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Stress and MDD effects on mPFC Glutamate and GABA during reward processing

奖励处理过程中压力和 MDD 对 mPFC 谷氨酸和 GABA 的影响

基本信息

批准号：
8788444
负责人：
Michael Tilghman Treadway
金额：
$ 3.23万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-26 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788444
关键词：
Address Affective Age Amino Acids Aminobutyric Acids Anhedonia Animal Model Behavior assessment Behavioral Model Behavioral inhibition Biological Psychiatry Cause of Death Corpus striatum structure Data Decision Making Depressed mood Development Environment Equilibrium Evaluation Functional Magnetic Resonance Imaging Functional disorder Gender Glutamates Goals Health Hormonal Human Hydrocortisone Individual Individual Differences Laboratories Learning Link Literature Magnetic Resonance Spectroscopy Major Depressive Disorder Measures Medial Mediating Mediator of activation protein Mental disorders Mentors Modeling Mood Disorders Motivation Multimodal Imaging Neurotic Disorders Neurotransmitters Operant Conditioning Participant Patient Self-Report Patients Performance Phase Prefrontal Cortex Preparation Prevalence Process Protons Psychological reinforcement Psychosocial Stress Punishment Reading Relative (related person)Research Rest Rewards Risk Factors Role Salivary Sampling Scanning Schools Signal Transduction Stress Supervision Symptoms Techniques Testing Training United States Work acute stress base behavior measurement cognitive neuroscience depressive behavior depressive symptoms design disability in vivo insight learned behavior meetings neuroimaging neurotransmission response reward processing skills social social stress stressor trait

项目摘要

DESCRIPTION (provided by applicant): With a lifetime prevalence of 16%, Major Depressive Disorder (MDD) is predicted to become the second leading cause of death and disability in the United States by the year 2020. A core feature of MDD is reward- processing deficits in the form of decreased reward motivation and anhedonia. These deficits have been linked to alterations in corticostriatal networks in MDD, but less is known about the specific mechanisms that may contribute to these changes. One candidate mechanism is alterations in medial prefrontal glutamate (Glu) and GABA, both of which have recently been implicated in both MDD, as well as a key risk-factor for the development of MDD, stress. To date however, no study has provided an in vivo assessment of Glu and GABA function in response to psychosocial stress in MDD or in healthy controls. To address this question, the K99 phase of this application proposes the following training goals. First, in order to develop the technical skills needed to assess Glu and GABA in vivo, the candidate will learn MR-Spectroscopy techniques from Dr. J. Eric Jensen (K99 Co-mentor) and Dr. Dost Ong¿r (Consultant). This will involve the completion of a combined MRS/fMRI study that will explore the relationships between baseline Glu and GABA function and BOLD fMRI signals during reinforcement learning in healthy participants. Second, the candidate will deepen his understanding of the role of Glu and GABA function in reward processing through directed readings with Dr. Kent Berridge (Consultant) as well as their relevance to the pathophysiology of mood disorders through readings supervised by Dr. Ong¿r. Third, he will build upon his behavioral modeling skills developed in graduate school through the application of a reinforcement learning paradigm and associated Q-learning model analysis, which will be supervised by Dr. Michael Frank (Consultant); the candidate will also attend Dr. Frank's lab meetings on a monthly basis as well as his course "Computational Cognitive Neuroscience". Finally, the candidate will receive guidance and supervision from his primary mentor, Dr. Diego Pizzagalli, in the integration multimodal imaging data, design and analysis of laboratory stressors, and preparation towards the development of an independent laboratory. During the independent phase, two additional multimodal imaging studies are proposed that will combine MRS assessment of Glu and GABA function with fMRI measures of reinforcement learning both before and after a psycho-social stressor. The first of these studies will be focused on healthy controls, while the second will include a sample of patients with MDD and matched controls. Through its use of multimodal imaging focused on two major neurotransmitters, a pre-post stress manipulation and inclusion of both controls and MDD patients, the proposed research will provide important new insights into the role of Glu and GABA function in the pathophysiology of reward processing deficits in MDD.

描述（由申请人提供）：重度抑郁症 (MDD) 的终生患病率为 16%，预计到 2020 年将成为美国死亡和残疾的第二大原因。MDD 的一个核心特征是奖励处理缺陷，表现为奖赏动机下降和快感缺乏。这些缺陷与 MDD 皮质纹状体网络的改变有关，但人们对可能导致这些变化的具体机制知之甚少。一种候选机制是内侧前额叶谷氨酸 (Glu) 和 GABA 的改变，这两种物质最近都与 MDD 以及压力形成 MDD 的关键风险因素有关。然而，迄今为止，尚无研究对 MDD 或健康对照者应对社会心理压力的 Glu 和 GABA 功能进行体内评估。为了解决这个问题，本应用的K99阶段提出了以下训练目标。首先，为了培养体内评估 Glu 和 GABA 所需的技术技能，候选人将从 J. Eric Jensen 博士（K99 联合导师）和 Dost Ong¿ 博士（顾问）学习 MR 光谱技术。这将涉及完成 MRS/fMRI 联合研究，该研究将探索健康参与者强化学习期间基线 Glu 和 GABA 功能与 BOLD fMRI 信号之间的关系。其次，考生将通过 Kent Berridge 博士（顾问）的指导阅读，加深对 Glu 和 GABA 功能在奖励处理中的作用的理解，以及通过 Ong¿ 博士指导的阅读，加深对 Glu 和 GABA 功能与情绪障碍病理生理学的相关性的理解。第三，他将通过应用强化学习范式和相关的 Q 学习模型分析，以在研究生院培养的行为建模技能为基础，该技能将由 Michael Frank 博士（顾问）监督；候选人还将参加弗兰克博士每月的实验室会议以及他的课程“计算认知神经科学”。最后，候选人将在整合多模态成像数据、实验室压力源的设计和分析以及为独立实验室的发展做好准备方面得到其主要导师Diego Pizzagalli博士的指导和监督。在独立阶段，提出了两项额外的多模态成像研究，将 Glu 和 GABA 功能的 MRS 评估与心理社会压力源前后的强化学习的 fMRI 测量结合起来。第一项研究将集中于第二个将包括重度抑郁症患者样本和匹配的对照。通过使用专注于两种主要神经递质的多模态成像、前后应激操纵以及纳入对照组和 MDD 患者，拟议的研究将为 Glu 和 GABA 功能在 MDD 奖励处理缺陷的病理生理学中的作用提供重要的新见解。