Functional Neuroimaging of Individual Differences in Affect and Motivation

描述（由申请人提供）：拟议的K23职业发展奖旨在培养有前途的候选人成为神经影像学，遗传学和情绪障碍的独立研究者，同时表征抑郁症遗传风险的神经生物学机制。候选人。候选人的教育和培训使他为这个项目做好了充分的准备。他在华盛顿大学读本科时对神经科学产生了兴趣，主修物理和生物。随后，他在密歇根大学获得了神经科学博士和医学博士学位。在他的论文项目中，他使用电生理学和计算技术来研究大脑皮层中声音感知的活动，在一项相关研究中，他研究了精神分裂症的听觉处理。他继续在密歇根大学接受精神病学住院医师和研究员的培训，在此期间，他被介绍到功能神经成像和情绪障碍的神经生物学。他最近被任命为密歇根大学精神病学助理教授。作为一名训练有素的神经科学家和精神病学家，他很适合从事以患者为导向的精神神经科学研究。为了实现完全的研究独立性，他确定了三个关键的培训目标：(1)指导情感障碍的转化神经科学研究，(2)功能磁共振成像（fMRI）实验的设计、执行和分析方面的培训，以及(3)发展分子遗传学的方法学专业知识。环境。拟议的K23项目将在密歇根大学精神病学和分子与行为神经科学研究所进行。该系和研究所得益于与其他单位的密切合作关系，包括生物工程、心理学、放射学和ctsa资助的密歇根临床与健康研究所。这个充满活力的研究环境包括充足的功能磁共振成像设备、基因分型资源和临床样本，它培养了一个不断扩大的转化精神病学研究小组。主要导师Jon-Kar Zubieta医学博士是一位富有成效和资金充足的神经科学家，他在神经成像和遗传学方面拥有超过15年的经验，并拥有指导初级研究人员的良好记录，其中包括最近的三位K奖获得者。该候选人还将受益于两位当地的共同导师，遗传学家Margit Burmeister博士和MRI物理学家Robert Welsh博士，以及三位精心挑选的顾问。研究。K23项目侧重于重度抑郁症（MDD）的神经生物学脆弱性，这是一种常见的、使人衰弱的、反复发作的脑部疾病，也是世界范围内的一个重大公共卫生问题。MDD被认为是由多种神经通路中的环境和遗传因素的相互作用引起的，但由于我们对人类回路水平的内表型的了解有限，进展受到阻碍。我们最近的研究结果表明神经肽Y （NPY）在负性情绪加工和重度抑郁症风险中的功能遗传变异，为进一步研究提供了线索。虽然NPY一直与回避行为和神经回路有关，但临床前数据也表明NPY在接近行为和神经回路（奖励、动机行为和食欲驱动）中起作用。我们的初步fMRI数据表明，NPY也会影响人类的神经通路，特别是涉及腹侧纹状体、内侧前额叶皮层以及这些区域的相互作用。NPY变化对接近电路和功能连通性的影响值得进一步研究。特异性目标1:NPY基因分型、血浆NPY和行为特征。我们拟招募240名健康受试者，按NPY基因型进行分类。我们将描述NPY变化对血浆NPY水平、动机行为和情绪特征的影响。（与培训目标1和3一致）具体目标2:NPY对奖赏回路和连通性的影响。我们将描述NPY对低表达或高表达的健康参与者的奖励加工和功能连接的影响（每组n=30）。我们将测试NPY是否会影响(i)在处理金钱损失和获得过程中奖励回路的激活，以及（ii）休息时功能连接的模式。（与培训目标2一致）总结。拟议的K23奖与NIH和PHS的使命非常一致。该项目将培养一名有前途的早期研究者成为临床转化神经科学家。与此同时，该项目将解决关于MDD遗传易感性的神经生物学的重要、可测试的问题，这是一个确定的公共卫生优先事项。

DESCRIPTION (provided by applicant): The proposed K23 career development award aims to train a promising candidate to become an independent investigator in neuroimaging, genetics, and mood disorders while characterizing neurobiological mechanisms that underlie genetic risk for depression. Candidate. The candidate's education and training have prepared him well for this project. His interest in neuroscience emerged as an undergraduate at the University of Washington, where he majored in Physics and Biology. He subsequently earned his MD and PhD in Neuroscience at the University of Michigan. For his thesis project, he employed electrophysiology and computational techniques to study activity in the cerebral cortex that underlies sound perception, and in a related study, he investigated auditory processing in schizophrenia. He continued his training in psychiatry residency and fellowship at the University of Michigan, during which he was introduced to functional neuroimaging and the neurobiology of mood disorders. He was recently appointed Assistant Professor of Psychiatry at the University of Michigan. As a trained neuroscientist and psychiatrist, he is well positioned for a career in patient-oriented psychiatric neuroscience research. To achieve full research independence, he has identified three key Training Objectives: (1) experience directing a translational neuroscience research study on affective disorders, (2) training in the design, execution, and analysis of functional magnetic resonance imaging (fMRI) experiments, and (3) development of methodological expertise in molecular genetics. Environment. The proposed K23 project will take place within the Department of Psychiatry and the Molecular & Behavioral Neuroscience Institute at the University of Michigan. The Department and Institute benefit from close collaborative relationships with other units including Bioengineering, Psychology, Radiology, and the CTSA-funded Michigan Institute for Clinical and Health Research. This vigorous research environment includes ample access to fMRI facilities, genotyping resources, and clinical samples, and it nurtures an expanding group of translational psychiatric researchers. The primary mentor, Jon-Kar Zubieta MD PhD, is a productive and well-funded neuroscientist who has more than 15 years of experience with neuroimaging and genetics, and an established track record of mentoring junior investigators, including three recent K awardees. The candidate will also benefit from two local co-mentors, geneticist Margit Burmeister PhD and MRI physicist Robert Welsh PhD, and three carefully chosen consultants. Research. The K23 project focuses on neurobiological vulnerability to major depressive disorder (MDD), a common, debilitating, recurrent brain illness, and a significant public health problem worldwide. MDD is thought to arise from the interaction of environmental and genetic factors within multiple neural pathways, but progress has been hindered by our limited understanding of circuit-level endophenotypes in humans. Our recent findings implicate functional genetic variation of neuropeptide Y (NPY) in negative emotional processing and risk for MDD, suggesting a way forward. While NPY has been consistently implicated in avoidance behavior and circuitry, preclinical data have also indicated a role in approach behavior and circuitry (reward, motivated behavior, and appetitive drive). Our preliminary fMRI data suggest that NPY influences approach circuitry in humans as well, specifically implicating ventral striatum, medial prefrontal cortex, and the interaction of these regions. The impact of NPY variation on approach circuitry and functional connectivity deserves further investigation. Specific Aim 1: NPY genotyping, plasma NPY, and behavioral characterization. We propose to recruit 240 healthy participants and classify them by NPY genotype. We will characterize the effects of NPY variation on plasma NPY levels, motivated behavior, and emotional traits. (Aligns with Training Objectives 1 and 3.) Specific Aim 2: Effects of NPY on reward circuitry and connectivity. We will characterize NPY effects on reward processing and functional connectivity in healthy participants classified as low- or high-expression (n=30 per group). We will test whether NPY influences (i) activation of reward circuitry differentially during processing of monetary loss versus gain and (ii) patterns of functional connectivity at rest. (Aligns with Training Objective 2.) Summary. The proposed K23 award is well aligned with the missions of the NIH and PHS. The project will train a promising early investigator to become a clinical translational neuroscientist. At the same time, the project will address important, testable questions about the neurobiology of genetic vulnerability to MDD, an identified public health priority.