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

项目摘要 严重抑郁障碍(MDD)的终生患病率为16%，预计将成为第二大 到2020年，成为美国主要的死亡和残疾原因。MDD的一个核心功能是奖励- 以奖励动机降低和快感缺乏为形式的加工缺陷。这些赤字一直是 与MDD中皮质纹状体网络的改变有关，但对其具体机制知之甚少 可能促成了这些变化。一个可能的机制是内侧前额叶谷氨酸(Glu)的变化。 和GABA，这两个最近都被认为与MDD有关，也是 MDD的发展，应激。然而，到目前为止，还没有研究提供对谷氨酸和GABA的体内评估。 MDD患者或健康对照组在应对心理社会压力时的功能。为了解决这个问题，K99 本申请阶段提出了以下培训目标。第一，为了发展技术技能 需要在体内评估Glu和GABA，候选人将从J.Eric博士那里学习磁共振波谱技术 Jensen(K99联合导师)和Dost Ongür博士(顾问)。这将涉及完成一项合并的 MRS/fMRI研究将探索基线Glu和GABA功能与BOLD fMRI之间的关系 健康参与者强化学习过程中的信号。其次，候选人将深化他的 通过与Dr的定向读数，了解Glu和GABA功能在奖赏处理中的作用。 肯特·贝里奇(顾问)以及他们与情绪障碍的病理生理学的相关性 由Ongür博士指导阅读。第三，他将建立在 通过应用强化学习范例和相关的Q-学习模型来学习研究生院 分析，将由Michael Frank博士(顾问)监督；候选人还将参加Frank博士的 每月一次的实验室会议，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博士的指导和监督 整合多模式成像数据，设计和分析实验室应激源，并为 发展一个独立的实验室。在独立阶段，两个额外的多模式成像 建议的研究将把谷氨酸和GABA功能的MRS评估与fMRI测量相结合 心理-社会应激源前后的强化学习。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。 通过使用多模式成像，集中在两种主要的神经递质上，一种应激前后的操作 并纳入对照和MDD患者，拟议的研究将提供重要的新见解 探讨谷氨酸和GABA功能在MDD奖赏加工缺陷的病理生理学中的作用。

Project Summary 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 Ongür (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. Ongür. 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.