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（由适用提供）：终生患病率为16％，重度抑郁症（MDD）预计到2020年将成为美国的第二大死亡和残疾。这些定义与MDD中皮质纹状体网络的变化有关，但是对可能导致这些变化的特定机制知之甚少。一种候选机制是培养基前谷氨酸（GLU）和GABA的改变，最近在MDD中都实施了它们，以及MDD开发的关键风险因素。然而，迄今为止，尚无研究对MDD或健康对照中的心理压力的GLU和GABA功能进行体内评估。为了解决这个问题，本申请的K99阶段提出以下培训目标。首先，为了开发评估GLU和GABA在体内所需的技术技能，候选人将从J. Eric Jensen博士（K99 Co-Incertor）和Dost Ong r博士（顾问）那里学习MR-Spectroscopy技术。这将涉及完成一项合并的MRS/FMRI研究，该研究将探索在健康参与者的加强学习过程中基线GLU和GABA功能与大胆的fMRI信号之间的关系。其次，候选人将通过与肯特·贝里奇（Kent Berridge）博士（顾问）的定向阅读来加深他对GLU和GABA功能在奖励处理中的作用的理解，并通过Ong¿r博士监督的阅读，与情绪障碍的病理生理学有关。第三，他将通过应用强化学习范式和相关的Q学习模型分析在研究生院发展的行为建模技巧，这将由迈克尔·弗兰克（Michael Frank）博士（顾问）进行监督；候选人还将每月参加弗兰克博士的实验室会议以及他的“计算认知神经科学”课程。最后，候选人将在其主要导师迭戈·帕萨加利（Diego Pizzagalli）博士的指导和监督下，在整合多模式成像数据，实验室压力源的设计和分析以及为开发独立实验室的发展准备方面。在独立阶段，提出了另外两项多模式成像研究，将MRS对GLU和GABA功能的评估与在心理社会压力源之前和之后的增强型学习的fMRI测量相结合。这些研究中的第一项将集中在在健康对照中，第二个将包括一个患有MDD和匹配对照的患者样本。通过使用集中于两个主要神经递质的多模式成像，前的应力操纵以及对照组和MDD患者的包含，该研究将为GLU和GABA功能在MDD中奖励处理定义的病理生理学中的作用提供重要的新见解。