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，怀孕期间患流感）增加了对 神经发育障碍如精神分裂症和自闭症谱系障碍。这些 疾病与一组异质性症状的表现有关，包括 在晚年出现的社交障碍这些社会的机械基础 破坏以及它们如何与环境相互作用还没有得到很好的理解， 确定有助于恢复力的因素与对心理挑战的敏感性的途径 健康功能。使用动物模型，我们的目标是确定这种不利的早期健康 经验改变了男性和女性大脑回路的发育， 干预和治疗。我们最近的研究表明，MIA引起了过度表达的 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Crhr 1， 大脑中对社会行为和认知至关重要的区域。妊娠母鼠的饲养 环境富集（一种预防性相关干预）通过以下方式保护胎儿： 维持胎盘11-β羟基类固醇脱氢酶（11 HSD）1和11 HSD 2 在产前免疫激发时母体皮质酮的代谢;这种住房 条件还保护免受Crh和Crhr 1过表达和相关的社会障碍 与MIA有关。为了证实母体血浆皮质酮水平过高， 负责晚年过度表达的压力敏感基因和社会障碍（目的 1），我们将采用临床上可用的细胞色素P450 11 B1，线粒体（11β-羟化酶），催化肾上腺皮质醇合成的最后一步的酶的抑制剂。 我们将使用这种抑制剂来减弱与MIA相关的内分泌激活，以测试这种抑制剂是否能抑制MIA。 阻止了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Crhr 1信号机制和表观遗传机制的变化。在 目的2，我们将使用Crhr 1拮抗剂来确定这种药物干预是否可以预防 和/或逆转MIA对社会行为的影响。最后，使用病毒工具，我们将开始 研究评估是否有针对性地删除Crhr 1可以防止的社会后果， MIA，如果过度表达可以反过来抵消环境保护作用， 丰富的住房。总之，这些研究将有助于识别和确认 临床上使用的环境操作，如富集，提供保护， 大脑发育

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.