumption of food and alcohol. Moreover, it produces a significantly stronger feeding response in rats maintained on a fat-rich diet, which also promotes alcohol intake. This evidence supports the existence of non-homeostatic, positive feedback circuits between GAL and both dietary fat and alcohol. These circuits are believed to contribute to the large meal size, over-consumption of alcohol, and obesity which are generally associated with fat-rich foods.

Neuropeptide Y (NPY) and agouti-related protein (AgRP), potent stimulants of feeding, have been linked in adult rats to both corticosterone (CORT) and dietary carbohydrate. To understand the significance of this relationship early in life, measurements were taken of these parameters at different ages around weaning, in rats given a choice of macronutrient diets or maintained on a carbohydrate-rich diet. The results demonstrate that, in both male and female rat pups, the expression and production of NPY and AgRP in the arcuate nucleus (ARC) peak on postnatal day 21 (P21), compared to P15 before weaning and P27 after weaning. These elevated levels of peptide were associated with peak levels of CORT and glucose and also a strong, natural preference for carbohydrate at weaning, which accounted for 55-65% of the pups' total diet. In subgroups defined by their body weight at these stages, rats with as little as 4% lower body weight (compared to higher weight pups) had 30-60% greater expression of NPY and AgRP in the ARC and elevated levels of CORT, with no difference in leptin or insulin. This response was significantly more pronounced at P21 than at P15 or P27. The importance of carbohydrate during this stage was suggested by additional results showing elevated NPY expression, CORT levels, body weight and inguinal fat pad weights in P27 pups raised on a 65% carbohydrate diet vs. 45% carbohydrate. These results suggest that hypothalamic NPY and AgRP, together with CORT, have glucoregulatory as well as feeding stimulatory functions that help mediate the transition from suckling of a fat-rich diet to independent feeding of a carbohydrate-rich diet. During this critical period, the carbohydrate together with the peptides and CORT provide the important signals, including elevated glucose, that promote de novo lipogenesis and enable weanling animals to survive periods of food deprivation.

Little is known about the impact of circulating lipids on brain processes. Building on evidence that chronic fat consumption stimulates hypothalamic peptides in close association with elevated triglycerides (TG), this study examined whether an acute rise in TG levels induced by fat emulsion can affect these hypothalamic systems. In normal weight rats, ip injection of Intralipid (20%, 5 ml) during the first 4 h after injection produced a robust increase in TG levels and nonesterified fatty acids, but had no impact on glucose, insulin, or leptin levels. This was accompanied by a marked increase in the expression of particular orexigenic peptides, galanin, orexins, and the opioid, enkephalin, which are known to be positively related to fat ingestion. This effect, similarly induced by 4 h of high fat diet consumption, was detected in the paraventricular nucleus (PVN) for galanin, in the perifornical hypothalamus (PFH) for orexins, and in the PVN, PFH, as well as the arcuate nucleus (ARC) for enkephalin. It was not seen, however, for neuropeptide Y and agouti-related protein localized in the ARC, which are unaffected or reduced by dietary fat. This site specificity was confirmed by c-Fos immunostaining, a marker of neuronal activity, which was increased by Intralipid in the PVN and PFH, but not in the ARC, and was detected in 20% of orexin-expressing neurons in the PFH. These findings suggest that circulating lipids, through different mechanisms, may stimulate hypothalamic neurons, which synthesize specific feeding stimulatory peptides that possibly contribute to hyperphagia during consumption of a fat-rich diet.

To compare the effects of acute exposure to dietary fat to those of chronic exposure, Sprague-Dawley rats were given a high-fat diet (50% fat) or moderate-fat diet (25% fat) for 1 day, 2 h or 3 weeks. With measurements of various parameters, the high-fat diet for 21 days produced the expected changes of: (1) a significant increase in total caloric intake and dissected fat pad weights; (2) a rise in leptin and the metabolites, triglycerides (TG), non-esterified fatty acids and glucose; (3) an increase in muscle beta-hydroxyacyl-CoA dehydrogenase (HADH) and adipose lipoprotein lipase (aLPL) activity, along with a decrease in LPL activity in muscle (mLPL); and (4) elevated galanin (GAL) expression and peptide levels in the anterior region of the paraventricular nucleus (PVN), with no change in the arcuate nucleus. The acute 1-day or 2-h high-fat diet similarly increased circulating lipids, HADH activity and PVN GAL mRNA but stimulated rather than suppressed mLPL activity. These effects occurred in the absence of a change in total caloric intake, fat pad weights, and adipose-related measures, suggesting that they resulted more from the rise in dietary fat from 25% to 50% than from increased adiposity or hyperphagia. Moreover, PVN GAL mRNA in the different groups was consistently and positively correlated with the specific measures of TG levels and both HADH and mLPL activity, linking it to metabolic processes related to the transport and capacity for oxidation of TG in muscle, rather than adipose tissue., (Copyright 2004 Elsevier B.V.)

Energy balance is maintained via a homeostatic system involving both the brain and the periphery. A key component of this system is the hypothalamus. Over the past two decades, major advances have been made in identifying an increasing number of peptides within the hypothalamus that contribute to the process of energy homeostasis. Under stable conditions, equilibrium exists between anabolic peptides that stimulate feeding behavior, as well as decrease energy expenditure and lipid utilization in favor of fat storage, and catabolic peptides that attenuate food intake, while stimulating sympathetic nervous system (SNS) activity and restricting fat deposition by increasing lipid metabolism. The equilibrium between these neuropeptides is dynamic in nature. It shifts across the day-night cycle and from day to day and also in response to dietary challenges as well as peripheral energy stores. These shifts occur in close relation to circulating levels of the hormones, leptin, insulin, ghrelin and corticosterone, and also the nutrients, glucose and lipids. These circulating factors together with neural processes are primary signals relaying information regarding the availability of fuels needed for current cellular demand, in addition to the level of stored fuels needed for long-term use. Together, these signals have profound impact on the expression and production of neuropeptides that, in turn, initiate the appropriate anabolic or catabolic responses for restoring equilibrium. In this review, we summarize the evidence obtained on nine peptides in the hypothalamus that have emerged as key players in this process. Data from behavioral, physiological, pharmacological and genetic studies are described and consolidated in an attempt to formulate a clear statement on the underlying function of each of these peptides and also on how they work together to create and maintain energy homeostasis.

Alcoholism can be viewed as a motivational disorder that results from alterations in brain systems for ingestive behavior. Therefore, it was hypothesized that alcohol intake might alter the expression of hypothalamic peptides that stimulate feeding. Earlier studies showed that hypothalamic injection of the feeding-stimulatory peptide, galanin (GAL), increases the release of dopamine (DA) in the nucleus accumbens (NAc), as does systemic alcohol, leading to a focus on GAL. Results of this study demonstrate the following: (1). Ethanol, injected daily (0.8 g/kg 10% v/v) for 7 days in male rats, markedly increased the expression of GAL but not of neuropeptide Y (NPY). This occurred in specific hypothalamic nuclei, namely the dorsomedial nucleus (DMN), paraventricular nucleus (PVN) and perifornical lateral hypothalamus (PLH). (2). Rats induced to drink ethanol ad libitum, by gradually increasing the concentration from 1% to 9% v/v without adding sugar or flavoring, exhibited a similar stimulation of GAL mRNA in the PVN and GAL immunoreactivity in the DMN and PVN. (3). Rats given increasing ethanol concentrations, with 12 h access starting 4 h into the dark cycle, had a mean blood alcohol concentration of 18 mg/dl and exhibited a similar increase in GAL expression in the DMN and PVN. (4) Withdrawal from the opioid effects of 9% ethanol, produced by injection of naloxone (3 mg/kg sc), reversed this ethanol effect by significantly reducing GAL expression in the DMN and PLH below baseline levels. These studies suggest a possible role for hypothalamic GAL in alcohol abuse.