Central Motivation of Depression; An Expanded Kynurenine Theory

修改项目摘要/摘要部分 重度抑郁症是一种主观情绪状态，导致情绪下降，失去科普压力生活事件的能力，并降低体验快乐的能力。抑郁症的发病率在全球范围内不断增加，并且患有抑郁症的患者中有很大比例具有激活的先天免疫系统的潜在共病状况。临床数据已经表明，抑郁情绪的症状是由细胞因子给药引起的。此外，临床前模型表明，生理应激源，包括心理应激或感染，诱导炎症细胞因子的产生，随后出现抑郁样行为。现在普遍认为抑郁症的症状与全身炎症有关。消极情绪、快感缺乏和疲劳都是由炎症事件引起的抑郁症的症状。然而，这些标准具有不同的精神病理学结构，表明负责特定症状的离散炎症依赖性途径。到目前为止，这些依赖于β-内酰胺酶的途径的生物学基础还没有得到表征。该提案中的实验将建立在我们的发现基础上，即色氨酸通过不同的吲哚胺2，3-双加氧酶（IDO）依赖性途径代谢，这些途径是唯一负责动机行为（快感缺乏和疲劳）和诱导负面影响（无助/绝望）的缺陷。三个重叠的领域将进行调查，以确定色氨酸代谢在抑郁症的具体症状的作用。在目标1中，我们将使用临床前遗传和药理学Ido floxed小鼠模型来表征负面影响所需的色氨酸代谢途径。在目标2中，将使用floxed小鼠来阐明色氨酸代谢在动机行为中的作用。在目标3中，我们将定义与抑郁症特定症状相关的特定脑区域内色氨酸代谢的调节，重点是纹状体和海马。这些令人兴奋和新颖的实验将是第一个将色氨酸代谢的神经免疫调节与重度抑郁症的特定症状相结合的实验。这一努力是基于神经病学开发治疗抑郁症新靶点的第一步。

Modified Project Summary/Abstract Section Major depression is a subjective emotional state resulting in decreased mood, loss of ability to cope with stressful life events and reduced ability to experience pleasure. The incidence of major depression is increasing worldwide, and a significant proportion of patients suffering from major depression have an underlying comorbid condition of an activated innate immune system. Clinical data have already shown that symptoms of depressed mood are elicited by cytokine administration. Also, preclinical models show that physiological stressors, including psychological stress or infection, induce the production of inflammatory cytokines followed by depression-like behaviors. It is now generally accepted that symptoms of depression are associated with systemic inflammation. Negative affect, anhedonia and fatigue are all symptoms of depression that are induced by inflammatory events. However, these criteria possess distinct psychopathological constructs, suggesting discrete inflammation-dependent pathways responsible for specific symptoms. To date, the biological underpinnings of these symptom-dependent pathways have eluded characterization. The experiments in this proposal will build on our discovery that tryptophan is metabolized through divergent indolamine 2,3-dioxygenase (IDO)-dependent pathways that are uniquely responsible for deficits in motivated behavior (anhedonia and fatigue) and induction of negative affect (helplessness/despair). Three overlapping areas will be investigated to define the role of tryptophan metabolism in specific symptoms of depression. In Aim 1, we will use preclinical genetic and pharmacological Ido floxed mouse models to characterize the tryptophan metabolizing pathways necessary for negative affect. In Aim 2, floxed mice will then be used to clarify the role of tryptophan metabolism in motivated behaviors. In Aim 3, we will define the regulation of tryptophan metabolism within specific brain regions relative to specific symptoms of depression, focusing on the striatum and hippocampus. These exciting and novel experiments will be the first to integrate neuroimmune regulation of tryptophan metabolism with specific symptoms of major depression. This effort is the first step toward the development of new targets to treat depression based on symptomology.