Neuroimmunology and Behavior: Natural Antagonism of Sickness and Depression

神经免疫学和行为：疾病和抑郁症的自然拮抗作用

• 批准号: 8228133
• 负责人: Robert H. McCusker
• 金额: $ 39.23万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228133
• 关键词: Address; Affect; Aging; Amino Acids; Amyloid; Animal Behavior; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Attenuated; Behavior; Behavioral; Binding; Blood Circulation; Body Weight decreased; Book Chapters; Brain; Cancer Patient; Cell Survival; Cells; Cessation of life; Chronic; Cognition; Cognitive deficits; Cytokine Receptors; Cytokine Signaling; Data; Development; Diabetes Mellitus; Dose; Endocrinology; Event; Exercise; Functional disorder; Goals; Growth; Growth Factor; Growth and Development function; Health; Heart Diseases; Hormones; Immune system; Immunology; Impaired cognition; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Insulin-Like Growth Factor I; Investigation; Knowledge; Lead; Learning; Life Style; Lipopolysaccharides; Literature; Measures; Mediating; Meningitis; Mental Depression; Microglia; Modeling; Modus; Mus; Muscle Cells; N-terminal; Nerve Degeneration; Neuraxis; Neurologic; Neurons; Neuroprotective Agents; Obesity; Paper; Peptides; Peripheral; Peripheral Nervous System; Process; Production; Psychopathology; Quality of life; Radiation therapy; Resistance; Role; Science; Signal Transduction; Sleep Disorders; Slice; Somatomedins; Source; Stimulus; Swimming; Symptoms; System; Systemic infection; Tail Suspension; Techniques; Testing; Toxoplasma gondii; Trauma; Work; base; bench to bedside; brain circulation; cancer cell; cell type; cellular targeting; chronic pain; cytokine; cytokine therapy; depressive symptoms; in vitro Model; in vivo; interdisciplinary approach; kainate; neuroimmunology; neuronal survival; prevent; public health relevance; research study; response; social

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. 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.

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变化。疾病行为是由大脑中促炎细胞因子表达的短暂发作引起的。如果不减弱，慢性炎症反应最终可能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），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（icv.）或外周注射（i. p.）。我们现在有令人兴奋的新的初步数据表明，IGF-I的体内作用是由天然存在的成熟IGF-I的N-末端三肽GPE模拟的。本申请基于这样的前提，即IGF-I的加工，产生GPE和脱-（1-3）-IGF-I，为大脑提供两种生物活性肽，这两种肽都起保护中枢功能的作用。四个目标的成功完成将使我们能够确定GPE和des-（1-3）-IGF-I在CNS中的抗炎作用。目的1将描述单独或与des-（1-3）-IGF-I一起补充GPE（均icv给药）阻断疾病和抑郁样行为的能力。该模型模拟了运动提高大脑中IGF-I的能力。外周引发的炎症发作，由腹腔注射脂多糖引发，将用于诱导脑细胞因子表达和信号传导。将使用完善的疾病指标（活动和养育减少、社会调查减少和体重减轻）对短暂性疾病行为进行量化。在小鼠从疾病行为中恢复后，使用两个已经验证的终点，即强迫游泳和悬尾试验中的不动持续时间，确定抑郁样行为。目标2是关键的，因为它将确定GPE和des-（1-3）-IGF-I在脑内作用以防止促炎性多巴胺依赖性行为变化的作用模式。在icv后定量促炎和抗炎细胞因子产生以及促炎细胞因子信号传导。用GPE或des-（1-3）-IGF-I治疗以检验我们的假设，即这两种肽在脑内使用不同的机制来阻断疾病和抑郁样行为。目的3将使用体外模型明确确定中枢神经系统内结合des-（1-3）-IGF-I和GPE并对其产生应答的细胞。第四个也是最后一个目的将使用体外和离体模型来确定参与des-（1-3）-IGF-I和GPE引起的中枢反应以拮抗炎症发作的机制。将比较CNS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物的反应，以确认体内使用的GPE和des-（1-3）-IGF-I的操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。该应用中的实验对于理解主要内源性激素如何在大脑中发挥作用以拮抗炎症期间发生的临床重要行为至关重要，该激素迄今为止主要以其生长促进作用而闻名。我们最近发现，大脑和激活的免疫系统之间的相互作用可以由IGF-I的天然片段GPE调节，这为定义IGF系统如何减少疾病和抑郁样行为打开了一扇新的机会之窗。由于有可能减少促炎细胞因子在大脑中的负面影响，IGF系统已被独立地证明可以减少各种依赖于多巴胺的精神病理学，包括认知功能障碍，慢性疼痛，抑郁症和疾病行为。该应用程序的主要优势是使用多学科方法来整合免疫学，行为学和内分泌学领域，以了解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并提高生活质量。