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

描述（由申请人提供）：儿童期虐待和忽视是许多儿童期精神病理学发展的主要风险因素，在许多情况下，这些精神病理学作为慢性精神疾病在成年后难以治疗。早期生活压力（ELS）改变人类对压力和认知的脆弱性的分子机制目前知之甚少。然而，在啮齿类动物和非人类灵长类动物中的类似观察表明，这一过程的至少某些方面是保守的，可以在动物模型中进一步研究。在这里，我们提出的初步数据表明，ELS损害海马功能在成年期下调基因的表达，如脂多糖结合蛋白（LBP），这是必要的，以支持小胶质细胞介导的突触修剪在一个关键时期的发展。异常的突触修剪导致建立低效的布线网格，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一致，这些工作表明小胶质细胞在突触修剪中发挥重要作用，并且暴露于ELS与持续到成年的边缘系统区域的棘密度增加有关。此外，糖皮质激素能够 在体内和体外抑制小胶质细胞活性使它们成为ELS可能的细胞靶。这些 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鼠小胶质细胞功能和突触修剪来介导的。我们预测，类似的MG功能失调将在儿童和青少年中得到证实，我们的小鼠模型将产生新的策略来诊断和治疗人类暴露于ELS引起的精神病理学。.

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. .