A Translational Investigation of Anhedonia and its Underlying Neural Mechanisms

快感缺乏及其潜在神经机制的转化研究

基本信息

批准号：
7693743
负责人：
ANDRE DER-AVAKIAN
金额：
$ 5.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2008-09-18 至 2011-09-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7693743
关键词：
Accounting Anhedonia Animal Model Attenuated Basic Science Behavior Behavioral Bipolar Disorder Chronic Clinical Complex Data Collection Depressed mood Detection Development Diagnosis Disease Environmental Risk Factor Etiology Event Exposure to Functional disorder GABA-B Receptor Generations Goals Human Investigation Laboratories Life Life Stress Lithium Measures Medial Mediating Mental disorders Microinjections Mind Mission Modeling Mood Disorders Motivation National Institute of Mental Health Neurobiology Outcome Patients Pharmacotherapy Phase Pre-Clinical Model Precipitation Prefrontal Cortex Process Psychosocial Stress Rattus Regulation Reinforcement Schedule Relative (related person)Research Research Design Rewards Role Sampling Schedule Self Stimulation Severities Signal Transduction Societies Stress Symptoms Testing Training Unipolar Depression Work base brain behavior clinically relevant depressed depression depressive symptoms disability environmental stressor experience hedonic innovation insight monoamine multidisciplinary neurobiological mechanism neuromechanism neurotransmission novel pleasure psychosocial public health relevance receptor receptor function research clinical testing response single episode major depressive disorder social stressor translational approach

项目摘要

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.

描述（由申请人提供）：情绪障碍是美国残疾的主要原因，并对社会构成巨大负担。该提案的广泛、长期目标是利用人类和大鼠的转化方法，了解环境压力源如何促进情绪障碍及其行为表现（例如快感缺乏）的发展。该提案的第一个目的是确定以前的生活压力源是否可以预测出现重度抑郁发作的临床样本中快感缺失症状的表达。这一目标将通过对生活压力和快感缺乏进行客观的、基于实验室的评估来衡量这些因素在抑郁状态下的双相情感障碍对象的严重程度来实现。开发类似于人类状况的大鼠模型将有助于研究导致这些疾病发生的神经生物学机制。因此，第二个目标是通过使用社会心理压力源诱发快感缺失（情绪障碍的核心症状）来开发和完善抑郁症样行为的有效临床前模型。这一目标将通过反复让老鼠遭受社会失败，然后使用奖励和动机的定量操作措施来评估快感缺失来实现。最后，内侧前额叶皮层 (mPFC) 某些区域的体积和活性丧失以及 GABA(B) 受体功能失调与情绪障碍有关。因此，第三个目标是使用第二个目标的临床前模型来探索 mPFC 中 GABA(B) 受体在这些享乐和动机缺陷表达过程中的作用。该目标的目标是发现药物治疗的新神经生物学靶点。总的来说，这项工作与 NIMH 的使命是一致的，即“通过对心智、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：更好地了解情绪障碍的沉淀和表达所涉及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）针对这些机制的新型药物疗法的发现。