Research

Meal-related satiety signals arise from the gastrointestinal tract in response to incoming nutrients and promote meal termination and continued “fullness” after the meal. We know that many satiety hormones, including cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) released from the small intestine, signal to the brain through the sensory fibers of the vagus nerve. These vagal fibers synapse in the hindbrain and directly activate neurons in the area postrema (AP) and nucleus tractus solitarius (NTS). Excitation of these hindbrain neurons correlates with and is necessary for the anorexic response to these hormones, but the conscious decision to stop eating involves additional processing in other brain regions. Our research has focused on connections between the NTS and a number of rostral forebrain areas that are known for their involvement in reward-motivated behavior. The working hypothesis is that these connections are a mechanism by which satiety signals rising over the course of a meal reduce the reward value of food and motivation to continue eating, ultimately leading to meal termination. Future directions include applying novel cell type-specific tracing methods to characterize and confirm synaptic connections among these neurons, and identify other brain regions and cell types that provide input to those rostral forebrain cells. Because the goal is to understand how activity within these circuits influences eating behavior, we are using chemogenetic techniques to selectively excite or silence specific pathways, and will determine how these manipulations affect eating and food-motivated behavior in a variety of behavioral tests.

It is clear that we do not eat only when we are metabolically depleted. Although we may feel full after a meal, the sight or aroma of desirable food can dramatically alter our sense of satiety. We hypothesize that this is the result of the brain’s anticipation of a highly rewarding food, and that this process suppresses the brain’s perception of and/or response to satiety signals arising from the gut. Gastrointestinal satiety signals do not disappear upon the ingestion of a sweet high-fat food, rather they are further stimulated. The fact that we eat more nonetheless suggests that the brain can override these normally potent signals. Numerous findings suggest that orexin neurons in the lateral hypothalamus are involved in anticipation of rewarding food. In rats and mice, these neurons are activated by cues that predict strong positive reinforcement, including chocolate or sugar treats. Orexin neurons project to many brain nuclei, including the hindbrain NTS and the AP, another region that receives feedback from the gastrointestinal tract. We hypothesized that this projection serves as a direct link between food anticipation and satiety signaling and published a series of studies demonstrating that hindbrain orexin receptor signaling increases food intake by reducing satiation, increasing motivation for sugar, and increasing food-seeking behavior. Next, we hypothesized that orexin may work to suppress satiation signals in other brain areas, as well. The ventral  tegmental area (VTA) is best known as the origin of the dopamine neurons that form the heart of the mesolimbic reward pathway, which plays a key role in natural and drug reward. We and others have shown that the VTA receives input from the NTS, potentially bringing gastrointestinal satiation signal information to this site, and in addition, orexin receptors are expressed there. In a series of experiments, we found that orexin works in the VTA to counteract the satiating effects of gastrointestinal nutrients. This work provided some of the first functional evidence that VTA neurons are indeed integrating satiety and food reward information. Future directions for this project include determining the neurochemical phenotypes of relevant orexin-receptive neurons, as well as their anatomical projections.

In humans, binge-eating is characterized by the consumption of an objectively large amount of food in a short period of time accompanied by a loss of control, and is a core feature of multiple eating disorders, including binge eating disorder, bulimia nervosa, and the binge/purge subtype of anorexia nervosa. Clinical studies suggest that impaired satiation is likely to play a role in the development and/or maintenance of binge-eating behavior, though the mechanisms are not yet well understood. Studies of individuals with eating disorders have been unable to determine whether these differences in satiation responses are pre-existing risk factors that contribute to the development of binge-eating or occur as a consequence of binge eating behavior and contribute to illness maintenance, but rodent models can help address these questions. Our lab uses a model in which rats or mice are given ad libitum access to standard rodent chow and are also presented with 20-hour time-limited access to palatable high-fat diet (HFD) on an intermittent schedule (e.g., every 4th day). While no rodent model can fully reproduce the complex features of human eating disorders, the intermittent HFD access model reliably reproduces the excessive intake phenotype that is characteristic of binge-eating. In a recent series of experiments, we demonstrated that repeated intermittent HFD access does impair the satiety response to gastrointestinal nutrients, and we identified an altered response to the pancreatic satiety hormone amylin that likely contributes to this impairment. We now aim to identify neural mechanisms underlying this change in sensitivity to gut signals.

Our rodent work in this direction has been informed in part by our collaboration with Dr. Pam Keel in our Psychology department at Florida State University, and our project focusing on related questions in human subjects. This study examines the biological mechanisms through which weight suppression (the difference between an individual’s highest and current weight) may contribute to binge-eating by increasing motivation for food and decreasing satiation. As we continue to obtain new data in humans, we are well positioned to use the complementary rodent model to perform experiments in which we can experimentally manipulate these factors and directly assess alterations in brain tissue.