Targeted inhibition of stress associated pathways to promote resilience against maternal immune activation

临床证据表明，暴露于母体免疫激活(MIA) 在产前期间(例如，在怀孕期间感染流感)会增加患上 神经发育障碍，如精神分裂症和自闭症谱系障碍。这些 障碍与一组不同的症状的表现有关，包括 在以后的生活中出现的社会缺陷。这些社会基础的机械论基础 中断以及它们如何与环境相互作用并不是很清楚，但很可能是 确定影响心理弹性的因素与应对心理挑战的敏感性的途径 健康功能。利用动物模型，我们的目标是确定这种不利的早期健康 经验改变男性和女性大脑回路的发展，以找到预防措施 干预和治疗。我们最近的工作表明，MIA导致了基因的过度表达 应激敏感基因促肾上腺皮质激素释放因子(CRH)及其相关受体Crhr1 大脑中对社会行为和认知起中心作用的区域。为怀孕的水坝提供住房 环境浓缩(一种翻译相关的干预措施)通过以下方式保护胎儿 维持胎盘11-β羟基类固醇脱氢酶(11HSD)1和11HSD2 母体皮质酮在产前免疫挑战时的代谢 疾病还可以防止CRH和CRHr1的过度表达和相关的社会损伤 与MIA相关。以确认孕妇血浆皮质酮水平过高 应对压力敏感基因的晚年过度表达和社会损伤负责(目的 1)，我们将使用一种临床可用的细胞色素P450 11B1的抑制剂，线粒体(11β-羟基酶)，该酶催化肾上腺皮质皮质醇合成的最后一步。 我们将使用这种抑制剂来减弱与MIA相关的内分泌激活，以测试这是否 防止这些MIA引起的神经和社会变化。与此相关，我们将探索保护 对抗MIA相关的Crhr1信号机制和表观遗传机制的变化。在……里面 目的2，我们将使用Crhr1拮抗剂来确定这种药物干预是否可以防止 和/或逆转MIA对社会行为的影响。最后，使用病毒式工具，我们将开始 研究评估靶向缺失Crhr1是否可以预防 如果过度表达可以反过来抵消环境的保护作用 富集型住房。总之，这些研究将有助于确定和确认通过哪些机制 临床上使用的环境操作，如浓缩，为 发育中的大脑。

Clinical evidence suggests that exposure to maternal immune activation (MIA) during the prenatal period (e.g., having the flu during pregnancy) increases the susceptibility for neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. These disorders are associated with the manifestation of a heterogeneous set of symptoms, including social impairments, which emerge in later life. The mechanistic underpinnings of these social disruptions and how they interact with the environment are not well understood but are a likely path for identifying factors contributing to resilience vs susceptibility against challenges to mental health functioning. Using an animal model, we aim to determine how this adverse early health experience alters the development of brain circuitry in males and females, to find preventative interventions and treatments. Our recent work shows that MIA causes an overexpression of the stress sensitive gene corticotropin releasing factor (Crh), and its associated receptor Crhr1, in areas of the brain central to social behavior and cognition. Housing pregnant dams in environmental enrichment (a translationally relevant intervention) protects the fetus by maintaining the placental 11-beta hydroxysteroid dehydrogenase (11HSD)1 and 11HSD2 metabolism of maternal corticosterone at the time of prenatal immune challenge; this housing condition also protects against Crh and Crhr1 overexpression and related social impairments associated with MIA. To confirm that excessive levels of maternal plasma corticosterone are responsible for the later life overexpression of stress sensitive genes and social impairments (Aim 1), we will employ a clinically available inhibitor of cytochrome P450 11B1, mitochondrial (11β-hydroxylase), the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex. We will use this inhibitor to attenuate the endocrine activation associated with MIA to test if this prevents these MIA-induced neural and social changes. Relatedly, we will explore protection against MIA-associated changes in Crhr1 signaling mechanisms and epigenetic machinery. In Aim 2, we will use a Crhr1 antagonist to determine if this pharmacological intervention can prevent and/or reverse the effects of MIA on social behaviors. Finally, using viral tools, we will begin studies to evaluate whether targeted deletion of Crhr1 can prevent the social consequences of MIA, and if overexpression can in turn counteract the protective effects of environmental enrichment housing. Together, these studies will help identify and confirm mechanisms by which clinically utilized environmental manipulations, such as enrichment, offer protection to the developing brain.