Neural mechanisms underlying abnormal food reward processing in depressed women

描述（由申请人提供）：流行病学和行为学研究证明，重度抑郁症（MDD）和肥胖之间的共病在女性中尤其明显，甚至可能仅限于女性，即使控制了人口统计学变量。此外，肥胖重度抑郁症患者的治疗效果比健康体重的患者差。考虑到与这些情绪调节和食物摄入的共病障碍相关的重大健康负担，更好地描述已确定但尚未充分研究的重度抑郁症和肥胖之间的关系是很重要的。指导研究科学家发展计划的目的是帮助候选人实现以下目标：a)在情绪障碍的临床症状学和精神治疗方面获得经验，b)发展神经内分泌系统的知识基础，与情绪障碍和异常食物动机的研究相结合，c)获得fMRI数据高级建模方面的专家培训，d)增强她对下丘脑离散核中关键激素和神经肽信号的理解。与此同时，e)继续拓展她在精神疾病中大脑性别差异领域的技能。在Jill Goldstein博士（Brigham and Women's Hospital， BWH）大脑性别差异和激素在精神障碍中的作用方面的专家)、Anne Klibanski博士（Massachusetts General Hospital， MGH）神经内分泌学专家)、David Silbersweig博士（BWH， MDD神经精神病学专家）的有力指导下，Laura Miller博士（BWH的女性心理健康专家）和Susan Whitfield-Gabrieli博士（麻省理工学院的数学家，擅长先进的功能磁共振成像方法），候选人将通过结合功能神经成像和神经内分泌技术的跨学科方法，培养在情绪障碍和异常食物动机研究中获得独立的必要技能。该研究计划的目的是：1)利用功能磁共振成像（fMRI）描述肥胖的重度抑郁症女性与健康体重的重度抑郁症女性、健康体重的非重度抑郁症女性和肥胖的非重度抑郁症女性相比，大脑中与食物奖励相关的区域的激活模式的潜在差异；2)研究重度抑郁症和肥胖女性大脑皮层下兴趣区激活与HPA- / hpg轴激素和食欲调节肽的关系；3)检验关于重度抑郁症症状与a) HPA-/ hpg轴激素和食欲调节肽，以及b)重度抑郁症和肥胖女性食物奖励回路功能之间关系的假设。候选人的长期目标是与治疗专家合作，利用这些技术和从这些初步研究中获得的知识来设计预防、预测和治疗效果研究。BWH精神科和放射科、妇女健康科、MGH马蒂诺斯生物医学成像中心以及哈佛临床和转化科学中心提供的设施，为候选人提供了一个世界级的环境，使她能够执行她的职业发展计划活动和拟议的研究。

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.