The 5-HT theory of depression tested in a naturalistic model of 5-HT deficiency

在 5-HT 缺乏的自然模型中测试的 5-HT 抑郁理论

• 批准号: 8895461
• 负责人: Marc G. Caron
• 金额: $ 10万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895461
• 关键词: 5-Hydroxytryptophan; Acute; Address; Affect; Amygdaloid structure; Animal Model; Antidepressive Agents; Anxiety; Behavior; Behavioral; Behavioral Model; Biochemical; Biological Markers; Brain; Chronic; Clinical; Data; Depressive Syndromes; Development; Disease; Etiology; Exhibits; Foundations; Functional disorder; Genes; Genetic Engineering; Glutamates; Goals; Homeostasis; Human; Ketamine; Lead; Mediating; Mental Depression; Mental disorders; Modeling; Molecular; Mood Disorders; Mus; Mutant Strains Mice; Mutation; Neurobiology; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Preclinical Testing; Predisposition; Psyche structure; Publishing; Reporting; Research; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Pathway; Signal Transduction; Stress; Symptoms; System; Testing; Therapeutic; Tissues; Tryptophan; Tryptophan 5-monooxygenase; Work; base; cohort; extracellular; frontal lobe; improved; indexing; insight; interest; mood regulation; mouse model; mutant; neurochemistry; neurotransmission; novel; novel therapeutic intervention; psychobiologic; research clinical testing; research study; response; social; stem; stressor; theories; tool; treatment-resistant depression

DESCRIPTION (provided by applicant): Alterations in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission have long been theorized to play an important role in the pathogenesis of psychiatric disorders, particularly depression. This theory stems from the facts that drugs (e.g., SSRIs) increasing levels of extracellular 5-HT (5-HTExt) treat depression with moderate efficacy and that anomalies in putative "biomarkers" of central 5-HT function have been repeatedly reported in depression. However, brain 5-HT dysfunction has never been directly demonstrated in depression patients and whether low 5-HT can elicit or predispose to depression remains unclear. The rate-limiting step in brain 5-HT synthesis is the conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase 2 (Tph2). The recent identification of functional mutations in several of the genes involved in 5-HT homeostasis, including tph2, and their associations with depression or impaired therapeutic responses to SSRIs have stimulated renewed interest in the 5-HT deficiency theory of depression. We have generated a mouse line carrying a rare Tph2(R439H) mutation originally identified in a depression cohort. In these mutant mice brain 5- HT synthesis and tissue storage are decreased by 80% and 5-HTExt levels by 60-80%, while evoked 5-HTExt responses are qualitatively preserved. The mice recapitulate several anomalies in putative 5-HT biomarkers reported in severe depression and exhibit depression-, anxiety-, and aggressive-like behaviors, seemingly providing a model of the behavioral alterations associated with 5-HT deficits in humans. Thus, our mutant (henceforth 5-HThypo) mice may represent a unique naturalistic model of 5-HT deficiency and, possibly, depression. Plausibly, multiple diverse insults to 5-HT homeostasis could each result in 5-HT deficiency, thus the 5-HThypo mouse likely represents a useful model of 5-HT deficiency in general as well as a model of impaired Tph2 catalytic function. The overall goal of our continued research is to use the 5-HThypo mouse to better understand how 5-HT deficiency contributes to depression etiology and affects antidepressant treatment, including the consequences for stress susceptibility and responses to current and novel therapies. For this goal, we propose four specific aims. Aim 1 will define whether 5-HT deficiency alters susceptibility to stress, as tested in the social defeat and chronic mild stress paradigms. Aim 2 will test whether antidepressant- like responses to SSRI and ketamine are affected by 5-HT deficiency. Aim 3 will pre-clinically test a novel 5- HTP-based antidepressant augmentation concept under 5-HT-deficient and normal conditions. In Aim 4 we will use conventional and state-of-the-art approaches to identify the cellular signaling pathway changes underlying the depression-like behaviors arising consequent to 5-HT deficiency. Collectively, the proposed experiments will address long outstanding questions in depression neurobiology and test a new treatment concept.

描述（由申请人提供）：长期以来，血清素（5-羟色胺，5-HT）神经传递的改变一直被认为在精神疾病，特别是抑郁症的发病机制中发挥重要作用。该理论源于以下事实：增加细胞外 5-HT (5-HTExt) 水平的药物（例如 SSRI）治疗抑郁症具有中等功效，并且在抑郁症中反复报道了中枢 5-HT 功能的推定“生物标志物”异常。然而，大脑 5-HT 功能障碍从未在抑郁症患者中得到直接证实，低 5-HT 是否会引发或诱发抑郁症仍不清楚。大脑 5-HT 合成的限速步骤是色氨酸羟化酶 2 (Tph2) 将色氨酸转化为 5-羟基色氨酸 (5-HTP)。最近发现了一些涉及 5-HT 稳态的基因（包括 tph2）的功能突变，以及它们与抑郁症或 SSRI 治疗反应受损的关系，这激发了人们对抑郁症 5-HT 缺乏理论的新兴趣。我们培育了一个携带罕见 Tph2(R439H) 突变的小鼠品系，该突变最初是在抑郁症队列中发现的。在这些突变小鼠中，大脑 5-HT 合成和组织储存减少了 80%，5-HTExt 水平减少了 60-80%，而诱发的 5-HTExt 反应却得到了定性保留。这些小鼠重现了严重抑郁症中报告的假定 5-HT 生物标志物的几种异常情况，并表现出抑郁、焦虑和攻击性行为，似乎提供了与人类 5-HT 缺陷相关的行为改变模型。因此，我们的突变小鼠（以下称为 5-HThypo）可能代表了 5-HT 缺乏以及可能的抑郁症的独特自然模型。似乎，对 5-HT 稳态的多种不同损害都可能导致 5-HT 缺乏，因此 5-HThypo 小鼠可能代表了 5-HT 缺乏的有用模型以及 Tph2 催化功能受损的模型。我们持续研究的总体目标是使用 5-HThypo 小鼠更好地了解 5-HT 缺乏如何导致抑郁症病因并影响抗抑郁治疗，包括压力敏感性的后果以及对当前和新型疗法的反应。针对这一目标，我们提出四个具体目标。目标 1 将确定 5-HT 缺乏是否会改变对压力的敏感性（经测试） 在社会失败和慢性轻度压力​​范式中。目标 2 将测试 5-HT 缺乏是否会影响对 SSRI 和氯胺酮的抗抑郁样反应。目标 3 将在 5-HT 缺乏和正常条件下对一种新型的基于 5-HTP 的抗抑郁增强概念进行临床前测试。在目标 4 中，我们将使用传统和最先进的方法来识别 5-HT 缺乏引起的抑郁样行为背后的细胞信号通路变化。总的来说，拟议的实验将解决抑郁症神经生物学中长期悬而未决的问题，并测试新的治疗概念。