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

描述(申请人提供)：严重抑郁障碍(MDD)终生患病率为16%，预计到2020年将成为美国第二大死亡和残疾原因。MDD的一个核心特征是奖赏加工缺陷，表现为奖赏动机降低和快感缺乏。这些缺陷与MDD中皮质纹状体网络的改变有关，但对可能导致这些变化的具体机制知之甚少。一种可能的机制是内侧前额叶谷氨酸(Glu)和GABA的变化，这两种物质最近都与MDD有关，也是MDD发展的关键风险因素，应激。然而，到目前为止，还没有研究提供对MDD或健康对照组的心理社会应激反应中Glu和GABA功能的体内评估。为了解决这个问题，该应用程序的K99阶段提出了以下培训目标。首先，为了培养在体内评估Glu和GABA所需的技术技能，候选人将从J.Eric Jensen博士(K99共同导师)和Dost Ong？r博士(顾问)那里学习磁共振波谱技术。这将包括完成一项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，候选人将通过与肯特·贝里奇博士(顾问)一起定向阅读来加深对Glu和GABA功能在奖励处理中的作用的理解，以及通过Ong？r博士指导阅读它们与情绪障碍的病理生理学的相关性。第三，他将通过应用强化学习范式和相关的Q-学习模型分析来加强他在研究生院培养的行为建模技能，这将由Michael Frank博士(顾问)指导；候选人还将每月参加Frank博士的实验室会议，以及他的课程“计算认知神经科学”。最后，候选人将接受他的主要导师Diego Pizzagalli博士在整合多模式成像数据、设计和分析实验室应激源以及为发展独立实验室做准备方面的指导和监督。在独立阶段，建议进行另外两项多模式成像研究，将在心理-社会应激源之前和之后对Glu和GABA功能的MRS评估与强化学习的fMRI测量相结合。这些研究的第一个将集中在 第二项研究将包括MDD患者和匹配对照组的样本。通过使用专注于两种主要神经递质的多模式成像，应激前操作和纳入对照组和MDD患者，拟议的研究将为了解Glu和GABA功能在MDD奖赏加工缺陷的病理生理学中的作用提供重要的新见解。

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.