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，对社会构成巨大负担。该提案的广泛，长期目标是了解环境压力源如何加速情绪障碍及其行为表现的发展，例如快感缺乏，使用人类和大鼠的翻译方法。这个建议的第一个目的是要确定是否以前的生活压力预测表达的快感缺失症状的临床样本，是目前的严重抑郁发作。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实现，以测量抑郁状态下双相情感障碍受试者中这些因素的严重程度。类似于人类状况的大鼠模型的开发将促进对这些疾病发展的神经生物学机制的研究。因此，第二个目标是开发和完善有效的临床前抑郁样行为模型，通过使用心理社会应激诱导快感缺乏，情绪障碍的核心症状。这一目标将通过反复将大鼠暴露于社会失败，然后使用奖励和动机的定量操作措施评估快感缺失来实现。最后，内侧前额叶皮质（mPFC）某些区域的体积和活动的损失以及GABA（B）受体功能失调与情绪障碍有关。因此，第三个目的是使用第二个目的的临床前模型来探索GABA（B）受体在这些享乐和动机缺陷的表达过程中在mPFC中的作用。这一目标的目的是发现新的神经生物学药物治疗靶点。总的来说，这项工作与NIMH的使命是一致的，即“通过对心灵、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：更好地了解参与情绪障碍的沉淀和表达的因素将有助于开发这些疾病的更相关和有效的动物模型。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，以及2）发现针对这些机制的新型药物疗法。

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.