Role of microglial IRF8 in the developmental consequences of early adversity

小胶质细胞 IRF8 在早期逆境发育后果中的作用

• 批准号: 9884887
• 负责人: ARIE KAFFMAN
• 金额: $ 43.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884887
• 关键词: Address; Adolescent; Adult; Affect; Age; Amygdaloid structure; Anxiety; Anxiety Disorders; Brain; Cells; Complex; Data; Development; Diffusion Magnetic Resonance Imaging; Exposure to; Female; Functional Magnetic Resonance Imaging; Gene Expression; Genetic; Hippocampus (Brain); Human; Immune response; Impairment; Individual; Life; Mediating; Microglia; Molecular; Mus; Names; Phagocytes; Phenocopy; Play; Prefrontal Cortex; Process; Psychopathology; Resolution; Rest; Risk; Rodent; Role; Stress; Structure; Testing; Transgenic Animals; Work; anxiety-like behavior; cell motility; early life adversity; early life stress; insight; male; mouse model; novel; novel imaging technique; overexpression; postnatal; postnatal period; programs; protein expression; sex; synaptic pruning; tool; transcription factor

Project Abstract Exposure to unpredictable and complex stress early in life increases the risk for developing anxiety disorder and abnormal connectivity between the amygdala, the prefrontal cortex (PFC), and the hippocampus (HPC). Exactly how early life stress (ELS) modifies fronto-limbic connectivity and how these changes contribute to increased anxiety are questions that are difficult to investigate in humans. Specifically, the question of how ELS interacts with sex to alter fronto-limbic connections and anxiety are not addressable with current human studies. To clarify these issues we developed a mouse model of ELS that we have named Unpredictable Postnatal Stress (UPS), in which mice are exposed to unpredictable and complex stress early in life. We found that UPS caused robust increase in anxiety that was not seen in mice exposed to simple and predictable form of ELS, known as limited bedding (LB). Moreover, we found that UPS and LB preferentially increased anxiety in male mice. Using resting state fMRI (rsfMRI), high resolution diffusion MRI (dMRI), and retrograde tracing we found increased connectivity in male UPS mice that was present during the juvenile period and adulthood and was highly correlated with anxiety. Preliminary data with dMRI indicate that fronto-limbic connectivity is not altered in females and that these sex specific effects are associated with abnormal synaptic pruning and reduced levels of the transcription factor IRF8 in male microglial, but not female microglia. We hypothesize that amygdala connectivity with the PFC and the HPC undergoes microglial-mediated pruning during the postnatal period. This process requires high levels of the transcription factor IRF8 in postnatal microglia and is critical for programming levels of anxiety during the juvenile period and adulthood. UPS reduces expression of IRF8 in males, but not female mice. This in turn leads to increase fronto-limbic connectivity and anxiety in UPS males, but not UPS females. Work in aim 1 will use rsfMRI, dMRI, and dual retrograde tracing to characterize the effects of UPS, sex and age on fronto-limbic connectivity. Studies in aim 2 will test whether reducing IRF8 in postnatal microglia is sufficient to phenocopy the effects of UPS on anxiety, fronto-limbic connectivity, microglial gene expression, and phagocytic activity. In aim 3 we ask whether overexpressing IRF8 in postnatal microglia can normalize anxiety and fronto-limbic connectivity in UPS mice. Successful completion of this application will define a novel role for microglial IRF8 in refining fronto-limbic connections and programming anxiety in the mouse; an important finding given the conserved role that IRF8 plays in guiding immune responses in humans and mice. In addition, this work will provide a new paradigm to explain how ELS differentially affects microglial function, amygdala connectivity, and anxiety in mice.

项目摘要 生命早期暴露于不可预测和复杂的压力会增加患焦虑症的风险 杏仁核，前额叶皮层（PFC）和海马（HPC）之间的连通性异常。 确切的早期生活压力（ELS）如何改变额 - 限制连接性以及这些变化如何促进 焦虑增加是人类难以调查的问题。具体而言，如何 Els与性相互作用以改变额 - 边缘的连接和焦虑与当前人类无法解决 研究。为了阐明这些问题，我们开发了一种我们命名不可预测的EL的鼠标模型 产后压力（UPS），其中小鼠在生命的早期就会暴露于不可预测和复杂的压力。我们发现 UPS导致焦虑的强劲增加，而暴露于简单且可预测形式的小鼠中看不到 EL，称为有限的床上用品（LB）。此外，我们发现UPS和LB优先增加焦虑症 在雄性老鼠中。使用静止状态fMRI（RSFMRI），高分辨率扩散MRI（DMRI）和逆行跟踪 我们发现在少年时期和成年期间存在的男性UPS小鼠的连通性提高 并与焦虑高度相关。使用DMRI的初步数据表明，额头连接不是 女性的改变，这些性别特定的影响与异常的突触修剪和 雄性小胶质细胞中的转录因子IRF8水平降低，但没有降低雌性小胶质细胞。我们假设 与PFC和HPC的杏仁核连接性在此期间经历小胶质细胞介导的修剪 产后期。此过程需要在产后小胶质细胞中高水平的转录因子IRF8，IS 在少年时期和成年期间对焦虑的编程至关重要。 UPS降低了 男性的IRF8，但不是雌性小鼠。这反过 男性，但没有女性。 AIM 1的工作将使用RSFMRI，DMRI和双逆行跟踪来表征 UPS，性别和年龄对额叶连通性的影响。 AIM 2中的研究将测试是否减少IRF8 在产后小胶质细胞中，足以表观化UPS对焦虑，额 - 边缘连通性的影响， 小胶质细胞表达和吞噬活性。在AIM 3中，我们询问是否过表达产后IRF8 小胶质细胞可以使UPS小鼠的焦虑和额额连通性正常化。成功完成 应用将定义小胶质IRF8在完善额 - 边缘连接和编程中的新作用 老鼠的焦虑；鉴于IRF8在指导免疫中所发挥的保守作用，这是一个重要的发现 人类和小鼠的反应。此外，这项工作将提供一个新的范式来解释如何 差异影响小鼠的小胶质功能，杏仁核连接性和焦虑。