Kellie L. Tamashiro - US grants

DESCRIPTION (provided by applicant): Exposure to stress elicits behavioral and physiological responses in animals and humans, including changes in food intake and body weight. This proposal will take advantage of a unique animal model of social stress, the Visible Burrow System (VBS). The VBS provides a semi-naturalistic environment in which a dominance hierarchy naturally develops among male rats producing dominant (DOM) and subordinate (SUB) animals that can be easily identified with minimal experimenter intervention. Although significant changes in body weight among the SUB group have been reliably observed, little if anything is known of its etiology. In addition, the long-term consequences of altered body weight regulation resulting from chronic social stress have not been examined in this model. The proposed experiments will lay the groundwork for understanding these and other stress-related conditions in humans and may point to novel therapeutic strategies. The specific aims are: 1) to test the hypothesis that body weight loss in subordinates during VBS housing is attributable to decreased food intake and/or to increases in energy expenditure, 2) to test the hypothesis that physiological, endocrine and neurochemical changes that are evident following 14 days of chronic stress in the VBS will return to control levels when the animals are allowed to recover outside the VBS. A secondary hypothesis is that SUB will gain weight during recovery preferentially as adipose tissue and DOM will gain weight primarily as lean body mass, 3) to test the hypothesis that multiple, intermittent episodes of social stress produce more severe and enduring changes of brain neurochemistry and energy homeostasis than a single episode.

[unreadable] DESCRIPTION (provided by applicant): Obesity is a major public health problem worldwide and recent work has suggested that exposure to a suboptimal early environment may increase the risk of becoming obese. Epidemiological data show that an unfavorable intrauterine environment has long-term consequences in offspring including hypertension, cardiovascular disease, type 2 diabetes, obesity and neuropsychiatric disease. Specifically, prenatal stress and/or consumption of a high fat diet, characteristics of modern day human lifestyle, have been shown to lead to metabolic disorders such as obesity and insulin resistance in offspring. However, the mechanisms involved are not well understood. The overall goal of this proposal is to characterize the short- and long-term effects of changes in the prenatal environment - stress and nutrition - on the behavioral and physiological development of offspring and to explore the possible neuropeptide and epigenetic mechanisms involved using a rat animal model. Specific aims are: 1) To determine the developmental time course of behavioral and endocrine alterations resulting from prenatal stress. We will also test the hypothesis that prenatal stress will accentuate diet-induced obesity. Time points during lactation, adolescence, and adulthood will be examined to characterize the phenotype and to direct examination of possible mechanisms; 2) To test the hypothesis that prenatal stress, high fat diet, or both result in alterations in neuropeptide systems regulating energy homeostasis that are consistent with other rodent models of obesity; and 3) To test the hypothesis that prenatal stress and nutrition results in obesity in offspring through epigenetic modifications via differential DNA methylation of genes that are critical to energy homeostasis. These experiments will enhance our understanding of the etiology of obesity and metabolic disease ultimately allowing the development of rational clinical interventions for such conditions. This proposal has also been structured to provide a rich and diverse training opportunity. The trainee has assembled a mentoring committee that will provide expertise in the development and regulation of ingestive behavior (Dr. Timothy Moran), neurobiology of stress and the hypothalamic-pituitary-adrenal axis (Dr. James Koenig) and the role of epigenetics in the etiology of disease (Dr. Andrew Feinberg and Dr. James Potash). The guidance of this committee in conjunction with the trainee's previous work in behavioral and molecular neuroendocrinology, will provide a solid foundation for the trainee to develop a multi-disciplinary program of research including behavioral, physiological, cellular/molecular, and genetic/epigenetic studies that will facilitate her transition to an independent investigator. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant: Anorexia nervosa (AN) is a severe eating disorder with a very high relapse rate and mortality. In addition to body image distortion, self-imposed eating restraint, serious weight loss, and fear of fat/weight gain, up to 80% of patients with AN are engaged in high levels of physical activity during the development of their eating disorders. One animal model that mimics several aspects of AN, including hyperactivity and voluntary reductions on food intake, is activity-based anorexia (ABA). In this rat model, animals have free access to running wheels and 1 h restricted access to food each day. During this free running and restricted food access schedule, rats become hyperactive and anorexic, and lose a significant amount of weight, and will eventually die of starvation if the scheduled is not terminated. Experience with ABA during adolescence increases anxiety-like behavior and facilitates food aversion learning in adulthood. These data suggest that adolescent experience with hyperactivity and food restriction has long- term behavioral consequences. The neurobiological mechanisms proposed involve brain regions that mediate stress and reward processes. We hypothesize that experience with AN-like behavior during adolescence could result in persistent epigenetic alterations in the brain that increase susceptibility to relapse of disordered behavior and contributes to the perpetuation of AN in patients. Combining the ABA animal model with a novel genome-wide epigenetic platform, Comprehensive High-throughput Array for Relative Methylation (CHARM), this proposal aims to determine the acute and long term consequences of ABA experience during adolescence on DNA methylation and gene expression in brain regions important to stress and reward. The experiments in this proposal will provide new information about the epigenetic consequences of adolescent experience with AN-like behavior and may facilitate development of more effective clinical therapy for AN and related eating disorders. PUBLIC HEALTH RELEVANCE: Anorexia Nervosa (AN) is a severe eating disorder for which there are no effective treatments. Adolescence is a critical period during development when many biological changes occur and can persist through adulthood. We will use an animal model of AN, activity-based anorexia (ABA), to determine the short- and long-term consequences of adolescent experience with ABA on epigenetic marks in the brain. The results of these experiments will provide new information about how AN develops and how the disease is maintained to identify novel targets in the brain that may be used to develop more effective treatment strategies for AN and related eating disorders.

Project Summary Cognition is a critical and complex higher brain function that controls behavioral outcomes. Several regions in the brain, including the prefrontal cortex and hippocampus, are involved in guiding key cognitive processes. Altered functioning in these brain areas lead to cognitive deficits which are core features in psychiatric disorders such as autism, schizophrenia and depression. Data from animal and human studies indicate that the prenatal environment plays a significant role in shaping neurocognitive development in offspring. Early life stress or low childhood socioeconomic status is associated with impaired cognitive functioning in adulthood. Studies also show that altered prenatal or postnatal nutrition (including under- /over-nutrition and nutritional imbalance) leads to cognitive deficits in adolescence and adulthood. Thus, what may appear to be distinct perturbations during gestation, i.e. maternal stress or altered maternal nutrition, can result in the same behavioral outcome in adolescent and adult offspring, i.e. cognitive deficits. The developmental mechanisms responsible for impaired cognitive function are not clear. Studies in humans and animal models have suggested the involvement of the neuroendocrine and immune systems in altering offspring brain development under conditions of prenatal stress or altered maternal nutrition and metabolic state during gestation. The finding that extracellular RNA (exRNA) molecules circulate, enter distant cells and alter their phenotype has transformed our notions of intercellular communication and opened new avenues of investigation for pathogenesis and biomarker studies. This proposal will utilize two animal models to determine whether exRNAs may be a route through which the early life environment affects brain development and cognitive performance. In addition, because exRNAs are present in circulating blood, we have the potential to identify peripheral biomarkers for assessing the trajectory of brain development. Such non-invasive biomarkers would have great value in both the clinic and the laboratory.