Suicide Endophenotypes and Molecular Mechanisms of Lithium Action

描述（由申请人提供）：自杀对受害者，他们的大家庭和美国以及全世界的公共卫生都有毁灭性的影响。很少有治疗方法被证明可以降低风险。一个例外，得到广泛临床证据的支持，是锂能有效降低自杀未遂和自杀未遂的风险。然而，锂的抗自杀作用的机制尚不清楚，限制了改进预防方法的发展。我们打算使用小鼠作为模式生物来阐明锂与人类自杀相关的生物和行为因素相互作用的分子途径。然而，而不是尝试在小鼠中建模自杀的不可行的任务，我们将专注于在与自杀相关的经过充分验证的内在表型（复杂行为表型的解构成分）相关的测试中评估小鼠行为的方法，包括攻击性和冲动性。这些内表型将与自杀研究中的人类遗传、生化和药理学发现结合使用，以提供构建有效的动物模型。为此，临床研究已经涉及到许多基因的多态性，包括神经元型一氧化氮合酶（NOS 1），与冲动，侵略和自杀的措施。同样，广泛的研究结果表明，自杀行为的病因学中5-羟色胺（5-HT）神经传递的缺陷以及冲动和攻击性的增加。来自临床前和人类遗传学研究的数据表明，锂可能通过抑制糖原合成酶激酶-3来发挥其稳定情绪的作用。（GSK-3！）。有趣的是，新兴的基础科学证据将NOS 1功能，5-HT神经传递和GSK-3联系起来！活性表明，它们可能在与自杀等精神疾病的病因学和治疗有关的病理生理过程中存在因果关系，其中冲动和攻击性发挥了作用。因此，我们的具体目标是：1）确定锂对具有遗传和药理学诱导的5-HT水平降低的小鼠的行为的影响; 2）确定锂对具有遗传和药理学介导的一氧化氮合酶1（NOS 1）活性缺陷的小鼠的行为的影响; 3）评估糖原合酶激酶-3！，锂的直接靶点，在通过降低5-HT和NOS 1功能介导的修饰行为中。这些研究将利用锂药理学的现有知识，并使用小鼠基因敲除和药理学方法来剖析分子和神经生物学机制，从而锂可以改变冲动和攻击行为，并确定锂和已知与自杀相关的生物标志物之间的相互作用点。公共卫生相关性：从这些研究中获得的数据应该促进改进药物干预的发展，以改变攻击性和冲动性行为，从而降低所有诊断类别的自杀风险。 公共卫生相关性：自杀既遂对家庭、社会和公共卫生都有毁灭性的影响。很少有治疗方法能降低风险;然而，锂治疗在降低自杀未遂和自杀完成的风险方面是有效的，原因不明。本申请提出了在内表型策略的背景下的实验，其将揭示锂发挥其治疗作用的分子机制。

DESCRIPTION (provided by applicant): Suicide has a devastating impact on victims, their extended families, and public health in the United States, as well as throughout the world. Few treatments have been shown to reduce risk. An exception, supported by extensive clinical evidence, is that lithium is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of improved prevention approaches. We intend to use the mouse as a model organism to elucidate molecular pathways by which lithium interacts with biological and behavioral factors associated with suicide in humans. However, rather than attempting the infeasible task of modeling suicide in mice, we will focus on approaches that assess mouse behavior in tests relevant to well validated endophenotypes (deconstructed components of complex behavioral phenotypes) associated with suicide including aggression and impulsivity. These endophenotypes will be used in combination with human genetic, biochemical, and pharmacological findings in suicide research to provide construct-valid animal models. Toward this end, clinical studies have implicated polymorphisms in a number of genes, including neuronal nitric oxide synthase (NOS1), with measures of impulsivity, aggression, and suicide. Similarly, the results of extensive research have implicated deficits in serotonin (5-HT) neurotransmission in the etiology of suicidal behavior as well as increased impulsivity and aggression. Data from preclinical and human genetic studies indicate that lithium may exert some of its mood stabilizing effects through inhibition of the enzyme glycogen synthase kinase-3! (GSK-3!). Intriguingly, emerging basic science evidence links NOS1 function, 5-HT neurotransmission, and GSK-3! activity suggesting that they may be causally linked in the pathophysiological processes relevant to the etiology and treatment of psychiatric diseases such as suicide, where impulsivity and aggression play a role. Thus, our Specific Aims are to: 1) Identify the effects of lithium on behavior in mice with genetically- and pharmacologically-induced decreases in 5-HT levels; 2) Identify the effects of lithium on behavior in mice with genetically- and pharmacologically-mediated deficiencies in nitric oxide synthase 1 (NOS1) activity; 3) Evaluate the role of glycogen synthase kinase-3!, a direct target of lithium, in modifying behaviors mediated by decreased 5-HT and NOS1 function. These studies will capitalize on current knowledge of lithium pharmacology and use mouse genetic knockouts and pharmacological approaches to dissect the molecular and neurobiological mechanisms whereby lithium may modify impulsive and aggressive behavior as well identify points of interaction between lithium and biological markers known to be associated with suicide. Public Health Relevance: The data derived rom these studies should promote the development of improved pharmacological interventions to modify aggressive and impulsive behaviors thereby decreasing the risk of suicide across all diagnostic categories. PUBLIC HEALTH RELEVANCE: A completed suicide has a devastating impact on families, society, and public health. Few treatments have been shown to result in reduced risk; however, lithium treatment is effective, for unknown reasons, in reducing the risk of both attempted and completed suicide. This application proposes experiments in the context of endophenotype strategies that will reveal molecular mechanisms whereby lithium acts to exert its therapeutics effects.