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Peripheral IL-6 from leukocytes controls susceptibility to social defeat stress

来自白细胞的外周 IL-6 控制对社交失败压力的易感性

基本信息

批准号：
9487761
负责人：
MIRIAM MERAD
金额：
$ 59.69万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-24 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9487761
关键词：
Anhedonia Animals Antidepressive Agents Anxiety Astrocytes Attention Behavior Behavioral Biological Markers Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation Brain Cell Compartmentation Cell Count Cells Cellular Stress Chimera organism Data Development Diagnostic tests Engineering Epigenetic Process Exhibits Expression Profiling Family Genetic Goals Grant Hematopoietic stem cells Hour Hyperactive behavior Immune Immune Cell Activation Immune response Immune system Inbred Strains Mice Individual Differences Inflammatory Inflammatory Response Interleukin-6 Knock-out Knockout Mice Leukocytes Lipopolysaccharides Measures Mediating Mental Depression Messenger RNA MicroRNAs Microglia Modeling Mus Neuraxis Nucleus Accumbens Organ Peripheral Phenotype Play Predisposition Prefrontal Cortex Regulation Resistance Rodent Role Social Development Social Interaction Source Stem cells Stress Stromal Cells Testing Transplantation Work anxiety-like behavior base behavior test behavioral response biological adaptation to stress brain reward regions cell type cytokine depression model irradiation neutralizing antibody novel novel therapeutics overexpression public health relevance reconstitution resilience response small hairpin RNA social stress disorder

项目摘要

DESCRIPTION (provided by applicant): Stress disorders such as depression and anxiety are associated with increases in the pro-inflammatory cytokine interleukin-6 (IL-6), however, the source and functional relevance of this elevation remains unknown. Using a repeated social defeat stress model in mice, we find individual differences in the peripheral immune response to stress-measured by increased IL-6 release from leukocytes-that predicts stress susceptibility. Susceptible mice develop social avoidance and anhedonia, which are established measures of depression-like behavior in rodents. To understand whether leukocyte derived IL-6 is necessary and sufficient for the development of social avoidance and anhedonia, we generated bone marrow (BM) chimeras transplanted with stem cells from stress susceptible or IL-6 knockout (IL-6-/-) mice. Stress susceptible BM chimeras exhibit baseline anhedonia and increased stress-induced social avoidance, whereas IL-6-/- BM chimeras were resistant to the effects of stress on these behaviors. In addition, we have preliminary evidence that IL-6 may be acting within key brain reward regions, such as the nucleus accumbens and prefrontal cortex, to mediate these behavioral effects. Together our work shows that pre-existing differences in stress responsive IL-6 release from leukocytes functionally contributes to depression-like behavioral phenotypes. In this application we will define the detailed mechanisms by which susceptible mice produce and release more IL-6. We will further define the functional relevance of such changes to development of depression-like behavior and test novel therapeutic strategies, such as bone marrow re-engineering to reduce stress susceptibility. We believe that this work holds promise for developing predictive diagnostic tests based on hyperactive IL-6 responses, as well as verification of important targets for novel antidepressant development.

描述（由申请人提供）：应激障碍（如抑郁和焦虑）与促炎细胞因子白细胞介素-6（IL-6）的升高相关，然而，这种升高的来源和功能相关性仍然未知。在小鼠中使用重复的社会失败压力模型，我们发现外周免疫反应对压力的个体差异-通过增加白细胞释放IL-6来测量-预测压力易感性。易感小鼠会出现社交回避和快感缺乏，这是啮齿动物抑郁样行为的既定指标。为了了解白细胞衍生的IL-6是否是社交回避和快感缺乏的发展所必需和充分的，我们产生了骨髓（BM）嵌合体，其移植有来自应激易感或IL-6敲除（IL-6-/-）小鼠的干细胞。应激敏感的BM嵌合体表现出基线快感缺乏和增加的应激诱导的社交回避，而IL-6-/- BM嵌合体对应激对这些行为的影响具有抗性。此外，我们有初步证据表明IL-6可能在关键的大脑奖励区域（例如伏隔核和前额叶皮质）中发挥作用，以介导这些行为效应。我们的工作表明，白细胞释放应激反应性IL-6的预先存在的差异在功能上有助于抑郁样行为表型。在本申请中，我们将定义易感小鼠产生和释放更多IL-6的详细机制。我们将进一步确定这些变化与抑郁样行为发展的功能相关性，并测试新的治疗策略，如骨髓重建以降低应激易感性。我们相信，这项工作有望开发基于过度活跃的IL-6反应的预测性诊断测试，以及验证新型抗抑郁药开发的重要靶点。