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

基本信息

批准号：
10615734
负责人：
ARIE KAFFMAN
金额：
$ 57.4万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615734
关键词：
Address Adolescent Adult Adverse event Affect Amygdaloid structure Anhedonia Animal Model Anxiety Beds 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 Genes Genetic Genomics Hippocampus 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 Testing Virus Work anxiety reduction anxiety-like behavior 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 synergism tool transcription factor

项目摘要

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.

抽象的儿童虐待增加了依赖剂量的焦虑和其他心理病理的风险方式。生命早期协同影响焦虑的多个不利事件的机制很差在人类中了解到，在早期生命压力的动物模型中几乎没有努力澄清这个问题（ELS）。我们最近表明，接触UPS，这是EL的复杂且无法预测的小鼠模型，导致焦虑症的强劲增加，这在暴露于简单且可预测的范式的小鼠中没有看到 Els被称为有限的床上用品（LB）。有趣的是，暴露于LB或UPS不会影响焦虑状雌性小鼠的行为。由于杏仁核与额 - 边缘大脑区域（例如海马（HPC）和前额叶皮层（PFC）在类似焦虑的行为和暴露于儿童虐待会导致我们使用的这些大脑区域之间的异常连通性静止状态fMRI（RSFMRI）将Amygdala连接与HPC和PFC进行UPS和Control中的PFC进行比较雄性老鼠。我们发现杏仁核与PFC之间以及杏仁核之间的连通性提高了和UPS男性的HPC。重要的是，论文连接的强度与焦虑高度相关 - 喜欢行为。在此应用中，我们假设与PFC和HPC的杏仁核连接性在围产期进行小胶质细胞介导的修剪。在男性中，EL的更严重形式，例如 UPS，导致主要调节剂PU.1在产后小胶质细胞中的表达更大。这是转弯会导致剂量依赖性损害，从而在调节焦虑的额 - 边缘连接的完善中。暴露于LB或UPS对女性的PU.1水平和小胶质功能没有影响。结果，女性暴露于LB或UPS时，显示正常的杏仁核连通性和焦虑。 AIM 1的工作将使用RSFMRI 和高分辨率DTI测试不同类型的EL（UPS和LB）如何与性相互作用以改变额额 - 连接性。在AIM 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。这种方法将使我们精确地绘制这些预测，确定它们对焦虑的贡献，并评估其诱导C-Fos激活和使用fMRI改变粗体信号。 AIM 3提出的研究将使用RSFMRI和高分辨率DTI 表征PU.1-HETS小鼠中功能和结构连通性。这种方法的优势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使用小胶质的特定遗传操纵，使用光学遗传学和化学遗传工具严格测试因果关系，并利用人类成像在EL的小鼠模型中评估大脑连通性的工具。