Interactions Between Depression, Neuroinflammation and Glycogen Synthase Kinase-3

描述（由申请人提供）：越来越多的证据表明，炎症对抑郁症的发展和治疗有很大的影响，抑郁症是一种使人衰弱的疾病，终生发病率约为20%。抑郁症患者血清中的炎症标志物通常会增加，干扰素的使用会诱发抑郁症，“心理”压力会诱发抑郁症，人类和啮齿类动物的炎症细胞因子增加，炎症细胞因子的使用会诱发啮齿动物的抑郁样行为，在人类中，细胞因子的增加与初级宿主防御系统的轻微刺激有关，对情绪有负面影响，抗抑郁药具有抗炎作用，重度抑郁症患者的免疫激活与抗抑郁治疗的耐药性有关。因此，为了了解和设计更好的抑郁症治疗方法，确定中枢神经系统中调节神经炎症和炎症分子积聚的机制是很重要的。糖原合成酶激酶3 （GSK3）最近被发现是外周细胞因子产生的强有力的调节剂。我们将其扩展到中枢神经系统，例如，显示GSK3抑制剂可使星形胶质细胞和小胶质细胞中促炎细胞因子白介素-6的产生减少约90%。我们还发现GSK3抑制剂促进对炎症的耐受性，下调对反复炎症刺激的炎症反应，这在控制可能与情绪障碍相关的慢性炎症中可能特别重要。GSK3在情绪障碍中也有深远的影响，它被情绪稳定剂和抗抑郁药抑制，GSK3活性的药理学或遗传学降低可以减少啮齿动物的抑郁样行为，并且在人类死后脑样本和血清中的证据表明，GSK3在情绪障碍中异常活跃。我们最近发现GSK3在小鼠的抑郁习得性无助模型中被激活。综上所述，这些发现表明GSK3的促炎作用可能有助于其促进情绪障碍，并且抑制GSK3的情绪稳定剂和抗抑郁药的治疗作用可能涉及抗炎作用。因此，对炎症系统的研究提供了一个模型系统来研究GSK3如何调节可能涉及情绪障碍的关键过程：表观遗传学、耐受性和行为。这些目标提供了独立但相关的目标，将确定失调的GSK3可能导致情绪障碍的新机制，并确定治疗干预如何改善这些结果。Specific Aim 1将测试GSK3在抑郁样行为中调节大脑先天和适应性免疫系统的假设。Specific Aim 2将测试GSK3调节表观遗传学的假设，使用炎症刺激诱导的变化作为模型。特异性目标3将验证GSK3促进炎症和环境应激的抑郁样行为反应的假设。

DESCRIPTION (provided by applicant): Accumulating evidence shows inflammation strongly influences the development and treatment of depression, a debilitating disease with a lifetime incidence of ~20%. Markers of Inflammation often are increased in the serum of depressed patients, interferon administration can induce depression, "psychological" stresses that can induce depression increase inflammatory cytokines in humans and rodents, administration of inflammatory cytokines induces depression-like behaviors in rodents, in humans increased cytokines associated with a mild stimulation of the primary host defense system has negative effects on emotions, antidepressants have anti-inflammatory effects, and immune activation in patients with major depression is associated with resistance to antidepressant treatment. Therefore, in order to understand and design improved therapeutics for depression, it is important to identify mechanisms regulating neuroinflammation, inflammatory molecule accumulation in the CNS. Glycogen synthase kinase-3 (GSK3) recently was found to be a powerful regulator of cytokine production in the periphery. We extended this to the CNS, e.g., showing that GSK3 inhibitors reduce by >90% the production of the proinflammatory cytokine interleukin-6 in astrocytes and microglia. We also found that GSK3 inhibitors promote tolerance to inflammation, down-regulating inflammatory responses to repeated inflammatory stimuli, which may be particularly important in controlling chronic inflammation that is likely associated with mood disorders. GSK3 also has profound influences in mood disorders, it is inhibited by mood stabilizers and antidepressants, pharmacological or genetic reduction of GSK3 activity reduces depression-like behaviors in rodents, and evidence in postmortem brain samples and serum from humans indicate GSK3 is abnormally active in mood disorders. We recently found GSK3 is activated in mouse brain by the learned helplessness model of depression. Taken together, these findings suggest that the pro-inflammatory action of GSK3 may contribute to its promotion of mood disorders, and that the therapeutic actions of mood stabilizers and antidepressants that inhibit GSK3 may involve anti-inflammatory effects. Thus, studies of the inflammation system provide a model system to study how GSK3 regulates key processes that are likely involved in mood disorders: epigenetics, tolerance, and behavior. These aims provide independent but associated goals that will identify new mechanisms by which dysregulated GSK3 can contribute to mood disorders and identify how therapeutic interventions ameliorate these outcomes. Specific Aim 1 will test the hypothesis that GSK3 regulates innate and adaptive immune system in the brain during depressive-like behavior. Specific Aim 2 will test the hypothesis that GSK3 regulates epigenetics, using changes induced by inflammatory stimuli as a model. Specific Aim 3 will test the hypothesis that GSK3 promotes depression-like behavioral responses to inflammatory and environmental stress. PUBLIC HEALTH RELEVANCE: Mood disorders afflict approximately 20% of the population of the United States at some point in their lifetimes. However, because the underlying biochemical causes of these diseases are not known, treatments often do not adequately provide therapeutic benefits. These diseases appear to develop due to genetic susceptibilities, life experiences, and environmental conditions, particularly stress. This project will address potential causes of susceptibilities to mood disorders and examine actions of mood stabilizers and antidepressants that may contribute to their therapeutic effects. The goals are to clarify potential causative mechanisms and discern how these are altered by therapeutic interventions with the aim of developing better therapeutic interventions for mood disorders.