Neuroimmunology and Behavior: Natural Antagonism of Sickness and Depression

描述（由申请人提供）：免疫系统和大脑之间的相互作用导致重要的行为改变。疾病行为是由大脑中促炎细胞因子的短暂表达引起的。如果不减轻，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）是一种对生长发育至关重要的激素，其内源性滋补存在具有神经保护作用，在中枢（icv.）或外周（i.p.）给予时可抑制疾病行为。我们现在有令人兴奋的新的初步数据表明，IGF-I的体内作用是由成熟的IGF-I的天然n端三肽GPE模拟的。这一应用的前提是，igf - 1的加工产生GPE和des-(1-3)- igf - 1，为大脑提供两种生物活性肽，这两种肽都能保护中枢功能。成功完成这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。目的1将描述单独补充GPE或与des-(1-3)- igf - i（均给予icv）的能力，以阻止疾病和抑郁样行为。这个模型模拟了运动提高大脑中igf - 1的能力。外周性炎症发作，由脂多糖引起，将用于诱导脑细胞因子表达和信号传导。短暂性疾病行为将使用完善的疾病测量方法（减少活动和饲养，减少社会调查和体重减轻）进行量化。抑郁样行为将在小鼠从疾病行为中恢复后确定，使用两个已经验证的终点，即强迫游泳和悬尾测试中不活动的持续时间。目标2至关重要，因为它将确定GPE和des-(1-3)- igf -i在脑内的作用模式，以防止促炎细胞因子依赖的行为改变。促炎和抗炎细胞因子的产生，以及促炎细胞因子信号，将在icv后被量化。用GPE或des-(1-3)- igf - i进行治疗，以验证我们的假设，即这两种肽利用大脑内不同的机制来阻止疾病和抑郁样行为。目的3将使用体外模型来清楚地确定中枢神经系统内结合des-(1-3)- igf - i和GPE并对其产生反应的细胞。第四个也是最后一个目标将使用体外和离体模型来确定des-(1-3)- igf - i和GPE引发的中枢反应的机制，以对抗炎症发作。将比较中枢神经系统的三种主要细胞类型（神经元、小胶质细胞和星形胶质细胞）和离体器官型切片培养的反应，以证实GPE和des-(1-3)- igf - i在体内的运作方式可以在受控系统中建模。成功完成这些目标所需的技术已经开发出来。这种应用中的实验对于理解一种主要的内源性激素如何在大脑中发挥作用，对抗炎症期间发生的临床重要行为至关重要。迄今为止，这种激素主要被认为具有促进生长的作用。

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 (decreased activity and rearing, reduced social investigation and body weight loss). Depressive-like behavior will be determined after mice have recovered from sickness behavior using two already validated end-points, duration of immobility in the forced-swim and the tail-suspension tests. 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.