Microglia play a critical role in the long-term sequelae of early life stress

小胶质细胞在早期生活压力的长期后遗症中发挥着关键作用

• 批准号: 8630734
• 负责人: ARIE KAFFMAN
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630734
• 关键词: Acute; Adolescent; Adult; Affect; Animal Model; Anxiety; Area; Behavior; Behavioral; Brain; Cells; Child; Child Abuse; Childhood; Chromatin; Chromatin Structure; Chronic; Chronic stress; Cognition; Complex; Corticosterone; Data; Development; Diagnosis; Down-Regulation; Event; Exposure to; Figs - dietary; Gene Expression; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Hippocampus (Brain); Histone Acetylation; Histones; Human; Human Development; Immune system; In Vitro; Intervention; Knockout Mice; Life; Life Stress; Maps; Mediating; Mental Depression; Microglia; Molecular; Morphology; Mus; Pathway interactions; Phagocytes; Play; Process; Proteins; Protocols documentation; Psychopathology; RU-486; Recruitment Activity; Refractory; Risk Factors; Rodent; Role; Stress; Synapses; Testing; Transgenic Animals; Vertebral column; Viral; Work; abuse neglect; acute stress; base; cellular targeting; chromatin immunoprecipitation; critical period; density; in vivo; indexing; insight; lipopolysaccharide-binding protein; maternal separation; mouse model; neglect; neurodevelopment; nonhuman primate; novel; novel diagnostics; novel strategies; promoter; protein expression; psychotic symptoms; public health relevance; pup; response; severe mental illness; synaptic function

Childhood abuse and neglect are major risk factors for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses that are refractory to treatment in adulthood. The molecular mechanisms by which early life stress (ELS) modifies vulnerability to stress and cognition in humans are currently poorly understood. However, similar observations in rodents and nonhuman primates suggest that at least some aspects of this process are conserved and can be further studied in animal models. Here we present preliminary data that suggest that ELS impairs hippocampal function in adulthood by down regulating expression of genes, such as the lipopolysaccharide binding protein (LBP), that are necessary to support microglia-mediated synaptic pruning during a critical period of development. Abnormal synaptic pruning leads to the establishment of inefficient wiring grid that persists into adulthood and affects complex behavior. This hypothesis is consistent with a growing body of work showing that microglia cells play an essential role in synaptic pruning and that exposure to ELS is associated with increased spine density in limbic areas that persist into adulthood. In addition, the ability of glucocorticoids to suppress microglia activity in vivo and in vitro makes them a likely cellular target for ELS. These findings provide the first evidence to suggest that some of the developmental consequences of ELS are mediated by impairing microglia function and synaptic pruning in the mouse. We predict that similar dysregulation of MG function will be confirmed in children and adolescents and that our mouse model will generate novel strategies to diagnose and treat psychopathologies caused by exposure to ELS in humans. .

童年时期的虐待和忽视是发展众多童年的主要风险因素 在许多情况下，心理病理学是持续的慢性精神疾病，对治疗的治疗难治性 成年。早期生活压力（ELS）通过的分子机制改变了压力和压力的脆弱性 目前对人类的认知知之甚少。但是，对啮齿动物和非人类的类似观察 灵长类动物表明，至少该过程的某些方面是保守的，可以在动物中进一步研究 型号。在这里，我们提供了初步数据，表明EL会损害成年后的海马功能 调节基因的表达，例如脂多糖结合蛋白（LBP），这是必要的 在关键的开发期间支持小胶质细胞介导的突触修剪。异常突触 修剪会导致建立效率低下的接线电网，该网格持续到成年并影响复杂 行为。该假设与越来越多的作品一致，表明小胶质细胞的作用 在突触修剪和暴露于ELS的基本作用与边缘的脊柱密度增加有关 持续到成年的地区。另外，糖皮质激素抑制体内小胶质细胞活性的能力 并在体外使其成为EL的细胞靶标。这些发现提供了第一个建议的证据 EL的某些发展后果是通过损害小胶质细胞功能和 鼠标中的突触修剪。我们预测，MG功能的类似失调将在 儿童和青少年，我们的鼠标模型将产生诊断和治疗的新型策略 受到人类EL的暴露引起的心理病理学。 。