Translational Measures of anhedonia in humans and rats

人类和大鼠快感缺失的转化测量

• 批准号: 7529425
• 负责人: Diego A Pizzagalli
• 金额: $ 25.06万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529425
• 关键词: Abbreviations; Acute; Address; Adverse event; Anhedonia; Animal Model; Animals; Anterior; Applications Grants; Beck depression inventory; Behavior; Behavioral; Biological Models; Brain; Brain region; Caring; Child Abuse and Neglect; Childhood; Chronic; Classification; Clinical; Clinical Psychology; Collaborations; Condition; Conflict (Psychology); Cues; DSM-IV; Data; Depressed mood; Depressive disorder; Depth; Detection; Development; Discrimination; Disease; Dopamine; EP300 gene; Electroencephalography; Electromagnetics; Epidemiologic Studies; Etiology; Event; Event-Related Potentials; Exploratory/Developmental Grant; Failure; Food deprivation (experimental); Fostering; Functional disorder; Future; Genetic; Goals; Guidelines; HPSE gene; Human; Image; Impairment; Individual; Interview; Invasive; Investigation; Laboratories; Laboratory Rat; Lead; Learned Helplessness; Left; Life; Light; Link; Maintenance; Measures; Medial; Mediating; Mental Depression; Mental disorders; Mus; Neurobiology; Neurosciences; Participant; Patient Self-Report; Pharmacological Treatment; Phenotype; Plant Roots; Population; Predictive Value; Prefrontal Cortex; Procedures; Proteins; Psychological reinforcement; Public Health; Rat-1; Rattus; Recording of previous events; Reinforcement Schedule; Reporting; Research; Resolution; Rewards; Risk; Rodent; Rodent Model; Role; Scientist; Self Stimulation; Severities; Shock; Signal Transduction; Site; Stimulus; Stress; Structure; Sucrose; Symptoms; System; Techniques; Technology; Testing; Translations; Work; abuse neglect; acute stress; analog; base; brain pathway; caregiving; center for epidemiological studies depression scale; cingulate cortex; depressive symptoms; design; deviant; early experience; evaluation/testing; experience; hedonic; hemodynamics; human data; human study; hypothalamic pituitary axis; hypothalamic-pituitary-adrenal axis; improved; infancy; innovation; insight; maltreatment; maternal separation; neuroimaging; novel; novel therapeutics; pre-clinical; preclinical study; preference; research study; response; reward processing; socioeconomics; stressor; tomography; tool; translational approach; translational study; young adult

DESCRIPTION (provided by applicant): Depressive disorders are a major public health problem. Epidemiological studies have highlighted links between stress, particularly early adverse life events, and increased vulnerability to depression. Although preclinical studies indicate that early stressors exert long-lasting neurobiological effects on the offspring, including altered stress responsiveness and blunted hedonic responsiveness, in humans, the precise mechanisms linking stress and depression are largely unknown. Further, progress in understanding the neurobiology of depression is hindered by the lack of objective measures of core depressive symptoms, such as anhedonia. The goals of the proposed work are: (a) to develop an objective measure of anhedonia, defined as decreased responsiveness to reward-related cues in a signal-detection task, in both humans and rats; and (b) to test the hypothesis that stress exerts its depressogenic effects by reducing hedonic capacity. To this end, the effects of early adverse events, specifically maltreatment and deviant care in infancy (human component) and early maternal separation (animal component) on reward responsiveness will be evaluated. Further, in humans, the effects of an acute stressor on reward responsiveness and brain mechanisms underlying stress-induced hedonic impairments will be investigated through 128-channel event-related potential (ERP) recordings. A particularly unique and innovative aspect of this application will be the use of a novel laboratory-based measure of hedonic capacity in 40 young adults, studied longitudinally from infancy, whose early caregiving histories, in particular maltreatment and deviant care, have been extensively characterized. In humans, we hypothesize that: (a) both deviant care in infancy and severity of childhood maltreatment will be linked to decreased reward responsiveness; (b) depressed individuals who have experienced early life adversity will show the most impaired reward responsiveness; and (c) an acute stressor will lead to reduced hedonic capacity and blunted ERP amplitudes to reward-related cues, due to blunted activation in cortical regions subserving reward processing. In rats, we hypothesize that: (a) animals exposed to a signal detection task in which one stimulus is disproportionally rewarded, will develop a response bias (i.e., a systematic preference) towards the more frequently rewarded stimulus; and (b) early maternal separation will lead to blunted hedonic capacity. In summary, the proposed work will utilize objective and parallel measures of hedonic capacity in humans and rats; will assess the effects of acute (laboratory) and chronic (naturalistic) stressors on the same measures; and will begin the exploration of brain regions that may be involved in stress-induced anhedonia. By creating a partnership between scientists with expertise in human neuroscience (Dr. Pizzagalli), animal neuroscience (Dr. Markou), and clinical psychology (Dr. Lyons-Ruth), this work will provide the building blocks for future interdisciplinary and translational work that may lead to a better understanding of the neurobiology and etiology of depression, and improved treatments for this debilitating disease. PUBLIC HEALTH RELEVANCE: Epidemiological studies emphasize the role of stress in the development and maintenance of depression, but in humans the precise mechanisms linking stress and depression are largely unexplored. The current project proposes a novel integration of human and animal studies to test the hypothesis that stress increases the risk for depression by reducing the individual's the ability to modulate behavior as a function of rewarding cues.

描述（由申请人提供）：抑郁症是一个主要的公共卫生问题。流行病学研究强调了压力，尤其是早期不良生活事件与抑郁症的脆弱性之间的联系。尽管临床前研究表明，早期的压力源对后代发挥持久的神经生物学作用，包括改变压力反应性和耻辱性的享乐反应性，在人类中，将压力和抑郁症联系在一起的确切机制在很大程度上是未知的。此外，缺乏核心抑郁症状（例如Anhedonia）的客观度量，理解抑郁症的神经生物学的进展受到了阻碍。拟议的工作的目标是：（a）在人类和大鼠中，在信号检测任务中对与奖励相关的提示的响应性降低定义为降低对奖励相关的提示的客观度量； （b）检验以下假设，即应力通过降低享乐能力来发挥其降低作用。为此，将评估早期不良事件的影响，特别是婴儿期（人类成分）和早期母体分离（动物成分）对奖励反应性的影响。此外，在人类中，急性应激源对应力引起的享乐障碍的奖励反应能力和大脑机制的影响将通过128频道事件相关电位（ERP）记录进行研究。该应用程序的一个特别独特和创新的方面将是在40名年轻人中使用一种新型的基于实验室的享乐主义措施，这些度量是从婴儿期开始纵向研究的，他们的早期护理历史，尤其是虐待和偏见的护理，已经广泛地表征了。在人类中，我们假设：（a）婴儿期的偏差护理和儿童虐待的严重程度将与奖励反应能力下降有关； （b）经历过早期逆境的沮丧的人将表现出最大的奖励反应能力； （c）急性应激源将导致享乐设施的能力降低，并使ERP振幅趋于奖励相关线索，这是由于皮质区域中钝化的激活而导致的奖励处理。在大鼠中，我们假设：（a）暴露于信号检测任务的动物，其中一种刺激受到了不成比例的奖励，将对更频繁地奖励的刺激产生响应偏见（即系统的偏爱）； （b）早期的产妇分离将导致享乐率钝化。总而言之，拟议的工作将利用人类和大鼠的享乐能力的客观和平行度量。将评估急性（实验室）和慢性（自然主义）压力源对相同措施的影响；并将开始探索可能与压力引起的抗抗甲基菌有关的大脑区域。通过在人类神经科学（Pizzagalli博士），动物神经科学（Markou博士）和临床心理学（Lyons-Ruth博士）方面具有专业知识的科学家之间建立合作伙伴关系，这项工作将为未来的跨学科和翻译工作提供基础，这些工作可能会导致对抑郁症的神经生物学和病学治疗的更好的理解，并为这种疾病的病学治疗，并为这种折衷的疾病而言。公共卫生相关性：流行病学研究强调压力在抑郁症的发展和维持中的作用，但是在人类中，将压力和抑郁症联系起来的确切机制在很大程度上没有探索。当前的项目提出了人类和动物研究的新型整合，以检验以下假设，即压力通过降低个人调节行为的能力来增加抑郁症的风险，这是奖励提示的函数。