Functional Neuroimaging of Individual Differences in Affect and Motivation

描述(由申请者提供)：拟议的K23职业发展奖旨在培养一名有前途的候选人，成为神经成像、遗传学和情绪障碍的独立研究员，同时表征抑郁症遗传风险的神经生物学机制。候选人。候选人所受的教育和培训使他为这个项目做好了充分的准备。他对神经科学的兴趣是在华盛顿大学读本科时产生的，在那里他主修物理和生物学。随后，他在密歇根大学获得了神经科学博士和博士学位。在他的论文项目中，他使用了电生理学和计算技术来研究作为声音感知基础的大脑皮层的活动，在一项相关的研究中，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奖学金方面的培训，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学家和精神病学家，他为面向患者的精神神经科学研究事业做好了充分的准备。为了实现完全的研究独立性，他确定了三个关键培训目标：(1)指导情感障碍的翻译性神经科学研究的经验，(2)设计、执行和分析功能磁共振成像(FMRI)实验的培训，以及(3)发展分子遗传学的方法学专业知识。环境拟议中的K23项目将在密歇根大学精神病学系和分子与行为神经科学研究所内进行。该部门和研究所受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。这一充满活力的研究环境包括充足的fMRI设施、基因分型资源和临床样本，它培养了越来越多的翻译精神病学研究人员。主要导师Jon-Kar Zubieta医学博士是一位多产且资金雄厚的神经科学家，他在神经成像和遗传学方面拥有超过15年的经验，并有指导初级调查人员的既定记录，其中包括最近获得K奖的三人。这位候选人还将受益于两位当地的共同导师，遗传学家玛吉特·伯梅斯特博士和核磁共振物理学家罗伯特·威尔士博士，以及三名精心挑选的顾问。研究。K23项目的重点是严重抑郁障碍(MDD)的神经生物学脆弱性，MDD是一种常见的、衰弱的、反复发作的脑部疾病，也是全球范围内的一个重大公共卫生问题。MDD被认为是由于环境和遗传因素在多条神经通路中的相互作用而产生的，但由于我们对人类电路级内表型的有限了解，进展受到了阻碍。我们最近的发现表明神经肽Y(NPY)的功能性遗传变异与负性情绪处理和MDD的风险有关，并提出了一条前进的方向。虽然NPY一直与回避行为和回路有关，临床前数据也表明了在接近行为和回路(奖励、动机行为和食欲驱动)中的作用。我们的初步fMRI数据表明，NPY也影响人类的入路回路，特别是涉及腹侧纹状体、内侧前额叶皮质，以及这些区域的相互作用。神经肽Y变异对通路和功能连通性的影响值得进一步研究。具体目标1：NPY基因分型、血浆NPY和行为特征。我们建议招募240名健康参与者，并根据NPY基因型对他们进行分类。我们将描述NPY变异对血浆NPY水平、动机行为和情绪特征的影响。(与培训目标1和3保持一致。)具体目标2：NPY对奖赏回路和连接的影响。我们将确定NPY对低表达或高表达(每组30人)的健康参与者的奖励处理和功能连接的影响。我们将测试NPY是否影响(I)在金钱损失与收益的加工过程中奖赏回路的不同激活，以及(Ii)静止时的功能连接模式。(与培训目标2保持一致。)总结。拟议的K23奖项与NIH和PHS的任务非常一致。该项目将培养一位有前途的早期研究员，使其成为一名临床翻译神经科学家。与此同时，该项目将解决有关MDD遗传脆弱性的神经生物学的重要、可测试的问题，MDD是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.