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

儿童期虐待和忽视是许多儿童发育的主要风险因素， 精神病理学，在许多情况下，作为慢性精神疾病，难以治疗， 成年早期生活压力（ELS）改变对压力的脆弱性的分子机制， 人类的认知能力目前还知之甚少。然而，在啮齿动物和非人类中的类似观察结果 灵长类动物表明，至少这个过程的某些方面是保守的，可以在动物中进一步研究。 模型在这里，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 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 修剪导致建立低效的布线网格，持续到成年期，并影响复杂的 行为这一假设与越来越多的研究结果一致，这些研究表明小胶质细胞在神经系统中起着重要的作用。 在突触修剪中起重要作用，暴露于ELS与边缘系统棘密度增加有关。 持续到成年期的区域。此外，糖皮质激素抑制体内小胶质细胞活性的能力 并且在体外使它们成为ELS的可能细胞靶点。这些发现提供了第一个证据， ELS的一些发育后果是通过损害小胶质细胞功能来介导的， 突触修剪我们预测，类似的MG功能失调将在 我们的小鼠模型将产生新的诊断和治疗策略， 暴露于ELS导致的精神病理学。 .

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. .