A Translational Investigation of Anhedonia and its Underlying Neural Mechanisms

点击翻译按钮获取中文摘要

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.