Role of Kynurenine System on Brain Inflammatory Responses in the Offspring of Immune Challenged Rats

妊娠期感染引起的并发症是出现 子代患精神分裂症(SZ)。产前免疫挑战的动物模型为 认为发育免疫异常会促进疾病的特定脆弱性的观点。转换为 从色氨酸到犬尿氨酸的氨基酸(KYN)及其相关代谢物(统称为 犬尿氨酸)是病毒和细菌感染时激活的机制之一。尤其是Kynuren 已知酸(KYNA)具有神经活性，在SZ的大脑皮层中也会升高 病人。本项目的目的是评价犬尿氨酸系统在 建立了产前感染的动物模型。中心假设是酶的激活 吲哚胺2，3-双加氧酶对病毒核糖核酸模拟物L：C在母亲体内的反应导致 增加犬尿氨酸的产生，包括胚胎大脑中的KYNA。KYNA的这一增长将在 反过来，负责促进小胶质细胞采用另一种激活状态，也称为M2 激活。进一步假设，激活状态的这种转变将始终保持 发育，至少在一定比例的小胶质细胞中，它将在应激源反应中加剧 从而增强了大脑中KYNA的产生。与中心的中心假说一致 格兰特说，大脑中KYNA水平的增加被认为是认知障碍的原因。我们会 用多聚L：C产前攻击的大鼠进行一系列研究，以检验这些假说 包括a)记录犬尿氨酸途径在出生前和出生后的变化轨迹 脑发育及其与小胶质细胞激活的关系；b)评估外周和中枢犬尿氨酸 和小胶质细胞对青春期前社会应激源的反应；以及c)测试Timed Kat II 抑制(减少KYNA的产生)可预防和/或逆转围术期出现的神经行为缺陷。 青少年。本项目还将涉及外周和胎盘细胞因子和 母亲的犬尿氨酸反应，以及后代的外周和中枢免疫反应。

Complications due to infections during pregnancy are a significant risk factor for the emergence of schizophrenia (SZ) in the offspring. Animal models of prenatal immune challenge provide support for the idea that developmental immune abnormalities promote specific vulnerabilities of the disease. Conversion of the amino acid tryptophan to kynurenine (KYN) and its associated metabolites (collectively referred to as kynurenines) is one ofthe mechanisms activated during viral and bacterial infections. In particular, kynurenic acid (KYNA) is known to have neuroactive properties and is also elevated in the cerebral cortex of SZ patients. The purpose ofthe present project is to evaluate the involvement ofthe kynurenine system in the established animal model of prenatal infection. The central hypothesis is that activation ofthe enzyme indoleamine 2,3-dioxygenase (IDO) in response to the viral RNA mimetic poly l:C in the mother leads to increased production of kynurenines, including KYNA in the brain of embryos. This increase in KYNA will in turn be responsible for promoting microglia to adopt an alternative activated state also known as M2 activation. It is further hypothesized that this shift in activation state will be maintained throughout development, at least in a proportion of microglia, and that it will be exacerbated in response to stressors resulting in enhanced production of KYNA in the brain. In concert with the central hypothesis ofthe center grant, an increase in KYNA levels in the brain is believed to be responsible for cognitive impairments. We will test these hypotheses using rats prenatally challenged with poly l:C and subjected to a series of studies including a) documenting the trajectory of changes in the kynurenine pathway during pre and post- natal brain development and in relation to microglia activation; b) evaluating peripheral and central kynurenines and microglial responses to social stressors during peri-adolescence; and c) testing whether timed KAT II inhibition (reduction of KYNA production) prevents and/or reverses the neurobehavioral deficits seen in peri- adolescents. The present project will also involve the study of peripheral and placental cytokine and kynurenine responses in the mothers, as well as peripheral and central immune responses in the offspring.