Influence of GABA on reinforcement learning in individuals with current and remitted depression

GABA 对当前和缓解抑郁症患者强化学习的影响

基本信息

批准号：
8969749
负责人：
POORNIMA KUMAR
金额：
$ 18.16万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969749
关键词：
Abate Age Anhedonia Animal Model Animals Basal Ganglia Behavior Behavioral Brain region Characteristics Complex Computer Simulation Decision Making Depressed mood Development Disease Disease remission Dopamine Exhibits Failure Functional Magnetic Resonance Imaging Functional disorder Goals Guilt Habenula Human Hyperactive behavior Image Imaging Techniques Individual Intervention Lateral Learning Learning Disorders Left Link MRI Scans Magnetic Resonance Spectroscopy Major Depressive Disorder Measurement Measures Medial Mental Depression Modeling Molecular Multimodal Imaging Nature One-Step dentin bonding system Organism Participant Pattern Performance Prefrontal Cortex Prevalence Process Psychological reinforcement Punishment Recurrence Relapse Relative (related person)Reporting Research Resolution Rewards Role Signal Transduction Social Reinforcement Symptoms System Techniques Testing Therapeutic Intervention Translating Update Ventral Tegmental Area Work animal data base burden of illness design disability dopaminergic neuron effective therapy gamma-Aminobutyric Acid heuristics innovation neural correlate neurobiological mechanism neuroimaging novel novel therapeutic intervention pre-clinical public health relevance stem theories trait transmission process

项目摘要

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is one of the leading causes of disease burden worldwide and is characterized by a high relapse rates. In spite of decades of research, findings have not translated into a reliable model of MDD that can be used to test novel therapeutic interventions. This modest progress might partially stem from the heterogeneous nature of MDD and the fact that animal models cannot probe key symptoms of MDD, including depressed mood, guilt or rumination. Within the context of reinforcement learning (RL) theories, anhedonia, depressed mood, inability to make decisions and excessive guilt may be explained by deficits in learning about rewards and punishments and a failure to update behavior accordingly. Consistent with this theory, MDD individuals show reduced reward and increased punishment learning. Of note, reduced reward responsiveness might persist after remission, whereas punishment processing normalizes when symptoms abate, suggesting that abnormal reward, but not punishment, learning might represent a trait marker of MDD. In spite of these promising leads, the neurobiological mechanisms underlying these dysfunctions remain unknown. Critically, animal studies have shown that dopamine (DA) transmission in the ventral tegmental area (VTA) and gamma-aminobutyric acid (GABA) signals originating from the lateral habenula (LHb), as well as interactions between these systems, influences RL. These interactions modulate DA release and basal ganglia (BG) activity, which helps organisms to choose or avoid an action. Despite compelling evidence from animal studies for these interactions, these processes have not been tested in MDD. The goal of the proposed research is to fill this critical gap and take us one-step closer to developing a mechanistic model of RL dysfunction in MDD. To achieve this goal, we will integrate an innovative multi-modal molecular and functional neuroimaging approach to test RL in 60 subjects (20 HC, 20 MDD and 20 rMDD). To this end, baseline GABA levels in the BG will be measured using a novel multi-voxel MRS technique, followed by an fMRI session while participants complete a social RL task. This will allow us to investigate the neural correlates of learning deficits in MDD and the influence of GABA on RL. We hypothesize that controls will exhibit reward learning signals in the BG and punishment signals in the LHb. Consistent with our proposal that MDD is an RL disorder, we hypothesize that MDD will show blunted reward and punishment signals in the BG and LHb, respectively. This abnormal pattern in MDD will be linked to enhanced punishment and reward signals in the BG and LHb, respectively. In addition, parsing state/trait effects of MDD, we hypothesize that reward and not punishment learning deficit will be observed in rMDD. Lastly, we hypothesize that baseline GABA levels will predict RL in all groups.

描述（由申请人提供）：重度抑郁症 (MDD) 是全世界疾病负担的主要原因之一，其特点是复发率高。尽管经过了数十年的研究，研究结果尚未转化为可靠的 MDD 模型。这种适度的进展可能部分源于MDD的异质性，以及动物模型无法在强化学习（RL）的背景下探究MDD的关键症状，包括抑郁情绪、内疚或沉思。）值得注意的是，MDD 个体表现出奖励和惩罚学习的减少和惩罚学习的增加。缓解后，奖励反应性的降低可能会持续存在，而当症状减轻时，惩罚处理就会正常化，这表明异常的奖励而非惩罚学习可能代表了 MDD 的特征标记。尽管有这些有希望的线索，但这些功能障碍背后的神经生物学机制仍然存在。重要的是，动物研究表明，腹侧被盖区 (VTA) 中的多巴胺 (DA) 信号和源自外侧缰核 (LHb) 的伽玛氨基丁酸 (GABA) 信号以及这些系统之间的相互作用会影响 RL。这些相互作用调节 DA 释放和基底神经节 (BG) 活性，从而帮助生物体选择或避免某种行为，尽管动物研究提供了这些相互作用的令人信服的证据，但这些过程尚未在 MDD 中得到测试。拟议研究的目标是填补这一关键空白，让我们更接近开发 MDD RL 功能障碍的机制模型。为了实现这一目标，我们将整合一种创新的多模式分子和功能神经影像方法进行测试。为此，将使用新型多体素 MRS 技术测量 60 名受试者（20 名 HC、20 名 MDD 和 20 名 rMDD）的 RL，然后进行功能磁共振成像 (fMRI)。参与者完成社交 RL 任务，这将使我们能够研究 MDD 中学习缺陷的神经相关性以及 GABA 对 RL 的影响。我们发现，对照将在 BG 中表现出奖励学习信号，在 LHb 中表现出惩罚信号。我们认为 MDD 是一种 RL 障碍，我们认为 MDD 将分别在 BG 和 LHb 中表现出钝化的奖励和惩罚信号，MDD 中的这种异常模式将与 BG 和 LHb 中增强的惩罚和奖励信号相关。此外，在解析 MDD 的状态/特质效应时，我们追求在 rMDD 中观察到奖励而不是惩罚学习缺陷。最后，我们追求基线 GABA 水平将预测所有组的 RL。