Neuroimmunology and Behavior: Natural Antagonism of Sickness and Depression

描述(申请人提供)：免疫系统和大脑之间的相互作用会导致重要的行为变化。疾病行为是由大脑中短暂的促炎细胞因子表达引起的。如果不减退，慢性炎症反应最终会导致抑郁样行为的发展。我们最近发现，胰岛素样生长因子-I(IGF-I)是一种对生长和发育至关重要的激素，其内源性紧张性存在具有神经保护作用，当中枢给予(ICV)时，它可以抑制疾病行为。或外围(IP)。我们现在有了令人兴奋的新的初步数据，表明IGF-I的体内作用是由成熟IGF-I的自然产生的N端三肽GPE模拟的。这一应用是基于这样的前提，即IGF-I的处理导致GPE和DES-(1-3)-IGF-I为大脑提供两个生物活性多肽，这两个多肽都可以保护中枢功能。成功完成四个目标将使我们能够确定GPE和DES-(1-3)-IGF-I在中枢神经系统中的抗炎作用。目标1将表征单独补充GPE或与DES-(1-3)-IGF-I一起给予icv的补充GPE阻止疾病和抑郁样行为的能力。这个模型模仿了运动提高大脑中IGF-I的能力。外周启动的炎症发作，由给予ip的内毒素启动，将被用来诱导脑细胞因子的表达和信号传递。暂时性疾病行为将使用公认的疾病测量方法进行量化。在小鼠从疾病行为中恢复后，将使用两个已经得到验证的终点来确定类似抑郁的行为。目标2是至关重要的，因为它将决定GPE和DES-(1-3)-IGF-I在脑内防止促炎细胞因子依赖的行为变化的作用模式。在ICV之后，将量化促炎和抗炎细胞因子的产生，以及促炎细胞因子信号。用GPE或DES-(1-3)-IGF-I治疗来验证我们的假设，即这两种多肽在大脑中使用不同的机制来阻止疾病和抑郁样行为。目的3利用体外模型明确确定中枢神经系统内结合和反应DES-(1-3)-IGF-I和GPE的细胞(S)。第四个也是最后一个目标将使用体外和体外模型来确定DES-(1-3)-IGF-I和GPE拮抗炎症发作的中枢反应所涉及的机制。我们将比较中枢神经系统三种主要细胞类型(神经元、小胶质细胞和星形胶质细胞)和体外器官切片培养的反应，以确认体内使用的GPE和DES-(1-3)-IGF-I的工作方式可以在受控系统中建模。已经开发出成功完成这些目标所需的技术。这一应用中的实验对于了解一种主要的内源性激素是如何在大脑中发挥作用以对抗炎症期间发生的临床重要行为至关重要的。到目前为止，这种激素主要以促进生长的作用而闻名。公共卫生相关性我们最近的发现，大脑和激活的免疫系统之间的相互作用可以由IGF-I的自然片段GPE来调节，这打开了一扇新的机会之窗，以定义IGF系统如何作用于减少疾病和抑郁样行为。IGF系统可以减少促炎细胞因子在大脑中的负面影响，独立地被证明可以减少各种细胞因子依赖的精神病理，包括认知功能障碍、慢性疼痛、抑郁和疾病行为。这一应用的一个主要优势是使用多学科方法整合免疫学、行为学和内分泌学领域，以了解与生理相关的生长因子和细胞因子如何相互作用，以维持和促进大脑功能，提高生活质量。

DESCRIPTION (provided by applicant): An interaction between the immune system and the brain causes important behavioral changes. Sickness behavior is induced by a transient episode of pro-inflammatory cytokine expression in the brain. If unabated, the chronic inflammatory response can ultimately lead to development of depressive-like behavior. We recently discovered that insulin-like growth factor-I (IGF-I), a hormone that is critical for growth and development and whose endogenous-tonic presence is neuroprotective, inhibits sickness behavior when given either centrally (icv.) or peripherally (i.p.). We now have exciting new preliminary data showing that the in vivo action of IGF-I is mimicked by the naturally occurring N-terminal tripeptide of mature IGF-I, GPE. This application is based on the premise that processing of IGF-I, resulting in GPE and des-(1-3)-IGF-I, provides the brain with two biologically active peptides that both work to protect central function. Successful completion of four objectives will allow us to define the anti-inflammatory role of GPE and des-(1-3)-IGF-I within the CNS. Objective 1 will characterize the ability of supplemental GPE alone or with des-(1-3)-IGF-I, both given icv, to block both sickness and depressive-like behaviors. This model mimics the ability of exercise to elevate IGF-I in the brain. Peripherally-initiated inflammatory episodes, initiated by lipopolysaccharide given i.p., will be used to induce brain cytokine expression and signaling. Transient sickness behavior will be quantified using well established measures of sickness. Depressive-like behavior will be determined after mice have recovered from sickness behavior using two already validated end-points. Objective 2 is critical as it will determine the mode of action by which GPE and des-(1-3)-IGF-I act within the brain to prevent pro-inflammatory cytokine-dependent behavioral changes. Pro-inflammatory and anti-inflammatory cytokine production, as well as pro-inflammatory cytokine signaling, will be quantified following icv. treatment with GPE or des-(1-3)-IGF-I to test our hypothesis that these two peptides use distinct mechanisms within the brain to block sickness and depressive-like behaviors. Objective 3 will use in vitro models to clearly determine the cell(s) within the central nervous system that bind and respond to des-(1-3)-IGF-I and GPE. The fourth and last objective will use in vitro and ex vivo models to define the mechanisms involved in the central responses elicited by des-(1-3)-IGF-I and GPE to antagonize an inflammatory episode. The responses of the three major cell types of the CNS (neurons, microglia and astrocytes) and ex vivo organotypic slice cultures will be compared to confirm that the modus operandi of GPE and des-(1-3)-IGF-I that are utilized in vivo can be modeled in controlled systems. Techniques that are needed to successfully complete these objectives have been developed. Experiments in this application are critical to understand how a major endogenous hormone, that until now has been known mainly for its growth promoting actions, functions in the brain to antagonize clinically-important behaviors that occur during inflammation. PUBLIC HEALTH RELEVANCE Our recent discovery that the interaction between the brain and an activated immune system can be regulated by a natural fragment of IGF-I, GPE, opens a new window of opportunity to define how the IGF system acts to reduce sickness and depressive-like behaviors. With the potential to diminish the negative impact of pro-inflammatory cytokines in the brain, the IGF system has independently been shown to decrease a variety of cytokine-dependent psychopathologies, including cognitive dysfunction, chronic pain, depression, and sickness behavior. A major strength of this application is the use of a multidisciplinary approach to integrate the fields of immunology, behavior and endocrinology to learn how a physiologically-relevant growth factor and cytokines interact to maintain and promote function of the brain and increase quality of life.