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，影响全球1-2%的人口。锂在BD中非常有效，但治疗反应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点对于理解这种主要情感障碍的分子发病机制至关重要。我们提出了这样一个假设，即锂通过抑制糖原合成酶激酶-3（GSK-3）（一种多种信号通路的中枢调节因子）对哺乳动物行为和情绪障碍起作用。本文提出的工作目标是确定细胞和分子对GSK-3抑制的反应如何与BD的治疗反应相关，长期目标是了解情感障碍的分子基础，并发现BD和其他情感障碍的新治疗靶点。该提案描述了定义锂对神经干细胞稳态和行为影响的信号传导机制的实验。我们的工作假设是GSK-3通过与Wnt信号传导和氧传感通路相互作用来调节行为和神经发生。此外，我们假设GSK-3是高度调节的正反馈电路，可以有针对性的情感障碍的新的治疗策略的发展。在目标1中，我们将测试Wnt信号传导是否是对锂的神经源性或行为反应所必需的。我们还将测试神经发生是否是锂的行为反应所必需的，使用遗传策略来靶向成年海马中的NSPCs。目的2解决了一个新发现的连接之间的氧传感（通过缺氧诱导因子-1）和Wnt通路，GSK-3的主要目标和调节神经发生。我们将探索HIF-1在神经发生和锂敏感行为的调节中的作用，并研究HIF-1靶基因在锂反应中的作用。在目标3中，我们将探索一种新的机制，该机制调节GSK-3对锂或参与情绪控制的内源性信号的抑制的敏感性。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。这些研究应该提供一个更好的理解的分子和细胞机制，基础BD和治疗的反应，并应导致新的方法来治疗这种常见的和毁灭性的情感障碍。

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.