BMP Signaling and Neurogenesis in Major Depressive Order

重度抑郁症中的 BMP 信号转导和神经发生

• 批准号: 10343695
• 负责人: JOHN A KESSLER
• 金额: $ 45.61万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343695
• 关键词: Address; Affective; Anatomy; Animal Model; Antidepressive Agents; Anxiety; Area; BMP4; Behavior; Behavioral; Biochemical; Bone Morphogenetic Proteins; Brain; Cells; Chronic; Clinical; Cognition; Cognitive; Coupled; Cytoplasmic Granules; Development; Disease; Disease model; Electrophysiology (science); Etiology; Exogenous Factors; Exposure to; Gene Expression; Glycoproteins; Goals; Heterogeneity; Hippocampus (Brain); Human; Label; Ligands; Link; Major Depressive Disorder; Mediating; Mental Depression; Modeling; Molecular; Motivation; Mus; Negative Valence; Neurons; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population; Positive Valence; Prefrontal Cortex; Prevention; Production; Productivity; Proteins; Rabies virus; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Social Behavior; Stress; Stress Tests; System; adult neurogenesis; antidepressant effect; behavioral phenotyping; behavioral response; cell type; dentate gyrus; depressed patient; depressive symptoms; disability; inhibitor; mutant; nerve stem cell; neurogenesis; neuronal circuitry; neurotransmission; newborn neuron; novel strategies; prevent; protective effect; receptor; response; stem; stem cells

Summary Major depressive disorder (MDD) is one of the leading causes of disability and lost productivity. Nearly half of all clinically depressed patients fail to respond to the first prescribed antidepressant, and about a third fail to respond to all medications. Development of new approaches will require better understand of the mechanisms underlying the disorder. This project has identified and is examining a signaling pathway not previously implicated in anxiety and depression-like behavior, bone morphogenetic protein (BMP) signaling. MDD is associated with reductions in volume of the hippocampus (HC) in humans and in neurogenesis in the HC in animal models of the disorder. Reduction of BMP signaling in the HC in mice is sufficient to produce antidepressant-like changes in behavior and to increase neurogenesis. Treatment with several different classes of antidepressant drugs reduces BMP signaling in the HC, and prevention of this reduction in BMP signaling blocks the effects of the drugs on both behavior and neurogenesis. Inhibition of BMP signaling in the HC also blocks the effects of unpredictable chronic mild stress on both depression- like behavior and neurogenesis. Thus BMP signaling in the hippocampus regulates both depression-like behavior. However, a causal link between the changes in neurogenesis and behavior has not been established. The proposed studies will determine whether there is a causal relationship between changes in neurogenesis, electrophysiological activity of newly generated neurons, and behavior after inhibition of BMP signaling in HC stem/progenitor cells. They also will define the role of BMP signaling in cellular and behavioral responses to stress, and test the hypothesis that that gene expression changes due to elevated BMP signaling contribute to the decrease in neurogenesis, increased proportion of quiescent neural stem cells, and behavioral changes associated with stress/depression.

概括 重度抑郁症 (MDD) 是导致残疾和生产力下降的主要原因之一。 近一半的临床抑郁症患者对第一种处方抗抑郁药没有反应， 大约三分之一的人对所有药物均无效。开发新方法将需要 更好地了解该疾病的潜在机制。该项目已确定并正在 检查以前与焦虑和抑郁样行为无关的信号通路， 骨形态发生蛋白 (BMP) 信号传导。 MDD 与细胞体积的减少有关 人类海马体 (HC) 以及该疾病动物模型中 HC 的神经发生。 小鼠 HC 中 BMP 信号传导的减少足以产生抗抑郁药样变化 行为并增加神经发生。使用几种不同类别的治疗 抗抑郁药物可减少 HC 中的 BMP 信号传导，并预防 BMP 的减少 信号传导阻断药物对行为和神经发生的影响。 BMP 的抑制 HC 中的信号传导还可以阻止不可预测的慢性轻度压力​​对抑郁症和抑郁症的影响。 比如行为和神经发生。因此，海马中的 BMP 信号传导调节 类似抑郁症的行为。然而，神经发生的变化和 行为尚未确定。拟议的研究将确定是否存在因果关系 神经发生变化与新产生的电生理活动之间的关系 HC 干细胞/祖细胞中 BMP 信号传导抑制后的神经元和行为。他们还 将定义 BMP 信号在细胞和行为应激反应中的作用，并测试 假设 BMP 信号传导升高导致基因表达发生变化，从而导致 神经发生减少、静止神经干细胞比例增加以及行为 与压力/抑郁相关的变化。