Translational Measures of anhedonia in humans and rats

描述(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，特别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，早期应激源对后代产生了长期的神经生物学影响，包括改变的应激反应和迟钝的享乐反应，但在人类中，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，缺乏对核心抑郁症状的客观测量，如快感缺失，阻碍了对抑郁症神经生物学的理解。这项拟议工作的目标是：(A)在人类和大鼠身上开发一种关于快感缺失的客观衡量标准，定义为在信号检测任务中对与奖励相关的线索的反应降低；以及(B)测试压力通过降低享乐能力而产生抑郁效应的假设。为此，将评估早期不良事件，特别是婴儿期虐待和异常护理(人的部分)和早期母亲分离(动物部分)对奖励反应的影响。此外，在人类中，将通过128个通道的事件相关电位(ERP)记录来研究急性应激源对奖励反应的影响以及应激诱导的享乐性损伤背后的大脑机制。这一应用的一个特别独特和创新的方面将是使用一种新的基于实验室的享乐能力测量方法，在40名年轻人中进行纵向研究，从婴儿期开始，他们的早期照料史，特别是虐待和异常护理，已被广泛描述。在人类中，我们假设：(A)婴儿期的异常照顾和童年虐待的严重程度都与奖赏反应的降低有关；(B)经历过早期生活逆境的抑郁个体的奖赏反应将表现出最严重的受损；以及(C)急性应激源将导致享乐能力降低和对奖赏相关线索的事件相关电位幅度钝化，这是由于服务于奖赏处理的皮层区域的钝化激活。在大鼠中，我们假设：(A)暴露在信号检测任务中的动物，其中一个刺激得到不成比例的奖励，将形成对更频繁获得奖励的刺激的反应偏向(即，系统偏好)；以及(B)早期母体分离将导致迟钝的享乐能力。总而言之，这项拟议的工作将利用对人类和大鼠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)应激源对相同测量的影响；并将开始探索可能涉及应激诱导的快感丧失的大脑区域。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)方面拥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更好地理解抑郁症的神经生物学和病因，并改进这种令人衰弱的疾病的治疗。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，但在人类中，压力和抑郁症的确切机制在很大程度上尚未被探索。目前的项目提出了一种新的人类和动物研究的整合，以检验这一假设，即压力通过降低个体作为奖励线索调节行为的能力来增加抑郁的风险。

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.