Laura M. Holsen - US grants

DESCRIPTION (provided by applicant): The comorbidity between major depressive disorder (MDD) and obesity appears especially strong in and perhaps limited to females, even controlling for demographic variables, as evidenced by epidemiological and behavioral studies. Further, obese patients with MDD demonstrate worse treatment outcomes compared to healthy-weight counterparts. Given the significant health burden associated with these comorbid disturbances of emotion regulation and food intake, it is important to better characterize the identified but understudied relationship between MDD and obesity. The purpose of this Mentored Research Scientist Development Plan is to assist the candidate in achieving the following goals: a) gain experience in clinical symptomatology and psychiatric treatment of mood disorders, b) develop a knowledge base in the neuroendocrine system, integral to the study of mood disorders and abnormal food motivation, c) obtain expert training in advanced modeling of fMRI data, d) enhance her understanding of critical hormone and neuropeptide signaling in discrete hypothalamic nuclei, all while e) continuing to expand her skills in the field of sex differences in the brain in psychiatric disorders. Under the strong mentorship of Dr. Jill Goldstein [an expert on sex differences in the brain and the role of hormones in psychiatric disorders at Brigham and Women's Hospital (BWH)], Dr. Anne Klibanski [an expert in neuroendocrinology at Massachusetts General Hospital (MGH)], Dr. David Silbersweig (an expert in neuropsychiatry in MDD at BWH), Dr. Laura Miller (an expert in women's mental health at BWH) and Dr. Susan Whitfield-Gabrieli (a mathematician at Massachusetts Institute of Technology with expertise in advanced fMRI methodology), the candidate will develop requisite skills to gain independence in the study of mood disturbances and abnormal food motivation using an interdisciplinary approach combining functional neuroimaging and neuroendocrine techniques. The research plan aims to 1) delineate, using fMRI, potential differences in brain activation patterns in regions implicated in food reward in obese women with MDD compared with healthy-weight women with MDD, healthy-weight women without MDD, and obese women without MDD;2) identify relationships between brain activation in subcortical regions of interest and HPA- /HPG-axis hormones and appetite-regulatory peptides in women with MDD and obesity;and 3) test hypotheses regarding associations between MDD symptoms and a) HPA-/HPG-axis hormones and appetite-regulatory peptides, and b) food reward circuitry functioning, in women with MDD and obesity. The candidate's long term goal is to collaborate with treatment specialists to use these techniques and the knowledge gained from these initial studies to design prevention, prediction, and treatment efficacy studies. Facilities provided through the BWH Departments of Psychiatry and Radiology and Division of Women's Health, MGH Martinos Center for Biomedical Imaging, and Harvard Clinical and Translational Science Center, offer the candidate a world-class environment in which to execute her career development plan activities and proposed research. PUBLIC HEALTH RELEVANCE: Women are at a higher risk of developing major depressive disorder and obesity, the co-occurrence of which is associated with poor treatment outcomes. This project will better characterize the identified but understudied relationship between depression and obesity by examining abnormalities in brain regions related to food reward and hormones that regulate mood and appetite in women with depression and obesity. Understanding the shared brain and hormonal pathways that lead to depression and obesity in women will provide a basis for the development of sex-specific preventative approaches to treatment and ease the disease burden associated with this comorbid condition.

? DESCRIPTION (provided by applicant): The chronic disease course of obesity reflects interactions between etiological traits and factors involved in maintenance, of which stress-induced hyperphagia offers unique prognostic value. Although occasional intake of high-calorie foods in response to stress does not directly cause obesity, for some, repeated exposure to stress triggers hyperphagic behaviors such that homeostatic pathways are overridden in favor of mesolimbic reward signaling, culminating in weight gain and obesity. In its most severe state, stress-induced hyperphagia may manifest as hyperphagic depression (or chronic stress-induced hyperphagia; increased appetite/weight gain in an episode). Stress-induced hyperphagic behaviors stem, in part, from disruption in mesolimbic regions governing reward. Despite data on abnormal dopamine (DA) signaling in obesity and mood disorders, the pathophysiology of chronic stress-induced hyperphagia remains poorly understood. Preclinical work supports involvement of ghrelin, a gut peptide primarily recognized for its orexigenic properties, in modulating DA transmission and reward signaling - a role recently corroborated in human obesity. We showed, in women with chronic stress-induced hyperphagia, that ghrelin was significantly related to self-reported reward capacity and stress-related eating, and to ventral tegmental area and nucleus accumbens activity in response to food reward. We hypothesize that chronic stress-induced hyperphagia is promoted by ghrelinergic signaling in response to psychosocial stress, and that these ghrelin-specific effects are significantly associated with differential reward activity in and connectivity between mesolimbic regions. This proposal will address the following Specific Aims: 1. To assess relationships between ghrelin and BOLD activity/connectivity related to food reward after psychosocial stress in chronic stress-induced hyperphagia, chronic stress-induced hypophagia, euphagic depression, and healthy controls; 2. To examine associations between ghrelin and BOLD activity/connectivity related to monetary reward in mesolimbic circuitry during reward anticipation/receipt after psychosocial stress in chronic stress-induced hyperphagia, chronic stress-induced hypophagia, euphagic depression, and healthy controls. We will study mesolimbic circuitry using functional MRI to measure BOLD activity and connectivity during food and non-food reward tasks following psychosocial stress in individuals with chronic stress-induced hyperphagia, chronic stress-induced hypophagia, euphagic depression, and healthy controls. Our study will identify acute and chronic effects of stress on relationships between ghrelin and brain reward circuitry, determine specificity of ghrelin-related reward potentiation to food or generalization beyond food-related reward, and explore associations between these variables and intake during ad libitum access to palatable foods. Understanding these effects will provide a mechanistic explanation for the maintenance of obesity in the context of triggers such as psychosocial stress, potentially informing the design of behavioral and pharmacologic treatments.