Terry L. Davidson - US grants

DESCRIPTION (Adapted from applicant's abstract): This is a proposal that integrates methods and concepts from both psychobiology and animal learning to exploit preparations developed by the investigator that are capable of assaying the cue properties of manipulation which effect food intake to determine the information that these manipulations provide about internal state. These paradigms, which involve training rats to use the sensory consequence of food deprivation, will assess the degree to which internal cues provided by metabolic and hormonal manipulation have stimulus consequences like those produced by different levels of food deprivation. Experiments are proposed that assess the role of vagal afferents in the ability of rats to detect or utilize energy state signals arising in the gut and the role of limbic structure in the processing of energy state information. In additional experiments the PI proposes to investigate a model that he has proposed of how energy state cues actually function to control food intake. This model suggests that these signals contribute to the control of feeding by modulating how easy it is for food cues to activate when hunger signals are absent. These latter experiments represent the major portion of the proposal and depend upon the results and techniques from the experiments in Section 1. Specifically, these experiments utilize the technique of comparing behavior of animals who have received first or second order conditioning and address how manipulations that effect food intake alter performance to first or second order conditioned cues. The idea behind these experiments is that manipulations which have physiological effects on food intake should affect the ability of a cue to elicit first order conditioned responses but not second order conditioned responses. The next series of experiments addresses the issue of whether fats and carbohydrates give rise to distinct US representation and whether the substrates for the mediation of these differ. These experiments depend upon paradigm in which rats are trained to perform different responses to receive either a high fat or a high carbohydrate reinforcement. The ability of lipoprivation or glucoprivation to differentially effect the two responses will then be assessed. Subsequent experiments in this section assess the role of vagal pathways and hippocampal structures in the mediation of these responses. In the final series of experiments the direct role of the hippocampus in the mediation of feeding responses to dietary, hormonal, and metabolic challenges will be assessed. This information will provide a background for the interpretation of the lesioning experiment under the various paradigms.

Models of regulatory feeding behavior often assume that animals (including humans) eat, and engage in behaviors that are instrumental to obtaining food, in response to interoceptive signals that are correlated with their level of energy need. Accordingly, much research has been devoted to specifying the metabolic and hormonal events that give rise to these types of signals and to specifying the neural substrates involved with their detection and transmission. This work has identified a variety of physiological and pharmacological manipulations that promote or suppress food intake. However, it has been difficult to separate the potential "hunger" or "satiety" signal properties of these manipulations from their possible effects on palatability, learning, nonspecific behavioral arousal or other mechanisms that are also known to influence feeding even in the absence of changes in energy need. Integrating methods and concepts from psychobiology and Pavlovian conditioning, the proposed research will develop and exploit a novel model of regulatory feeding behavior that describes how interoceptive signals of energy need act in conjunction with food cues (e.g., tastes and other sensory properties of food) and the postingestive consequences of intake to determine the strength or probability of appetitive and consummatory feeding behavior. Based on studies of Pavlovian conditioned modulation involving conventional auditory and visual stimuli, this model assumes that energy state signals influence feeding behavior by modulating the capacity of food-related stimuli to activate the memory of the appetitive postingestive consequences of intake. New research strategies are proposed to examine the involvement of metabolic, hormonal, subdiaphragmatic vagal, and central nervous system mechanisms in this "memory modulation" process. In addition, several experiments will assess the nature of the information that animals encode about the foods that they eat as well as the nature of the signals involved with the retrieval/activation of that information. It seems likely that disordered patterns of human feeding behavior involve impairments in the detection, utilization, or modulatory function of energy state signals or in the encoding of information about food. Thus, the proposed research may have important implications with respect to understanding the etiology and developing effective treatments for these disorders.

[unreadable] DESCRIPTION (provided by applicant): The regulation of intake involves multiple types of interacting behavioral and physiological control mechanisms. Malfunctions in one or more of these control mechanisms are presumed to underlie disordered patterns of food intake and body weight regulation, such as those associated with obesity or anorexia. A property of food that may play a role in the maintenance of energy balance is viscosity, defined as the resistance of a substance to flow. Recent reports suggest that the ability of humans to adjust their intake to compensate for calories consumed depends, at least in part, on the viscosity of the food. The potential role of food viscosity on intake regulation has not been investigated systematically within a non-human animal model. The purpose of the proposed research is to use the control that is afforded by a rat model of appetitive and consummatory behavior to begin this investigation. Our research will assess the effects of feeding rats foods that are the same in terms of their caloric and nutritive content, but that differ in viscosity. Studies will examine both short-term and long-term effects of differences in viscosity on food intake and body weight regulation. Further, there is good reason to believe that the viscosity of human breast milk and rat milk varies over time in a manner that is directly correlated with the milk's caloric and macronutrient content. It may be that the influence of viscosity on intake regulation of both species, during the early stages of life as well as during adulthood, depends on exposure to this relationship. Thus, additional experiments will examine the sensitivity of young rats to differences in diet viscosity and the age at which such sensitivity begins to influence food intake and body weight regulation. Further, we will examine the effects of experience, both early in life and later in adulthood, with foods that differ in viscosity and calories on subsequent intake regulation by viscosity, and will examine the importance of viscosity as a signal-modulating intake (compared to other sensory signals like taste). Finally, we will explore the mechanisms that may contribute to ability of differences in the viscosity food to produce differences in the regulation of food intake. A careful examination of the role of viscosity in regulation of food intake and body weight is particularly critical given the rapid rise in overweight during the last 20 years. This rise has been accompanied by large increases in the consumption of soft drinks, fruit juices and other beverages, that are high calorie, but low viscosity. Our studies will provide us the increased control afforded by the use of non-human subjects in order to directly test the hypothesis that high calorie, low viscosity foods may compromise the ability to effectively regulate intake, and thereby may contribute to recent trends toward obesity and overweight, including dramatic increases in the prevalence of childhood obesity. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The Surgeon General has stated that environmental and lifestyle changes may hold the most promise for the treatment of obesity. Gaps in knowledge about the physiological and behavioral control mechanisms on which dietary and environmental factors operate impede progress toward effective therapies. Thus, the goal of this Program Project is to integrate multi-disciplinary perspectives to investigate, using both human and rodent models, the environmental basis of obesity. It seems clear that under conditions where highly palatable, energy-rich, food is available continuously, energy balance depends on the ability to inhibit eating when food or stimuli associated with food are present. Examining how information provided by the cue properties of food can inhibit ingestive behavior is the central aim of this program project, with individual projects examining three levels of inhibitory control. First, inhibition of food intake may depend on the ability of orosensory stimuli, such as taste and flavor, to signal the nutritive consequences of eating. We will investigate the idea that animals use these sensory properties to anticipate the nutritive impact of foods, and that impairing this anticipatory response disturbs energy regulation. Second, we will study how signals that are detected by post-oral, gastrointestinal sensors are transmitted to the brain to suppress eating, and how the functions of these gut cues is influenced by dietary factors. Finally, the information provided by orosensory and gastrointestinal signals must be integrated and processed by the brain to produce adaptive behavioral outcomes. We will investigate the possibilities that inhibition of eating and appetitive behavior relies on the hippocampus, a brain structure that appears to play an important role in behavioral inhibition, and that certain dietary factors may promote energy dysregulation by impairing hippocampal function. Expertise in psychological, behavioral, biological, and food sciences will be integrated with the aim of discovering specific behavioral or dietary interventions that could strengthen or reinstate adaptive inhibitory control over eating and thus, ameliorate, stop, or reverse current trends toward obesity. An Administrative Core will provide statistical consulting, data management and other organizational support and will monitor and evaluate all program activities. The Analytical Core will oversee, coordinate, and standardize technological and behavior assays that are used by all Program Project personnel.

Project III: Hippocampal inhibition and obesity Although specification of physiological substrates will be central to any comprehensive account of food intake regulation, it is now clear that such accounts must also describe the role of learning and memory in the control of eating and appetitive behavior. As noted above, food intake regulation is likely to depend on the ability to inhibit responding to orosensory and other food related stimuli that are associated with rewarding post-ingestive consequences. New data and new interpretations of older findings suggest that this type of inhibitory ability may depend on the hippocampus, a brain structure long implicated as a substrate for learning and memory. Encouraged by a variety of physiological and behavioral evidence, Project III will evaluate the hypothesis that the regulation of food intake (and ultimately body weight) is, at least in part, a hippocampal-dependent function. Of special importance are findings that consumption of diets high in fat and/or processed sugars alters hippocampal neuronal activity and impairs the performance of rats on memory tasks that are thought to rely on hippocampus. These data suggest that dietary factors might contribute to overweight and obesity in humans by interfering with hippocampal-dependent inhibitory processes. Project III will evaluate this possibility in both rats and humans. This project will also study the effects of damage confined to selected regions of the hippocampus (e.g., dorsal, ventral, ventral pole) on intake and body adiposity and on sensitivity to neuropeptide signals that appear to mediate short-term meal termination (e.g., cholecystokinin) and longer term inhibition of feeding behavior (e.g., leptin, insulin). These hippocampal regions differ in terms of their connections to hypothalamic feeding control centers. This project will be directed by Dr. Davidson (PI), Department of Psychological Sciences, at Purdue University, in collaboration with Dr. Leonard Jarrard, Department of Psychology and Neuroscience Program, Washington &Lee University, and Drs. Stephen Benoit and Debra Clegg, Department of Psychiatry, University of Cincinnati Medical School.