The Role of HIF-1 in Neurogenic and Behavior Responses to Antidepressants.

描述(由申请人提供)：严重抑郁障碍(MDD)是一种与严重的发病率和死亡率相关的衰弱情绪障碍。不同类别的抗抑郁药通过独特的机制作用于特定但不同的神经递质系统。值得注意的巧合是，糖原合成酶激酶-3(GSK-3)的抑制是不同类别的抗抑郁药物以及情绪稳定剂治疗的常见分子后果。我们提出了GSK-3是情绪稳定剂锂的分子靶点的假设，并调节了几种抗抑郁药物敏感的行为。GSK-3参与多种细胞内途径，包括Wnt和胰岛素信号转导。在上下文中 在激活的Wnt信号中，GSK-3被抑制，导致转录因子-连环蛋白的积聚。因此，锂通过抑制GSK-3来重写Wnt/？-catenin信号。在我们的研究过程中，我们发现了几种受锂影响的抗抑郁药物敏感行为。锂和抗抑郁药抑制GSK-3并影响小鼠的行为，这是一个有趣的相似之处。事实上，GSK-3b的杂合性丢失在这些测试中模仿了抗抑郁药的效果。GSK-3下游与抗抑郁治疗行为效应相关的关键分子效应因子(S)尚不清楚。这项提议将检验这样一种假设，即最近发现的作为Wnt/β-连环蛋白信号调节器的缺氧诱导因子1α(Hif-1a)是锂以及抗抑郁药丙咪嗪和氟西汀对行为影响所必需的。值得注意的是，锂和抗抑郁药也促进了成年人的神经发生，作为一种共同的细胞相关性！增强的海马神经发生已被认为是抗抑郁药物和情绪稳定治疗反应的一个重要组成部分，但关于抗抑郁药物对神经发生的影响却知之甚少。WNT/β-连环蛋白信号对成年海马区的神经发生至关重要。在最近的一次合作中，我们发现Hif-1a调节胚胎干细胞和神经干细胞/祖细胞中Wnt/β-catenin的转录，但不调控分化后的神经元。在小鼠中，Hif-1a的神经元特异性缺失导致了严重的成年海马区神经再生缺陷。值得注意的是，抑制GSK-3或稳定β-catenin可以挽救Hif-1a KO小鼠的神经发生缺陷，这两种方法都激活了下游的Wnt信号。这些新的发现证明了神经发生中对Hif-1a的需求，以及一种新的机制，即调节Wnt/β-catenin介导的转录，这是神经干细胞独有的。这项提议将检验HIF1a是抗抑郁剂诱导的神经发生增强所必需的，并且抗抑郁剂直接作用于神经干细胞的假设。这项建议将确定Hif-1a缺失对Wnt/β-catenin信号转导的影响，以及抗抑郁药物在分子、细胞和行为水平拯救Hif-1a KO表型的能力。低氧信号与情绪稳定剂和抗抑郁药的作用之间的新联系可能会导致对情感障碍的更好理解和新的治疗方法。 公共卫生相关性：严重抑郁障碍(MDD)是一种与严重的发病率和死亡率相关的衰弱情绪障碍。抗抑郁药对几种临床前行为的影响需要增强神经发生。然而，抗抑郁药对神经干细胞/祖细胞的作用机制尚不完全清楚。我们最近发现，成年海马区的干细胞生态位相对低氧，缺乏缺氧诱导因子-1β(Hif-1a)基因的小鼠在成年神经发生方面存在严重缺陷。这项建议探索了Hif-1a调节成人神经发生并在抗抑郁药物的神经源性和行为反应中发挥核心作用的假设。低氧信号和抗抑郁药物作用之间的新联系可能会导致对情感障碍的更好理解和新的治疗方法。

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Different classes of antidepressants act through unique mechanisms on specific, yet distinct neurotransmitter systems. It is a noteworthy coincidence that inhibition of glycogen synthase kinase-3 (GSK-3) is a common molecular consequence of treatment with diverse classes of antidepressants as well as mood stabilizers. We have forwarded the hypothesis that GSK-3 is the molecular target of lithium, a mood stabilizer, and modulates several antidepressant-sensitive behaviors. GSK-3 participates in multiple intracellular pathways including Wnt and insulin signaling. In the context of active Wnt signaling, GSK-3 is inhibited, resulting in the accumulation of the transcription factor ¿-catenin. Thus lithium recapitulates Wnt/¿-catenin signaling by inhibiting GSK-3. During the course of our studies, we found several antidepressant-sensitive behaviors that were similarly affected by lithium. It is an intriguing parallel that lithium and antidepressants inhibi GSK-3 and affect mouse behaviors similarly. Indeed, heterozygous loss of GSK-3b mimicked the effect of antidepressants on these tests. The critical molecular effectors(s) downstream of GSK-3, relevant to the behavioral effects of antidepressant treatment have yet to be identified. This proposal will test the hypothesis that hypoxia-induced factor 1¿ (Hif-1a), recently discovered as a modulator of Wnt/¿-catenin signaling, is required for the effects of lithium and the antidepressants, imipramine and fluoxetine on behavior. Remarkably, lithium and antidepressants also enhance adult neurogenesis as a common cellular correlate! Enhanced hippocampal neurogenesis has been proposed as an integral component of the response to antidepressant and mood stabilizing therapy, yet little is known regarding the effect of antidepressants on neurogenesis. Wnt/¿-catenin signaling is critical for adult neurogenesis in the hippocampus. In a recent collaboration we found that Hif-1a regulates Wnt/¿-catenin transcription in embryonic stem cells and neural stem/progenitor cells but not in differentiated neurons. Neuron-specific deletion of Hif-1a in mice results in a severe adult neurogenesis defect in the hippocampus. Remarkably, the neurogenesis defect in Hif-1a KO mice can be rescued by inhibition of GSK-3 or stabilization of ¿-catenin, both of which activate downstream Wnt signaling. These novel findings demonstrate a requirement for Hif-1a in neurogenesis and a novel mechanism of regulating Wnt/¿-catenin mediated transcription unique to NSCs. This proposal will test the hypothesis that Hif1a is required for antidepressant-induced enhancement of neurogenesis and that antidepressants act directly on NSCs. This proposal will determine the impact of Hif-1a deletion on Wnt/¿-catenin signaling and the ability antidepressants to rescue Hif-1a KO phenotypes at the molecular, cellular and behavior level. A new connection between hypoxia signaling and the actions of mood stabilizers and antidepressants could lead to a better understanding of and new approaches for the treatment of affective disorders. PUBLIC HEALTH RELEVANCE: Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Enhancement of neurogenesis is required for the effect of antidepressants on several pre-clinical behaviors. However, the mechanisms through which antidepressants act on neural stem/progenitor cells are not fully understood. We recently found that the stem cell niche in the adult hippocampus is relatively hypoxic and mice lacking the hypoxia-induced factor-1¿ (Hif-1a) gene have a profound defect in adult neurogenesis. This proposal explores the hypothesis that Hif-1a regulates adult neurogenesis and plays a central role in the neurogenic and behavioral responses to antidepressants. A new connection between hypoxia signaling and the actions antidepressants could lead to a better understanding of and new approaches to the treatment of affective disorders.