Neuroscience of Reward-Related Learning and Memory in Depression

抑郁症中奖励相关学习和记忆的神经科学

基本信息

批准号：
8299722
负责人：
DANIEL G DILLON
金额：
$ 9万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299722
关键词：
Accounting Affect Algorithms Anhedonia Behavior Brain region Collection Computer Simulation Controlled Study Corpus striatum structure Cues Data Delayed Memory Depressed mood Diagnostic Diffusion Magnetic Resonance Imaging Dopamine Dorsal Faculty Failure Foundations Functional Magnetic Resonance Imaging Functional disorder Funding Heterogeneity Hippocampus (Brain)Hour Human Image Analysis Interview Laboratories Learning Literature Magnetic Resonance Imaging Major Depressive Disorder Mediating Memory Memory impairment Mental Depression Mentors Modeling Molecular Neurocognitive Neurosciences Occupations Operant Conditioning Outcome Participant Pathway interactions Patient Self-Report Phase Prefrontal Cortex Probability Psychological reinforcement Public Health Relative (related person)Reporting Research Research Training Rest Rewards Role Stimulus Symptoms Testing Time Training Ventral Striatum Work animal data classical conditioning cognitive neuroscience depressive symptoms dopaminergic neuron endophenotype experience hedonic infancy memory encoding memory process neural circuit patient oriented research pleasure positive emotional state psychologic response reward processing skills

项目摘要

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is a costly public health problem, and the diagnostic heterogeneity of MDD complicates treatment. One approach is to study endophenotypes, key facets of MDD that may involve dysfunction in discrete neural circuits. Anhedonia (loss of pleasure) is a promising endophenotype, but the neurocognitive mechanisms underlying this core symptom of MDD are unclear. The current application would test the hypothesis that failures of stimulus-reward and action-reward learning contribute to anhedonia. During the two-year K99 phase, the applicant will pursue four aims. First, in order to develop quantitative hypotheses about how MDD affects reinforcement learning, he wil learn computational modeling from Dr. Michael Frank (K99 co-mentor). With guidance from Dr. Frank and Dr. Diego Pizzagalli (K99 mentor), the K99 research funds will support collection of fMRI data from controls performing a rewarded Pavlovian conditioning task. This will lay the foundation for a study with MDD subjects in the R00 phase, while also providing valuable data that will be used to test temporal difference algorithms of reinforcement learning. To learn additional skills for the R00 phase, the applicant will also complete a semester-long "Computational Cognitive Neuroscience" course offered by Dr. Frank. Second, Dr. Nicholas Lange wil train the applicant to conduct diffusion tensor imaging analyses in order to probe the structural integrity and connectivity of brain regions implicated in memory and reward processing, and that may be degraded in MDD. Third, the applicant will pursue focused training in diagnostic interviewing, which will be invaluable when he transitions to independence and begins directing a laboratory focused on patient-oriented research. Fourth, with input from Dr. Pizzagalli and Dr. Frank, the applicant will develop an effective job talk and conduct a faculty jo search in order to establish a laboratory focused on reward-related learning and memory in MDD. During the independent phase, three functional magnetic resonance imaging (fMRI) studies of reward- related learning and memory in controls and MDD subjects will be conducted. The first study will focus on the ventral striatum and will use Pavlovian conditioning to examine effects of MDD on cue-reward contingency learning. The second study will focus on the dorsal striatum and will use instrumental conditioning to examine action-reward learning in MDD. The third study will involve explicit encoding of stimulus-reward associations, followed by delayed recall at two time-points, to investigate how MDD affects hippocampal-striatal interactions during encoding and consolidation of rewarding information. Finally, the MRI data from these studies will be pooled to determine whether anhedonia reflects weak functional or structural connections among the striatum, hippocampus, and regions of prefrontal cortex previously implicated in different facets of reward processing. The proposed combination of rigorous paradigms, computational models, and cutting-edge connectivity analyses has the potential to significantly advance understanding of the pathophysiology of MDD. PUBLIC HEALTH RELEVANCE: Depression is a costly public health problem, and it is difficult to treat because its pathophysiology is not well- understood. Anhedonia is a key symptom of depression that refers to the loss of pleasure or lack of reactivity to pleasurable stimuli. The gol of this project is to investigate the neurocognitive mechanisms implicated in anhedonia, so that these can ultimately be targeted for treatment.

描述（由申请人提供）：重度抑郁症（MDD）是一个昂贵的公共卫生问题，MDD的诊断异质性使治疗变得复杂。一种方法是研究内表型，MDD的关键方面，可能涉及离散神经回路功能障碍。 Anhedonia（失去愉悦）是一种有希望的内表型，但是MDD核心症状的神经认知机制尚不清楚。当前的应用将检验以下假设：刺激奖励和行动奖励学习的失败会导致抗议。在为期两年的K99阶段，申请人将追求四个目标。首先，为了建立有关MDD如何影响强化学习的定量假设，他将从Michael Frank博士（K99 Co-Ins-Encormor）学习计算建模。在Frank博士和Diego Pizzagalli博士（K99导师）的指导下，K99研究基金将支持从执行奖励的Pavlovian调节任务的控件中收集fMRI数据。这将为在R00阶段与MDD受试者进行研究奠定基础，同时还提供有价值的数据，这些数据将用于测试增强学习的时间差异算法。为了学习R00阶段的其他技能，申请人还将完成由Frank博士提供的一个学期“计算认知神经科学”课程。其次，尼古拉斯·兰格（Nicholas Lange）博士训练申请人进行扩散张量成像分析，以探测与记忆和奖励处理有关的大脑区域的结构完整性和连通性，并且可能会在MDD中降低。第三，申请人将在诊断面试中进行重点培训，当他过渡到独立性并开始指导专注于以患者为导向的研究的实验室时，这将是无价的。第四，在Pizzagalli博士和Frank博士的意见下，申请人将开展有效的工作谈话，并进行乔搜索的教师搜索，以建立专注于MDD中与奖励相关的学习和记忆的实验室。在独立阶段，将对对照组和MDD受试者进行奖励相关学习和记忆的三个功能磁共振成像（fMRI）研究。第一项研究将重点放在腹侧纹状体上，并将使用帕夫洛维亚的调节来检查MDD对提示 - 奖励意外学习的影响。第二项研究将重点放在背纹状体上，并将使用工具条件来检查MDD中的动作奖励学习。第三项研究将涉及刺激 - 奖励关联的明确编码，然后在两个时间点处延迟召回，以研究MDD在编码和巩固奖励信息期间如何影响海马 - 斜形相互作用。最后，将汇总来自这些研究的MRI数据，以确定ANHEDONIA是否反映了纹状体，海马室之间的功能弱或结构连接，以及先前与奖励处理不同方面相关的前额叶皮层区域。所提出的严格范式，计算模型和尖端连通性分析的组合具有显着提高对MDD病理生理学的理解。公共卫生相关性：抑郁症是一个昂贵的公共卫生问题，很难治疗，因为它的病理生理学尚不清楚。 Anhedonia是抑郁症的关键症状，它是指对愉悦刺激的愉悦感或缺乏反应性。该项目的GOL是研究涉及Anhedonia的神经认知机制，以便最终可以将其靶向治疗。