Central Motivation of Depression; An Expanded Kynurenine Theory

修改后的项目摘要/摘要部分 重度抑郁是一种主观情绪状态，导致情绪下降，失去应对应激生活事件的能力，体验快乐的能力降低。严重抑郁症的发病率在全世界范围内都在增加，相当大比例的重度抑郁症患者有一种潜在的共病条件，即天然免疫系统被激活。临床数据已经表明，情绪低落的症状是由细胞因子引起的。此外，临床前模型显示，生理应激源，包括心理应激或感染，诱导炎性细胞因子的产生，随后是抑郁样行为。现在人们普遍认为抑郁症的症状与全身炎症有关。消极情绪、快感减退和疲劳都是由炎症事件引起的抑郁症状。然而，这些标准具有不同的精神病理结构，表明导致特定症状的离散的炎症依赖途径。到目前为止，这些症状依赖途径的生物学基础还没有得到描述。这项提案中的实验将建立在我们发现色氨酸是通过发散的吲哚胺2，3-双加氧酶(IDO)依赖的途径代谢的基础上，这些途径是动机行为(快感缺失和疲劳)和负面情绪(无助/绝望)诱导的唯一负责因素。将对三个重叠区域进行调查，以确定色氨酸代谢在抑郁症特定症状中的作用。在目标1中，我们将使用临床前遗传学和药理学的IDO小鼠模型来表征负面影响所必需的色氨酸代谢途径。在目标2中，随后将使用带牙线的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大脑区域内色氨酸代谢的调节，重点是纹状体和海马体。这些令人兴奋和新颖的实验将首次将色氨酸代谢的神经免疫调节与严重抑郁症的特定症状相结合。这一努力是开发基于症状学治疗抑郁症的新目标的第一步。

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.