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（由适用提供）：重度抑郁症（MDD）是伯恩伯恩（Burnen）疾病的主要原因之一，其特征是高继电器率。尽管进行了数十年的研究，但发现并未转化为可靠的MDD模型，该模型可用于测试新型的治疗干预措施。这种适度的进步可能部分源于MDD的异质性质，而动物模型无法探测MDD的关键症状，包括情绪低落，内gui或反省。在强化学习（RL）理论的背景下，可以通过确定学习奖励和惩罚以及未能相应地更新行为来解释，可以解释出Anhedonia，Anhedonia，沮丧的情绪，无法做出决策和过度的内gui。与该理论一致，MDD个人表现出减少的奖励和惩罚学习的减少。值得注意的是，减少的奖励反应能力可能会在缓解后持续存在，而在症状减轻时进行惩罚的处理归一化，表明奖励异常但不是惩罚，学习可能代表了MDD的特质标记。尽管有这些承诺导致这些功能障碍的神经生物学机制，但这些功能障碍仍然未知。至关重要的是，动物研究表明，腹侧对段区域（VTA）和γ-氨基丁酸（GABA）信号的多巴胺（DA）传播来自源自外侧Habenula（LHB）的信号，以及这些系统之间的相互作用，影响RL。这些相互作用调节DA释放和基本神经节（BG）活动，这有助于有机体选择或避免作用。尽管动物研究中有令人信服的证据证明了这些相互作用，但这些过程尚未在MDD中进行测试。拟议的研究的目的是填补这一关键空白，并使我们更接近开发MDD中RL功能障碍的机械模型。为了实现这一目标，我们将集成创新的多模式分子和功能性神经影像学方法，以测试60名受试者（20 HC，20 MDD和20 RMDD）中的RL。为此，BG中的基线GABA水平将使用新颖的多素MRS技术进行测量，然后进行fMRI会议，而参与者完成社交RL任务。这将使我们能够研究MDD学习缺陷的神经元相关性以及GABA对RL的影响。我们假设控件将在BG中显示出奖励学习信号，并在LHB中表现出惩罚信号。与我们关于MDD是RL障碍的建议一致，我们假设MDD分别在BG和LHB中显示出钝的奖励和惩罚信号。 MDD中的这种异常模式将分别与BG和LHB中的惩罚和奖励信号有关。此外，在RMDD中将观察到MDD的解析状态/性状效应，我们假设将观察到这种奖励而不是惩罚学习防御。最后，我们假设基线GABA水平将预测所有组的RL。