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

描述(申请人提供)：童年虐待和忽视是许多儿童精神病态发展的主要风险因素，在许多情况下，这些疾病作为慢性精神疾病挥之不去，成年后难以治疗。早期生活应激(ELS)改变人类对应激和认知的易感性的分子机制目前知之甚少。然而，在啮齿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后的海马体功能，这些基因是在发育的关键时期支持小胶质细胞介导的突触修剪所必需的。不正常的突触修剪导致低效连接网格的建立，这种连接网格会持续到成年期，并影响复杂的行为。 这一假设与越来越多的工作相一致，这些工作表明，小胶质细胞在突触修剪中发挥着重要作用，暴露于ELS与边缘区域脊柱密度的增加有关，这种密度一直持续到成年。此外，糖皮质激素能够 在体内和体外抑制小胶质细胞的活性使它们可能成为ELS的细胞靶点。这些 这些发现首次证明ELS的一些发育后果是由小鼠小胶质细胞功能受损和突触修剪介导的。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诊断和治疗人类暴露于ELS引起的精神病理的新策略。。

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. .