Translational Measures of anhedonia in humans and rats

人类和大鼠快感缺失的转化测量

基本信息

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
项目类别：
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

项目摘要

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）与抑郁症易感性增加之间的联系。尽管临床前研究表明，早期压力源会对后代产生持久的神经生物学影响，包括改变人类的压力反应性和减弱的享乐反应性，但将压力和抑郁联系起来的确切机制在很大程度上尚不清楚。此外，由于缺乏对核心抑郁症状（例如快感缺失）的客观测量，阻碍了对抑郁症神经生物学的理解。拟议工作的目标是：（a）开发一种客观的快感缺失测量方法，定义为人类和大鼠在信号检测任务中对奖励相关线索的反应性降低； (b) 检验压力通过降低享乐能力来发挥抑郁作用的假设。为此，将评估早期不良事件，特别是婴儿期虐待和异常护理（人类成分）和早期产妇分离（动物成分）对奖励反应的影响。此外，在人类中，将通过 128 通道事件相关电位 (ERP) 记录来研究急性压力源对奖赏反应性和压力引起的享乐障碍的大脑机制的影响。该应用的一个特别独特和创新的方面将是使用一种基于实验室的新型测量方法来测量 40 名年轻人的享乐能力，从婴儿期开始进行纵向研究，他们的早期护理历史，特别是虐待和异常护理，已得到广泛的描述。在人类中，我们假设：（a）婴儿期的异常护理和儿童期虐待的严重程度都与奖励反应能力的下降有关； (b) 经历过早年逆境的抑郁症患者的奖赏反应能力受损最严重； (c) 由于促进奖励处理的皮质区域的激活减弱，急性应激源将导致享乐能力降低，并削弱与奖励相关的 ERP 幅度。在大鼠中，我们假设：（a）接受信号检测任务的动物，其中一种刺激得到不成比例的奖励，会对更频繁奖励的刺激产生反应偏差（即系统偏好）； (b) 过早与母亲分离会导致享乐能力减弱。总之，拟议的工作将利用人类和大鼠的享乐能力的客观和平行测量；将评估急性（实验室）和慢性（自然）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快感缺失有关的大脑区域。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转化工作提供基础，可能会导致人们更好地了解抑郁症的神经生物学和病因学，并改善这种使人衰弱的疾病的治疗方法。公共卫生相关性：流行病学研究强调压力在抑郁症发生和维持中的作用，但在人类中，压力和抑郁症之间联系的精确机制在很大程度上尚未被探索。当前的项目提出了一种人类和动物研究的新颖整合，以检验这样的假设：压力通过降低个体根据奖励线索调节行为的能力来增加抑郁风险。