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

描述（由申请人提供）：本项目旨在阐明早期生活应激（ELS）在动物模型中的交互神经生物学和免疫学作用。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以后生活中的行为缺陷。研究结果可能转化为识别哪些暴露于els的个体易患精神疾病的技术，以及哪些可能受益于预防性治疗。我们在大鼠身上获得了令人兴奋的初步数据，显示ELS导致青春期前额皮质（PFC）中表达小白蛋白（PVB）的中间神经元的缺失和认知缺陷，这是几种精神疾病的关键特征。此外，这些影响可以通过青春期前神经炎症活性的抑制来预防。神经炎症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，在暴露于els的青少年中，循环细胞因子和谷氨酸能受体都发生了改变。因此，该实验将确定ELS如何详细描述PFC中免疫信号和谷氨酸能受体的健康发育轨迹，从而在以后的生活中引起有害的变化。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志物，可以预测ELS的后期影响。我们将使用一种高度敏感的测定方法来测量暴露于不同时间过程的ELS的年轻大鼠的循环细胞因子。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。比较不同ELS时程的效应也有助于澄清文献中存在的不一致之处。我们将通过将循环细胞因子的早期水平与后期PVB和行为的变化相关联来评估其预测价值。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。在一项实验中，我们将瞄准NMDA受体亚基NR2A，我们已经证明NR2A在ELS青少年中过度表达。在青春期前的窗口期，我们将向PFC微注射细胞渗透性肽TAT2A，以便将NR2A从细胞内机制中解耦。我们将确定阻断NR2A过表达是否有助于保护els暴露的动物免受PVB丢失和行为功能障碍的影响。在另一项实验中，我们将研究els诱导的神经炎症是否会产生与其他炎症事件相同的AMPA受体有害变化。综上所述，我们将验证以下假设：ELS增加炎症信号，与PFC谷氨酸能受体发育改变相互作用，导致青少年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.