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. .

童年虐待和忽视是许多童年发展的主要危险因素 在许多情况下作为慢性精神疾病挥之不去的精神病理学，这些疾病在 成人期。早期生活应激(ELS)改变应激易感性的分子机制 目前人们对人类的认知知之甚少。然而，在啮齿动物和非人身上也观察到了类似的现象 灵长类动物认为，这一过程至少有某些方面是保守的，可以在动物身上进一步研究。 模特们。在这里，我们提供了初步数据，表明ELS通过以下方式损害成年时的海马体功能 下调必需基因的表达，如脂多糖结合蛋白(LBP) 在发育的关键时期支持小胶质细胞介导的突触修剪。异常突触 修剪会导致建立低效的配电网，这种配电网会一直持续到成年，并影响复杂的 行为。这一假设与越来越多的工作相一致，表明小胶质细胞在 突触修剪中的重要作用以及暴露于ELS与边缘脊椎密度增加相关 持续到成年期的区域。此外，糖皮质激素在体内抑制小胶质细胞活性的能力 在体外，它们可能成为ELS的细胞靶点。这些发现提供了第一个证据，表明 ELS的一些发育后果是通过损害小胶质细胞功能和 小鼠的突触修剪。我们预测，类似的MG功能失调将在 儿童和青少年，我们的小鼠模型将产生新的诊断和治疗策略 暴露于ELS对人类造成的精神病态。 。