Amygdala hyper-connectivity in a mouse model of unpredictable early life stress

不可预测的早期生活压力小鼠模型中的杏仁核超连接性

• 批准号: 9816070
• 负责人: ARIE KAFFMAN
• 金额: $ 50.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816070
• 关键词: Address; Adolescent; Adult; Adverse event; Affect; Amygdaloid structure; Anhedonia; Animal Model; Anxiety; Behavior; Brain; Brain region; Child Abuse and Neglect; Complex; Data; Diffusion Magnetic Resonance Imaging; Dose; Etiology; Exposure to; FOS gene; Female; Functional Magnetic Resonance Imaging; Genetic; Genomics; Hippocampus (Brain); Human; Imaging Device; Impairment; Individual; Label; Lead; Life; Maps; Mediating; Mental Depression; Microglia; Microscopic; Mus; Names; Pattern; Phagocytes; Play; Prefrontal Cortex; Process; Psychopathology; Resolution; Rest; Risk; Rodent; Role; Signal Transduction; Stress; Structure; Testing; Transgenic Organisms; Virus; Work; anxiety-like behavior; base; cell motility; early life stress; genetic manipulation; human imaging; male; maternal separation; mouse model; multidisciplinary; novel; novel imaging technique; optogenetics; perinatal period; postnatal; postnatal period; programs; protein expression; resilience; sex; synaptic pruning; tool; transcription factor

Abstract Childhood maltreatment increases the risk for anxiety and other psychopathologies in a dose-dependent manner. The mechanisms by which multiple adverse events early in life synergize to affect anxiety is poorly understood in humans and little effort has been made to clarify this issue in animal models of early life stress (ELS). We recently showed that exposure to UPS, which is a complex and unpredictable mouse model of ELS, leads to robust increase in anxiety that was not seen in mice exposed to a simple and predictable paradigm of ELS known as the limited bedding (LB). Interestingly, exposure to LB or UPS did not affect anxiety-like behavior in female mice. Since amygdala connectivity with fronto-limbic brain regions such as the hippocampus (HPC) and the prefrontal cortex (PFC) play an important role in anxiety-like behavior and exposure to childhood maltreatment leads to abnormal connectivity between these brain regions we used resting state fMRI (rsfMRI) to compare amygdala connectivity with the HPC and the PFC in UPS and control male mice. We found increased connectivity between the amygdala and the PFC and between the amygdala and the HPC in UPS males. Importantly, the strength of theses connections was highly correlated with anxiety- like behavior. In this application we hypothesize that amygdala connectivity with the PFC and the HPC undergo microglial-mediated pruning during the perinatal period. In males, more severe forms of ELS, such as UPS, lead to greater reduction in the expression of the master regulator PU.1 in postnatal microglia. This in turn causes a dose-dependent impairment in the refinement of fronto-limbic connections that regulate anxiety. Exposure to LB or UPS has no effect on PU.1 levels and microglial function in females. As a result, females show normal amygdala connectivity and anxiety when exposed to LB or UPS. Work in aim 1 will use rsfMRI and high resolution DTI to test how different types of ELS (UPS and LB) interact with sex to alter fronto-limbic connectivity. In aim 2 we will use optogenetics and chemogenetics viruses to label and manipulate basolateral amygdala (BLA) projections to the PFC and HPC. This approach will allow us to precisely map the size of these projections, determine their contribution to anxiety, and assess their ability to induce c-fos activation and to alter BOLD signal using fMRI. Studies proposed in aim 3 will use rsfMRI and high resolution DTI to characterize functional and structural connectivity in PU.1-hets mice. The strength of this approach lies in the diverse expertise of our team. This multidisciplinary effort allows us to use microglial specific genetic manipulations, rigorously test causality using optogenetic and chemogenetic tools, and utilize human imaging tools to assess brain connectivity in a mouse model of ELS.

抽象的 童年虐待会增加焦虑和其他精神病理学的风险，且呈剂量依赖性 方式。生命早期的多种不良事件协同影响焦虑的机制尚不清楚 人类已经理解了这个问题，但在早期生活压力的动物模型中却很少努力去澄清这个问题 （ELS）。我们最近表明，接触 UPS（一种复杂且不可预测的 ELS 小鼠模型）， 导致焦虑的急剧增加，而这在暴露于简单且可预测的范式的小鼠中没有观察到。 ELS称为有限层理(LB)。有趣的是，接触 LB 或 UPS 并不会影响类焦虑 雌性小鼠的行为。由于杏仁核与额叶边缘大脑区域（例如 海马体（HPC）和前额叶皮层（PFC）在焦虑样行为和焦虑行为中发挥着重要作用。 童年时期遭受虐待会导致我们使用的这些大脑区域之间的连接异常 静息态 fMRI (rsfMRI)，用于比较 UPS 和控制中的杏仁核与 HPC 和 PFC 的连接性 雄性小鼠。我们发现杏仁核和前额皮质之间以及杏仁核之间的连接性增强 以及 UPS 男性的 HPC。重要的是，这些联系的强度与焦虑高度相关—— 喜欢的行为。在此应用中，我们假设杏仁核与 PFC 和 HPC 的连接 在围产期进行小胶质细胞介导的修剪。在男性中，更严重的 ELS 形式，例如 UPS 导致出生后小胶质细胞中主调节因子 PU.1 的表达大幅减少。这在 转角会导致调节焦虑的额叶边缘连接的细化出现剂量依赖性损害。 暴露于 LB 或 UPS 对女性的 PU.1 水平和小胶质细胞功能没有影响。结果，女性 当暴露于 LB 或 UPS 时，显示出正常的杏仁核连接和焦虑。目标 1 的工作将使用 rsfMRI 和高分辨率 DTI 来测试不同类型的 ELS（UPS 和 LB）如何与性相互作用以改变额叶边缘 连接性。在目标 2 中，我们将使用光遗传学和化学遗传学病毒来标记和操纵基底外侧 杏仁核 (BLA) 对 PFC 和 HPC 的预测。这种方法将使我们能够精确地绘制出 这些预测，确定它们对焦虑的贡献，并评估它们诱导 c-fos 激活和 使用功能磁共振成像改变 BOLD 信号。目标 3 中提出的研究将使用 rsfMRI 和高分辨率 DTI 表征 PU.1-hets 小鼠的功能和结构连接性。这种方法的优点在于 我们团队的多元化专业知识。这种多学科的努力使我们能够利用小胶质细胞特异性遗传 操作，使用光遗传学和化学遗传学工具严格测试因果关系，并利用人体成像 评估 ELS 小鼠模型中大脑连接性的工具。