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: 10078284
• 负责人: ARIE KAFFMAN
• 金额: $ 41.96万
• 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/10078284
• 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、前额皮质 (PFC) 和海马体 (HPC) 之间的连接异常。 早期生活压力 (ELS) 究竟如何改变额叶边缘连接以及这些变化如何促进 焦虑增加是很难在人类身上进行研究的问题。具体来说，问题是如何 ELS 与性相互作用以改变额叶边缘连接，而当前人类无法解决焦虑问题 研究。为了澄清这些问题，我们开发了一个 ELS 小鼠模型，我们将其命名为 Unpredictable 产后应激 (UPS)，小鼠在生命早期就面临不可预测且复杂的应激。我们发现 UPS 导致焦虑急剧增加，而在暴露于简单且可预测的形式的小鼠中未观察到这种情况 ELS，称为有限层理 (LB)。此外，我们发现 UPS 和 LB 优先增加焦虑 在雄性小鼠中。使用静息态功能磁共振成像 (rsfMRI)、高分辨率扩散磁共振成像 (dMRI) 和逆行追踪 我们发现雄性 UPS 小鼠在青少年期和成年期的连通性增强 并且与焦虑高度相关。 dMRI 的初步数据表明，额叶边缘连接不是 女性中发生改变，这些性别特异性效应与异常的突触修剪有关 雄性小胶质细胞中转录因子 IRF8 的水平降低，但雌性小胶质细胞中则没有。我们假设 杏仁核与 PFC 和 HPC 的连接在 产后期。这个过程需要出生后小胶质细胞中高水平的转录因子 IRF8，并且是 对于青少年时期和成年时期的焦虑水平至关重要。 UPS 减少表达 IRF8 存在于雄性小鼠中，但不存在于雌性小鼠中。这反过来又导致 UPS 中额叶边缘连接性和焦虑的增加 男性，但 UPS 女性除外。目标 1 的工作将使用 rsfMRI、dMRI 和双逆行追踪来表征 UPS、性别和年龄对额边缘连接的影响。目标 2 的研究将测试是否减少 IRF8 出生后小胶质细胞中的 UPS 足以模拟 UPS 对焦虑、额叶边缘连接、 小胶质细胞基因表达和吞噬活性。在目标 3 中，我们询问 IRF8 是否在产后过度表达 小胶质细胞可以使 UPS 小鼠的焦虑和额叶边缘连接正常化。顺利完成本次 该应用将定义小胶质细胞 IRF8 在完善额边缘连接和编程方面的新作用 小鼠的焦虑；鉴于 IRF8 在指导免疫方面发挥的保守作用，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 ELS 如何 对小鼠的小胶质细胞功能、杏仁核连接和焦虑有不同的影响。