Targeting and preventing a mechanistic basis of risk after early life stress

描述(申请人提供)：该项目旨在阐明早期生活应激(ELS)在动物模型中的相互作用的神经生物学和免疫学效应。这些研究的首要目标是通过在早期和关键时期进行干预来预防晚年的行为缺陷。这一结果可能会转化为识别哪些接触ELS的人容易患精神障碍，哪些可能从预防性治疗中受益的技术。我们有令人兴奋的大鼠初步数据表明，ELS导致前额叶皮质(PFC)表达小白蛋白(PVB)的中间神经元丢失，并在青春期出现认知障碍，这是几种精神疾病的关键特征。此外，ELS的这些影响可以通过抑制青春期前的神经炎性活动来预防。神经炎性损伤主要通过细胞因子和谷氨酸的作用发生。我们最近发现，在ELS暴露的青少年中，循环中的细胞因子和谷氨酸受体都发生了变化。因此，拟议的实验将确定ELS如何破坏PFC中免疫信号和谷氨酸受体的健康发育轨迹，从而在以后的生活中造成有害的变化。这些研究实现了两个具体目标。首先，我们将检查潜在的免疫生物标记物，这些标记物可以预测ELS的后续效果。我们将使用一种高灵敏度的方法来测量暴露于不同时间段的ELS的幼鼠的循环细胞因子。与免疫学测量专家的合作将使我们能够从少量血液样本中检测多种细胞因子。不同ELS时间进程的效果的比较也将有助于澄清文献中存在的不一致之处。我们将通过将早期水平与PVB和行为的后期变化相关联来评估循环细胞因子的预测价值。其次，我们将通过研究谷氨酸受体在ELS效应中的作用来定位细胞和行为功能障碍的机制原因。在一个实验中，我们将针对NMDA受体亚单位NR2a，我们已经证明它在ELS青少年中过度表达。在青春期前的窗口期，我们将向PFC微量注射细胞渗透性多肽TAT2A，以便将NR2A从细胞内机制中分离出来。我们将确定阻断NR2A过度表达的影响是否有助于保护暴露于ELS的动物免受PVB丢失和行为功能障碍的影响。在另一个实验中，我们将调查ELS诱导的神经炎症是否会产生与其他炎症事件相同的AMPA受体的有害变化。综上所述，我们将检验以下假设：ELS增加炎症信号，该信号与改变的PFC谷氨酸能受体发育相互作用，导致青春期行为和神经功能障碍。

DESCRIPTION (provided by applicant): This project aims to elucidate the interactive neurobiological and immunological effects of early life stress (ELS) in an animal model. The overarching goal of these studies is to prevent behavioral deficits later in life by intervening during an early and critical period. The results could potentially translate to techniques for identifying which ELS-exposed individuals are vulnerable to psychiatric disorders, and which might benefit from prophylactic therapies. We have exciting preliminary data in rats that shows ELS leads to the loss of parvalbumin (PVB)- expressing interneurons in the prefrontal cortex (PFC) and cognitive deficits during adolescence, which are key features of several psychiatric disorders. Moreover, these effects of ELS are preventable with pre-adolescent inhibition of neuroinflammatory activity. Neuroinflammatory damage occurs largely through the actions of cytokines and glutamate. We recently showed that both circulating cytokines and glutamatergic receptors are altered in ELS-exposed adolescents. Therefore, the proposed experiments will determine how ELS derails the healthy developmental trajectory of immune signals and glutamatergic receptors in the PFC to cause deleterious changes later in life. These studies accomplish two specific aims. First, we will examine potential immunological biomarkers that could predict later effects of ELS. We will use a highly sensitive assay to measure circulating cytokines in young rats exposed to varied time-courses of ELS. Collaboration with an expert on immunological measurements will allow us to assay multiple cytokines from small blood samples. The comparison of effects from different ELS time-courses will also help clarify existing inconsistencies in the literature. We will assess the predictive value of circulating cytokines by correlating early levels with later changes in PVB and behavior. Second, we will localize a mechanistic cause of cellular and behavioral dysfunction by investigating the role of glutamatergic receptors in ELS effects. In one experiment, we will target the NMDA receptor subunit NR2A, which we have shown is over-expressed in ELS adolescents. During the pre-adolescent window, we will microinject the cell-permeable peptide TAT2A into the PFC in order to uncouple NR2A from the intracellular machinery. We will determine whether blocking the effects of NR2A overexpression will help protect ELS-exposed animals from PVB loss and behavioral dysfunction. In another experiment, we will investigate whether ELS-induced neuroinflammation produces the same deleterious changes in AMPA receptors as other inflammatory events have been shown to produce. Taken together, we will test the following hypothesis: ELS increases inflammatory signaling that interacts with altered PFC glutamatergic receptor development to cause behavioral and neural dysfunction in adolescence.