权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
9908179
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
项目类别：
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/9908179
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 therapeutics social

项目摘要

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.

摘要