Mechanism of Lithium in Neurogenesis and Behavior

项目总结 双相情感障碍(BPD)是一种情感障碍，会导致躁狂和抑郁之间的终身循环， 折磨着1-2%的人口，并导致15%的患者自杀。BPD的病因尚不清楚， 锂等一线治疗方法还没有已知的作用机制。我们的实验室已经证明，锂 直接抑制GSK-3，锂激活Wnt/β-连环蛋白-被GSK-3抑制的信号通路-在 GSK-3的抑制介导了锂对小鼠的行为影响。这项建议结合了 用尖端的脑成像技术和现代小鼠遗传学来定义行为分析 细胞分辨率大脑中直接以锂为靶点的细胞，跟踪细胞命运的决定 锂诱导的神经发生，并测试对GSK3的需求，使用条件基因缺失，在 调节锂的行为和神经源性效应。第一个具体目标采取不偏不倚的方法 使用一种新的荧光素来识别大脑中哪些神经元和其他类型的细胞对锂有直接反应 Wnt/β-catenin活性报告作为GSK-3抑制的替代。我们将进一步确定细胞的命运 成年海马神经干细胞在锂离子诱导下神经发生的决定 确定锂的促神经性作用是否可能在其治疗中发挥直接作用 作用机制。第二个特定目的是问GSK3是否在出生后的前脑中特异性丢失 神经元需要模仿锂对行为的影响，这在之前的GSK-3研究中没有得到测试 对行为的抑制。此外，我们将确定GSK3在特定的成年NSCs中的缺失 锂对成年海马神经发生和神经干细胞命运决定的影响。这项研究 本建议书中描述的战略将为申请者梅琳达·斯尼托博士提供全面的 神经发生、小鼠神经行为测试和最先进的成像技术领域，这些技术包括 对于发展研究BPD的病因和治疗的事业至关重要。建议的研究地点，即 宾夕法尼亚大学佩雷尔曼医学院提供全面的最先进的体检 资源，结合广泛的神经科学和行为学专家社区。赞助商是Dr。 彼得·S·克莱因是锂和GSK3的分子和行为影响方面的领先专家。克莱恩医生的 在BPD研究和药理学领域有丰富的经验，并与神经发生学合作 和行为专家阿米莉亚·J·艾施博士、宋宏军博士和伊丽莎白·A·海勒博士，加上咨询 关于与Chang-Gyu Hahn博士的临床相关性，将提供理想的行为神经科学培训 和神经精神药理学，为斯尼托博士在BPD研究方面的职业生涯做好准备，成为一名独立的PI。这个 拟议中的研究将阐明锂的直接细胞靶标，这些靶标调控行为和神经发生，以及 为未来在适当的细胞环境中研究锂的分子机制奠定了基础。

PROJECT SUMMARY Bipolar disorder (BPD) is an affective disorder causing life-long cycling between mania and depression, afflicting 1-2% of the population and resulting in suicide in 15% of patients. The etiology of BPD is unknown, and first-line treatments such as lithium have no known mechanism of action. Our lab has shown that lithium directly inhibits GSK-3, that lithium activates Wnt/β-catenin—a signaling pathway inhibited by Gsk3—in the brain, and that GSK-3 inhibition mediates the behavioral effects of lithium in mice. This proposal combines behavioral analysis with cutting-edge brain imaging techniques and modern mouse genetics to define with cellular resolution the cells that are directly targeted by lithium in the brain, track cell fate decisions following lithium-induced neurogenesis, and test the requirement for Gsk3, using conditional genetic deletion, in mediating the behavioral and neurogenic effects of lithium. The first specific aim takes an unbiased approach to identify which neurons and other cell types in the brain directly respond to lithium using a novel fluorescent reporter for Wnt/β-catenin activity as a surrogate for GSK-3 inhibition. We will further identify the cell fate decisions of adult hippocampal neural stem cells (NSCs) undergoing lithium-induced neurogenesis to determine whether the pro-neurogenic effect of lithium is likely to play a direct role in its therapeutic mechanism of action. The second specific aim asks whether Gsk3 loss specifically in postnatal forebrain neurons is required to mimic lithium's effects on behavior, which was not tested in previous studies of GSK-3 inhibition on behavior. Furthermore, we will determine whether deletion of Gsk3 in specifically adult NSCs phenocopies lithium's effects on adult hippocampal neurogenesis and NSC fate decisions. The research strategy described in this proposal will provide the applicant, Dr. Melinda Snitow, comprehensive training in the field of neurogenesis, mouse neurobehavioral testing, and state-of-the-art imaging techniques, which are critical to develop a career studying the etiology and treatment of BPD. The proposed site of research, The University of Pennsylvania's Perelman School of Medicine, provides comprehensive state-of-the-art physical resources, combined with an extensive community of experts in neuroscience and behavior. The sponsor, Dr. Peter S. Klein, is a leading expert on the molecular and behavioral effects of lithium and Gsk3. Dr. Klein's extensive experience in the field of BPD research and pharmacology, and collaborations with neurogenesis and behavior experts Dr. Amelia J. Eisch, Dr. Hongjun Song, and Dr. Elizabeth A. Heller, plus consultation regarding clinical relevance with Dr. Chang-Gyu Hahn, will provide ideal training in behavioral neuroscience and neuropsychopharmacology to prepare Dr. Snitow for a career in BPD research as an independent PI. The proposed research will elucidate lithium's direct cellular targets that regulate behavior and neurogenesis, and lay the foundation for future studies of lithium's molecular mechanisms in the appropriate cellular context.