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: 10559642
• 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/10559642
• 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; Cytoplasmic Granules; Development; Disease; Disease model; Electrophysiology (science); Etiology; Exogenous Factors; Exposure to; G-Protein-Coupled Receptors; Gene Expression; Glycoproteins; Goals; Heterogeneity; Hippocampus; Human; Label; Ligands; Link; Major Depressive Disorder; Mediating; Mental Depression; Modeling; Molecular; Motivation; Mus; Negative Valence; Neurons; Pharmaceutical Preparations; Physiological; Play; Population; Positive Valence; Predisposition; Prefrontal Cortex; Prevention; Production; Productivity; Rabies virus; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Social Behavior; Stress; System; Testing; 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; pharmacologic; prevent; protective effect; response; 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 主要抑郁症（MDD）是残疾和生产力失去的主要原因之一。 在所有临床抑郁症患者中，几乎一半未能对第一个处方抗抑郁药做出反应， 大约三分之一未能应对所有药物。开发新方法将需要 更好地了解该疾病的基础机制。该项目已经确定，是 检查以前不涉及焦虑和抑郁行为的信号通路， 骨形态发生蛋白（BMP）信号传导。 MDD与减少的体积相关 人类的海马（HC）和该疾病动物模型中HC中的神经发生。 小鼠中HC中BMP信号的降低足以产生抗抑郁药样变化 在行为和增加神经发生。用几个不同类别的治疗 抗抑郁药减少了HC中的BMP信号传导，并预防了BMP的降低 信号传导阻碍了药物对行为和神经发生的影响。抑制BMP HC中的信号传导还阻止了不可预测的慢性轻度压力​​对这两种抑郁的影响 - 像行为和神经发生。因此，海马中的BMP信号调节 类似抑郁的行为。但是，神经发生变化与 行为尚未建立。拟议的研究将确定是否有因果关系 神经发生变化，新产生的电生理活性 神经元，以及抑制HC茎/祖细胞中BMP信号传导后的行为。他们也是 将定义BMP信号在对压力的细胞和行为反应中的作用，并测试 假设该基因表达因BMP信号升高引起的变化有助于 神经发生的减少，静态神经干细胞的比例增加和行为 与压力/抑郁症相关的变化。