BMP Signaling and Neurogenesis in Major Depressive Order

摘要 严重抑郁障碍(MDD)是导致残疾和生产力丧失的主要原因之一。 近一半的临床抑郁症患者对第一种处方的抗抑郁药没有反应， 大约三分之一的人对所有药物都没有反应。开发新的方法将需要 更好地了解这种疾病的潜在机制。该项目已经确定并正在实施 研究之前并未牵涉到焦虑和抑郁样行为的信号通路， 骨形态发生蛋白(BMP)信号传导。MDD与容量的减少有关 在人类的海马体(HC)中，以及在这种疾病的动物模型中，HC中的神经发生。 小鼠HC中BMP信号的减少足以产生抗抑郁药样变化 在行为上和增加神经发生。用几种不同级别的 抗抑郁药物减少了HC中的BMP信号，并阻止了这种BMP的减少 信号传导阻断了药物对行为和神经发生的影响。骨形态发生蛋白的抑制 HC中的信号也阻止了不可预测的慢性轻度应激对两种抑郁症的影响- 比如行为和神经发生。因此，海马体中的BMP信号调节两者 类似抑郁的行为。然而，神经发生的变化和 行为还没有建立起来。拟议的研究将确定是否存在因果关系 新生大鼠神经发生与电生理活动变化的关系 在HC干细胞/祖细胞中，BMP信号被抑制后的行为。他们也 将确定BMP信号在细胞和行为对应激反应中的作用，并测试 假设由于BMP信号升高而导致的基因表达变化有助于 神经发生减少，静止的神经干细胞比例增加，以及行为 与压力/抑郁相关的变化。

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.