A Translational Investigation of Anhedonia and its Underlying Neural Mechanisms

描述（由申请人提供）：情绪障碍是美国残疾的主要原因，对社会构成了巨大的负担。这项提议的广泛的、长期的目标是了解环境压力源如何促进情绪障碍及其行为表现的发展，如快感缺乏，在人类和大鼠中使用翻译方法。本建议的第一个目的是确定是否先前的生活压力源预测表现为重度抑郁发作的临床样本中的快感缺乏症状的表达。这一目标将通过使用客观的、基于实验室的生活压力和快感缺乏评估来衡量双相情感障碍受试者抑郁状态下这些因素的严重程度来实现。类似于人类状况的大鼠模型的发展将有助于研究导致这些疾病发展的神经生物学机制。因此，第二个目标是通过使用社会心理压力源诱发快感缺乏（心境障碍的核心症状）来开发和完善有效的抑郁样行为的临床前模型。这一目标将通过反复将老鼠暴露在社交失败中来实现，然后使用奖励和动机的定量操作测量来评估快感缺乏症。最后，内侧前额叶皮层（mPFC）某些区域的体积和活动减少以及GABA(B)受体功能失调与情绪障碍有关。因此，第三个目标是利用第二个目标的临床前模型来探索GABA(B)受体在mPFC中表达这些享乐和动机缺陷时的作用。这个目的的目的是发现新的药物治疗的神经生物学靶点。总的来说，这项工作与NIMH的使命是一致的，即“通过对精神、大脑和行为的研究来减轻精神疾病的负担”。公共卫生相关性：更好地了解与情绪障碍的沉淀和表达有关的因素将有助于开发更相关和有效的这些疾病的动物模型。这些模型将极大地促进1)我们对所涉及的潜在神经生物学机制的理解，2)发现针对这些机制的新型药物治疗。

DESCRIPTION (provided by applicant): Mood disorders are the leading cause of disability in the U.S. and constitute an immense burden on society. The broad, long-term objectives of this proposal are to understand how environmental stressors may precipitate the development of mood disorders and their behavioral manifestations, such as anhedonia, using a translational approach in both humans and rats. The first aim of this proposal is to determine whether prior life stressors predict the expression of anhedonic symptoms in a clinical sample that is presenting major depressive episodes. This goal will be accomplished by using objective, laboratory-based assessments of both life stress and anhedonia to measure the severity of these factors in bipolar subjects in a depressed state. The development of a rat model that is analogous to the human condition will facilitate the investigation of the neurobiological mechanisms responsible for the development of these disorders. Thus, the second aim is to develop and refine valid preclinical models of depression-like behaviors by using a psychosocial stressor to induce anhedonia, a core symptom of mood disorders. This goal will be accomplished by repeatedly exposing rats to social defeat, then assessing anhedonia using quantitative operational measures of reward and motivation. Finally, loss of volume and activity in certain regions of the medial prefrontal cortex (mPFC) and dysregulated GABA(B) receptor function are associated with mood disorders. Thus, the third aim is to use the preclinical model from the second aim to explore the role of GABA(B) receptors in the mPFC during the expression of these hedonic and motivational deficits. The goal of this aim is to discover novel neurobiological targets for pharmacotherapy. Collectively, this work is consistent with the mission of NIMH, which is to "reduce the burden of mental illness through research on mind, brain, and behavior." PUBLIC HEALTH RELEVANCE: A better understanding of the factors that are involved in the precipitation and expression of mood disorders will aid in the development of more relevant and valid animal models of these disorders. Such models will greatly facilitate 1) our understanding of the underlying neurobiological mechanisms that are involved and 2) the discovery of novel pharmacotherapies that target these mechanisms.