Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

应激引起的神经血管损伤促进免疫浸润和抑郁样行为的机制

基本信息

批准号：
10517505
负责人：
SCOTT JAMES RUSSO
金额：
$ 63.28万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-24 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10517505
关键词：
Affect Affinity Chromatography Anhedonia Antidepressive Agents Area Astrocytes Automobile Driving Bacterial Artificial Chromosomes Behavior Bioinformatics Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Cells Chronic Chronic stress Clinical Research Clinical Trials Coupled Cytometry Data Disease Drug Targeting Endothelial Cells Endothelium Gene Expression Gene Expression Profile Genes Goals Health Immune Immune signaling Immune system Immunologics Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-6 Link Major Depressive Disorder Measures Mediating Mental Depression Messenger RNA Molecular Monitor Moods Mus Nucleus Accumbens Pathogenesis Patients Peripheral Phenotype Play Predisposition Proteins Recruitment Activity Research Ribosomes Role Signal Transduction Stress Structure Surface Antigens Testing Tight Junctions Translating Work anxiety-like behavior behavioral phenotyping behavioral response blood-brain barrier penetration blood-brain barrier permeabilization brain circuitry brain parenchyma comorbidity cytokine depressive symptoms design high risk immune cell infiltrate immune depression immune modulating agents monocyte mouse model neural circuit neurovascular injury novel therapeutic intervention preclinical study prevent recruit resilience response social social defeat social stress symptomatology systemic inflammatory response transcriptome sequencing

项目摘要

Multiple clinical studies suggest that heightened peripheral inflammation contributes to major depressive disorder (MDD) pathogenesis. Co-morbidity of inflammatory disease with MDD is highly prevalent, and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating inflammatory molecules are released following chronic stress, penetrate the blood brain barrier (BBB), and affect neural circuits, mediating stress vulnerability and depression. However, despite years of intensive research into the role of cytokines in depression, we have very little direct evidence of how cytokines enter the brain and in which circuits they act. Recently, we have begun to investigate the effect of chronic social defeat stress (CSDS), a mouse model of stress that induces depression-like behavior, on BBB permeability. Endothelial cells and astrocytes play critical roles in maintaining vascular impermeability. Endothelial cells, via expression of tight junction proteins, establish the paracellular barrier between the perivascular space and brain parenchyma. Breakdown of the endothelial barrier can lead to infiltration of peripheral immune signals— such as IL-6—that we have shown previously to increase stress susceptibility. Our new data shows that 10 days of CSDS downregulates expression of the tight junction protein Cldn5 in the NAc of stress-susceptible mice leading to loss of integrity of the endothelial barrier, immune infiltration and expression of depression-like behaviors. Expanding upon these preliminary observations, we will probe the detailed molecular and cellular mechanisms by which peripheral immune signals interface with mood-related brain circuitry to control depression-like behaviors following social stress. By understanding how chronic stress affects the BBB we may be able to augment current antidepressant treatment or design new therapeutic strategies promoting vascular health by preventing BBB degeneration.

多项临床研究表明，外周感染增加有助于主要抑郁症（MDD）发病机理。炎症性疾病与MDD的合并症非常普遍， MDD患者患有这些疾病的风险更高。已经假设循环炎症分子在慢性应激后释放，穿透血脑屏障（BBB），并且影响神经元电路，介导压力脆弱性和抑郁症。但是，多皮特的年度密集是研究细胞因子在抑郁症中的作用，我们几乎没有直接证据表明细胞因子如何进入大脑以及它们在哪些电路上进行的行动。最近，我们开始研究慢性社会失败的影响应力（CSD）是一种影响抑郁症行为的小鼠压力模型，对BBB渗透性。内皮细胞和星形胶质细胞在维持血管不渗透方面起关键作用。内皮细胞，通过紧密连接蛋白的表达，建立血管周空间和脑实质。内皮屏障的崩溃会导致周围免疫信号的渗透 - 例如IL-6 - 我们先前已显示出增加应力敏感性。我们的新数据表明10 CSD的天数下调了紧密的连接蛋白CLDN5在应力吸收的NAC中小鼠导致内皮屏障的完整性丧失，免疫浸润和抑郁状的表达行为。在这些初步观察方面扩展，我们将探测详细的分子和细胞外围免疫信号与情绪相关的脑电路接口的机制以控制社会压力之后的抑郁症行为。通过了解慢性压力如何影响BBB，我们可能会能够增强当前的抗抑郁治疗或设计新的治疗策略，以促进血管通过预防BBB变性来进行健康。