Airway inflammation and fear: neuroimmune mechanisms and forebrain circuits

气道炎症和恐惧：神经免疫机制和前脑回路

基本信息

批准号：
10668648
负责人：
Ian Paul Lewkowich
金额：
$ 35.09万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10668648
关键词：
Area Asthma Attenuated Autoimmune Diseases Behavior Biological Response Modifiers Brain Cells Chronic Complex Data Disease Endothelial Cells Ensure Extinction (Psychology)Extrinsic asthma Female Freezing Fright Functional disorder Gene Expression Profile Genetic House Dust Mite Allergens Immune Immune Targeting Immune response Immunoglobulin G Impairment Inbred BALB C Mice Individual Inflammation Inflammation Mediators Inflammatory Interleukin-17 Link Measures Mediating Mediator of activation protein Mental Health Mental disorders Meta-Analysis Modeling Mus Nature Neuroglia Neuroimmune Neuroimmunomodulation Neurons Organ Pathology Peripheral Post-Traumatic Stress Disorders Predisposition Prefrontal Cortex Prevalence Prosencephalon Publishing Pulmonary Inflammation Pyroglyphidae Receptor Signaling Recombinants Recording of previous events Regulation Reporting Risk Risk Factors Role Safety Signal Pathway Signal Transduction Stains Subfornical Organ T-Lymphocyte Testing Tissues Transcription Alteration Trauma Validation Virus airborne allergen airway inflammation antagonist combat veteran comorbidity designer receptors exclusively activated by designer drugs disorder risk inhibitory neuron male mouse model neutralizing antibody neutralizing monoclonal antibodies new therapeutic target novel novel therapeutics outcome prediction receptor response single-cell RNA sequencing small molecule inhibitor symptom treatment systemic inflammatory response therapeutic target therapy resistant transcriptomics trauma exposure

项目摘要

PROJECT SUMMARY: Effective regulation of fear is essential for optimal mental health. Fear dysregulation is a hallmark of post- traumatic stress disorder (PTSD), a debilitating condition afflicting 22% of combat veterans. Impaired prefrontal cortex (PFC) functioning contributes to fear dysregulation in PTSD. Not all trauma-exposed individuals develop PTSD suggesting pre-trauma risk factors. Elucidating the nature of such factors will help identify novel therapeutics. Recent evidence supports an association between chronic inflammation and PTSD risk. Accordingly, many inflammatory diseases are linked to increased PTSD. Growing evidence supports a strong association between severe asthma and PTSD, however the severe asthma associated factors and mechanisms that regulate PTSD relevant PFC deficits remain unknown. Our published and recent data using unique mouse paradigms of aeroallergen house dust mite (HDM)-induced driven inflammation, show compromised fear extinction only in mice with Th17/IL17A expansion, an effect dependent on IL17A receptor signaling and peripheral IL17A. Importantly, this is accompanied by 1) reduced neuronal activation in the PFC an extinction- regulatory area and 2) microglial/T cell/endothelial alterations within the subfornical organ (SFO), a BBB-devoid area projecting to the PFC. Collectively these observations inform our hypothesis: severe asthma relevant IL- 17A activates a complex, multi-cellular signaling cascade within the SFO which engages the PFC to regulate fear. This hypothesis will be tested in 3 aims. Aim 1 will determine if IL-17A signaling, and Th17 cell activity is necessary and sufficient for HDM-Th17/IL17A driven fear extinction deficits The ability of IL-17A blockade (neutralizing mAb) or Th17 antagonism (small molecule inhibitor) to reverse fear extinction deficits/neuroimmune alterations in mice with Th2/Th17 responses, or recombinant IL17A to induce fear extinction deficits/neuroimmune alterations in mice with Th2 responses will be assessed. Aim 2 will determine if SFO?IL projections are necessary and sufficient for HDM-Th17/IL17A driven fear extinction deficits Using a retroCre-dependent chemogenetic strategy we will inhibit or activate SFO?IL projections to assess effects on fear extinction in HDM treated mice with Th2 versus Th2/Th17A Aim 3 will identify transcriptomic profiles in the SFO and PFC associated with HDM-Th2/Th17 effects and fear Using single-cell RNAseq, the transcriptional profile of SFO and PFC derived cells will be generated with cell-specific signatures of immune cells, glia, endothelial cells and neurons to identify DEGs and signaling pathways uniquely activated in HDM TH2 vs Th2/Th17 mice. Validation and association with HDM-Th2/Th17 effects on fear will be performed using Aim 1/Aim 2 tissue. Impact: Our data reveals a unique core mechanism by which adaptive immune mediators associated with chronic lung inflammation regulate cortical deficits and fear, relevant to mental health. Completion of these studies will broaden our understanding of how peripheral inflammatory mediators modulate brain function and behavior and identify novel risk factors and therapeutic targets for fear-associated pathologies.

项目摘要：有效的恐惧调节对于最佳心理健康至关重要。担心失调是后期的标志 - 创伤性应激障碍（PTSD），这是一种使战斗退伍军人的衰弱的疾病。前额叶受损皮层（PFC）的功能导致PTSD中的恐惧失调。并非所有暴露于创伤的人都会发展 PTSD提出了创伤前风险因素。阐明此类因素的性质将有助于识别新颖疗法。最近的证据支持慢性炎症与PTSD风险之间的关联。因此，许多炎症性疾病与PTSD增加有关。越来越多的证据支持一个强大的严重的哮喘和PTSD之间的关联，但是严重的哮喘相关因素和机制调节PTSD相关的PFC缺陷仍然未知。我们使用唯一鼠标发布的发布和最新数据 Aeroallergen House House Dust Mite（HDM）引起的驱动炎症的范例，表现出受损的恐惧仅在具有TH17/IL17A膨胀的小鼠中灭绝，效果取决于IL17A受体信号和外围IL17A。重要的是，这伴随着1）PFC中神经元激活降低的灭绝 - 调节区域和2）小胶质细胞/T细胞/内皮器官（SFO），BBB-devoid 投射到PFC的区域。总的来说，这些观察结果为我们的假设提供了有关：严重哮喘相关的IL- 17a激活SFO中的复杂的多细胞信号传导级联害怕。该假设将以3个目标进行检验。 AIM 1将确定IL-17A信号是否和Th17细胞活性是否对于HDM-TH17/IL17A驱动的恐惧灭绝使IL-17A的能力不足封锁（中和mAb）或Th17拮抗作用（小分子抑制剂）以逆转恐惧灭绝 Th2/Th17反应的小鼠的缺陷/神经免疫性改变，或重组IL17A以诱发恐惧将评估具有TH2反应的小鼠的灭绝缺陷/神经免疫性改变。 AIM 2将确定如果SFO？IL预测对于HDM-Th17/IL17A驱动的恐惧灭绝赤字是必要的和足够的使用逆转录依赖性的化学遗传策略，我们将抑制或激活SFO？IL投影以评估对用TH2与TH2/TH17A AIM 3治疗的HDM治疗小鼠恐惧灭绝的影响将识别转录组与HDM-TH2/TH17相关的SFO和PFC中的轮廓，并使用单细胞RNASEQ恐惧， SFO和PFC衍生细胞的转录曲线将使用免疫的细胞特异性特征产生细胞，神经胶质，内皮细胞和神经元，以识别在HDM中唯一激活的DEG和信号通路 th2 vs th2/th17小鼠。验证和与HDM-TH2/TH17对恐惧的影响将使用 AIM 1/AIM 2组织。影响：我们的数据揭示了一种独特的核心机制与慢性肺炎症有关，调节与心理健康有关的皮质缺陷和恐惧。这些研究的完成将扩大我们对外围炎症介体如何调节的理解大脑功能和行为，并确定与恐惧相关病理的新型风险因素和治疗靶标。