Impact of immune cell-derived exosomes and miRNAs on brain function and behavior

免疫细胞衍生的外泌体和 miRNA 对大脑功能和行为的影响

• 批准号: 10083112
• 负责人: Shinichi Kano
• 金额: $ 34.64万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-16 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083112
• 关键词: Adaptive Immune System; Address; Adoptive Transfer; Adult; Affect; Attenuated; B-Lymphocytes; Back; Basic Science; Behavior; Behavioral; Brain; Cells; Communication; Data; Development; Disease; Enzymes; Exhibits; FOS gene; Foundations; Functional disorder; Future; Gene Expression; Genes; Goals; Health; Homeostasis; Immune; Immunodeficient Mouse; Impairment; Injections; Lead; Learning; Medial; Mediator of activation protein; Memory; Mental Depression; Mental disorders; Methods; MicroRNAs; Microglia; Molecular; Morphology; Mus; Neurons; Peripheral; Phenotype; Prefrontal Cortex; Production; Proteins; Rag1 Mouse; Reporting; Rodent; Role; SCID Mice; Schizophrenia; Serum; Social Behavior; Splenocyte; Synapses; T-Lymphocyte; Techniques; Testing; Therapeutic; Wild Type Mouse; adeno-associated viral vector; anxiety-like behavior; anxiety-related behavior; autism spectrum disorder; base; brain cell; cytokine; design; excitatory neuron; exosome; experimental study; genetic approach; gut microbiota; hippocampal pyramidal neuron; mind control; mouse model; novel; novel therapeutic intervention; social

ABSTRACT Adaptive immune cells in the periphery (T and B cells) and innate immune cells in the brain (microglia) have been implicated in the brain homeostasis in health and disease. Rodent studies using immunodeficient mice have revealed that the loss of adaptive immune cells (T and B cells) led to impaired learning and memory, anxiety-like behaviors, and impaired sociability. Nevertheless, it is not clear how adaptive immune cells communicate with microglia and affect brain development and function. Our long-term goal is to understand the molecular and cellular mechanisms underlying the communication between adaptive immune cells and brain cells during brain development and in adulthood. Our preliminary studies revealed that Rag1-/- and [Rag2- /-mice], lacking both T and B cells, exhibited impaired social behaviors. In Rag1-/- mice, increased c-Fos expression and altered microglial phenotypes in the medial prefrontal cortex (mPFC) were observed. This is consistent with previous reports that mPFC dysfunction is involved in social behaviors. [Notably, adoptive transfer of wild-type (WT) splenocytes (containing T and B cells) rescued Rag1-/- social behavioral deficits. Further, injection of WT serum exosomes rescued the same phenotype. The social behavioral deficits were also observed in Rag2-/- mice despite the fact that Rag2 is normally absent in the WT brain. Together, these findings suggest that T and B cells contribute to social behaviors via exosomes.] Indeed, we observed that exosomes from the sera of Rag1-/- mice lacked the expression of T and B cell markers and multiple microRNAs (miRNAs) presumably derived from T and B cells. The expression of predicted target gene(s) of these miRNAs, such as Ski, was enhanced in the PFC of Rag1-/- mice. In contrast, WT serum exosomes decreased Ski expression in microglia. Recent studies showed that microglia control neuronal synapses. Thus, our data suggest that deficient adaptive immune cell-microglia communication via exosomes impairs social behaviors by altering mPFC function. Hence, in this study, we will test our hypothesis that the lack of adaptive immune cell-derived exosomes and their miRNAs results in impaired social behaviors via altered microglial control of neuronal function in the medial PFC. We will first validate and extend our findings on serum exosomes and the mPFC neurons in Rag1-/- mice, and determine the causal role for the lack of adaptive immune cells by restoring them back into Rag1-/- mice with adoptive transfer technique (Aim 1). We will also examine the direct impact of impaired exosome release and miRNA production in adaptive immune cells on microglia and neurons in the mPFC and social behaviors by genetic approaches (Aim 2). [In addition, we will address the contribution of pyramidal neurons and microglia in the mPFC to impaired social behaviors (Aim 3).] This study will reveal novel mechanisms whereby adaptive immune cell-derived exosomes influence brain function and behavior and may eventually lead to novel therapeutic strategies in psychiatric disorders.

抽象的 周围（T和B细胞）中的自适应免疫细胞和大脑中先天免疫细胞（小胶质细胞）具有 与大脑体内平衡有关。使用免疫缺陷小鼠的啮齿动物研究 已经揭示了自适应免疫细胞（T和B细胞）的丧失导致学习和记忆力受损， 类似焦虑的行为和社交性障碍。然而，尚不清楚自适应免疫细胞如何 与小胶质细胞交流并影响大脑发育和功能。我们的长期目标是了解 适应性免疫细胞与 大脑发育和成年期间的脑细胞。我们的初步研究表明Rag1 - / - 和[Rag2-- /-MICE]缺乏T和B细胞，表现出社交行为受损。在rag1 - / - 小鼠中，C-FOS增加 观察到内侧前额叶皮层（MPFC）中的小胶质细胞表型改变。这是 与以前的报道一致，即MPFC功能障碍参与社会行为。 [值得注意的是，收养 野生型（WT）脾细胞（包含T和B细胞）的转移挽救了RAG1 - / - 社会行为缺陷。 此外，注射WT血清外泌体挽救了相同的表型。社会行为不足是 尽管在WT脑中通常不存在RAG2，但在RAG2 - / - 小鼠中也观察到。在一起，这些 研究结果表明，T和B细胞通过外泌体有助于社会行为。]的确，我们观察到， Rag1 - / - 小鼠血清的外泌体缺乏T和B细胞标记的表达和多个microRNA （miRNA）大概源自T和B细胞。这些预测的靶基因的表达 在Rag1 - / - 小鼠的PFC中，miRNA（例如滑雪）得到了增强。相反，WT血清外泌体降低 小胶质细胞中的滑雪表达。最近的研究表明，小胶质细胞控制神经元突触。因此，我们的数据 表明通过外泌体不足的适应性免疫细胞 - 神细胞传播会损害社会行为 通过更改MPFC函数。因此，在这项研究中，我们将检验我们缺乏适应性免疫的假设 细胞来源的外泌体及其miRNA通过改变对 内侧PFC中的神经元功能。我们将首先验证并扩展我们对血清外泌体的发现和 RAG1 - / - 小鼠中的MPFC神经元，并确定缺乏适应性免疫细胞的因果作用 使用收养转移技术将它们恢复为rag1 - / - 鼠标（AIM 1）。我们还将检查直接 自适应免疫细胞中外泌体释放和miRNA产生受损的影响对小胶质细胞和 MPFC中的神经元和通过遗传方法的社会行为（AIM 2）。 [此外，我们将解决 MPFC中金字塔神经元和小胶质细胞对社会行为受损（AIM 3）的贡献。] 将揭示新的机制，从而自适应免疫细胞衍生的外泌体影响脑功能和 行为，最终可能导致精神疾病的新型治疗策略。