Regulation of neurogenesis and behavior by GSK-3

描述（由申请人提供）：双相情感障碍（BD）是一种使人衰弱的情绪障碍，影响全世界1-2%的人口。锂对双相障碍非常有效，但治疗反应背后的神经药理学机制尚不清楚。确定锂在成人大脑中的细胞和分子靶标对于理解这种主要情感障碍的分子发病机制至关重要。我们提出了锂通过抑制糖原合成酶激酶-3 （GSK-3）作用于哺乳动物行为和情绪障碍的假设，GSK-3是多种信号通路的中心调节因子。本文提出的工作目标是建立细胞和分子对GSK-3抑制的反应与双相障碍治疗反应的关系，长期目标是了解情感性障碍的分子基础，并发现双相障碍和其他情感性障碍的新治疗靶点。本研究描述了锂对神经干细胞稳态和行为影响的信号机制。我们的工作假设是GSK-3通过与Wnt信号和氧感应途径的相互作用调节行为和神经发生。此外，我们假设GSK-3受到正反馈回路的高度调节，这可以作为开发情感障碍新治疗策略的目标。在目的1中，我们将测试Wnt信号是否对锂的神经源性或行为反应是必需的。我们还将测试神经发生是否需要锂的行为反应，使用遗传策略来靶向成人海马体中的NSPCs。Aim 2解决了新发现的氧感应（通过缺氧诱导因子-1）和Wnt通路之间的联系，Wnt通路是GSK-3的主要靶点和神经发生的调节剂。我们将探索HIF-1在神经发生和锂敏感行为的调控中的作用，并研究HIF-1靶基因在锂反应中的作用。在目标3中，我们将探索一种调节GSK-3对锂或参与情绪控制的内源性信号抑制的敏感性的新机制。我们将研究干扰这些GSK-3调节回路的方法，作为治疗双相情感障碍和其他情感障碍的潜在新治疗靶点。这些研究有助于更好地了解双相障碍的分子和细胞机制以及治疗反应，并为治疗这种常见的破坏性情感障碍提供新方法。

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a debilitating mood disorder that affects 1-2% of the population worldwide. Lithium is highly effective in BD, but the neuropharmacological mechanisms that underlie the therapeutic response is unknown. Defining the cellular and molecular targets of lithium in the adult brain will be crucial to understanding te molecular pathogenesis of this major affective disorder. We have advanced the hypothesis that lithium acts on mammalian behavior and mood disorders through inhibition of glycogen synthase kinase-3 (GSK-3), a central regulator of multiple signaling pathways. The goals of the work proposed here are to establish how cellular and molecular responses to GSK-3 inhibition relate to the therapeutic response in BD, with a long-term goal to understand the molecular basis of affective disorders and to discover new therapeutic targets in BD and other affective disorders. This proposal describes experiments to define the signaling mechanisms that account for the effects of lithium on neural stem cell homeostasis and behavior. Our working hypothesis is that GSK-3 modulates both behavior and neurogenesis through interaction with Wnt signaling and oxygen sensing pathways. In addition, we hypothesize that GSK-3 is highly regulated by positive feedback circuits that can be targeted for the development of new therapeutic strategies in affective disorders. In aim 1, we will test whether Wnt signaling is required for neurogenic or behavioral responses to lithium. We will also test whether neurogenesis is required for behavioral responses to lithium using a genetic strategy to target NSPCs in the adult hippocampus. Aim 2 addresses a newly uncovered connection between oxygen sensing (through hypoxia inducible factor-1) and the Wnt pathway, a major target of GSK-3 and a regulator of neurogenesis. We will explore the role of HIF-1 in the regulation of neurogenesis and lithium-sensitive behaviors and investigate the role of HIF-1 target genes in the response to lithium. In aim 3 we will explore a novel mechanism that regulates the sensitivity of GSK-3 to inhibition by lithium or by endogenous signals involved in the control of mood. We will investigate approaches to perturb these GSK-3 regulatory circuits as potentially new therapeutic targets in the treatment of bipolar disorder and other affective disorders. These studies should provide a better understanding of the molecular and cellular mechanisms that underlie BD and the response to therapy and should lead to new approaches to the treatment of this common and devastating affective disorder.