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

针对和预防早期生活压力后风险的机械基础

基本信息

批准号：
8738713
负责人：
Heather C Brenhouse
金额：
$ 26.41万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738713
关键词：
AMPA Receptors Address Adolescence Adolescent Adult Affect Animal Model Animals Behavior Behavioral Biological Assay Biological Markers Biomedical Research Blood specimen Caring Cells Child Childhood Cognitive deficits Collaborations Data Detection Development Disease Event Exploratory/Developmental Grant Exposure to Flow Cytometry Functional disorder Glutamate Receptor Glutamates Goals Image Immune Individual Inflammatory Interneurons Intervention Investigation Late Effects Life Life Stress Literature Longevity Measurement Measures Medical Mental disorders Molecular N-Methyl-D-Aspartate Receptors National Institute of Mental Health Neurobiology Neurons Parvalbumins Peptides Plant Roots Predictive Value Predisposition Prefrontal Cortex Prevention Publishing Rattus Research Risk Risk Factors Role Signal Transduction Strategic Planning Stress Symptoms Techniques Testing Time Translating Vulnerable Populations Work base critical period cytokine emerging adult excitotoxicity experience high risk improved neuroinflammation overexpression prevent prophylactic public health relevance receptor relating to nervous system research study young adult

项目摘要

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.

描述（由申请人提供）：该项目旨在阐明动物模型中早期生活压力（ELS）的交互神经生物学和免疫学影响。这些研究的总体目标是通过在早期关键时期进行干预来预防晚年的行为缺陷。研究结果可能转化为技术，用于识别哪些 ELS 暴露个体易患精神疾病，以及哪些个体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，表明 ELS 会导致前额皮质 (PFC) 中表达小清蛋白 (PVB) 的中间神经元丢失，并导致青春期认知缺陷，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青春期前抑制神经炎症活动来预防。神经炎症损伤主要是通过细胞因子和谷氨酸的作用发生的。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受体都发生了改变。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，我们将检查可以预测 ELS 后期效果的潜在免疫生物标志物。我们将使用高度灵敏的测定法来测量暴露于不同时间段 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小量血液样本中检测多种细胞因子。比较不同 ELS 时间进程的效果也将有助于澄清文献中现有的不一致之处。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。在一项实验中，我们将针对 NMDA 受体亚基 NR2A，我们已证明该受体亚基在 ELS 青少年中过度表达。在青春期前的窗口期，我们将细胞渗透性肽 TAT2A 显微注射到 PFC 中，以便将 NR2A 与细胞内机制解偶联。我们将确定阻断 NR2A 过度表达的影响是否有助于保护 ELS 暴露的动物免受 PVB 损失和行为功能障碍。在另一项实验中，我们将研究 ELS 诱导的神经炎症是否会像其他炎症事件一样在 AMPA 受体中产生相同的有害变化。综上所述，我们将检验以下假设：ELS 增加炎症信号传导，与改变的 PFC 谷氨酸受体发育相互作用，从而导致青春期的行为和神经功能障碍。