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

描述（由申请人提供）：童年虐待和忽视是许多儿童精神病理发展的主要危险因素，在许多情况下，这些精神病理在成年后难以治疗的慢性精神疾病。早期生活压力（ELS）改变人类对压力和认知脆弱性的分子机制目前尚不清楚。然而，在啮齿类动物和非人灵长类动物中的类似观察表明，至少这一过程的某些方面是保守的，可以在动物模型中进一步研究。在这里，我们提供的初步数据表明，ELS通过下调脂多糖结合蛋白（LBP）等基因的表达来损害成年期的海马功能，这些基因在发育的关键时期支持小胶质细胞介导的突触修剪是必要的。异常的突触修剪会导致低效的神经网络的建立，这种网络会持续到成年，并影响复杂的行为。

DESCRIPTION (provided by applicant): 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. .