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：
10677767
负责人：
Ian Paul Lewkowich
金额：
$ 31.99万
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/10677767
关键词：
Area Asthma Attenuated Autoimmune Diseases Behavior Biological Response Modifiers Brain Cells Chronic Complex Data Disease Endothelial Cells Endothelium Ensure Extinction Extrinsic asthma Female Freezing Fright Functional disorder Gene Expression Profile Genetic House Dust Mite Allergens IL17 gene Immune Immune Targeting Immune response Immunoglobulin G Impairment Inbred BALB C Mice Individual Inflammation Inflammation Mediators Inflammatory Link Measures Mediating Mediator Mental Health Mental disorders Meta-Analysis Modeling Mus Nature Neuroglia Neuroimmune Neuroimmunomodulation Neurons Organ Outcome 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 Symptoms T-Lymphocyte Testing Tissues Transcription Alteration Trauma Validation Virus airborne allergen airway inflammation antagonist combat veteran comorbidity designer receptors exclusively activated by designer drugs genetic approach inhibitory neuron male mouse model neutralizing antibody neutralizing monoclonal antibodies new therapeutic target novel novel therapeutics receptor response single-cell RNA sequencing small molecule inhibitor 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.

项目概要：有效调节恐惧对于最佳心理健康至关重要。恐惧失调是后应激障碍的一个标志创伤性应激障碍 (PTSD)，一种使 22% 的退伍军人衰弱的疾病。前额叶受损皮质（PFC）功能导致 PTSD 患者的恐惧失调。并非所有经历过创伤的人都会发展 PTSD 提示创伤前危险因素。阐明这些因素的本质将有助于识别新的疗法。最近的证据支持慢性炎症与创伤后应激障碍风险之间的关联。因此，许多炎症性疾病与创伤后应激障碍 (PTSD) 增加有关。越来越多的证据支持强有力的严重哮喘与PTSD之间的关联，然而严重哮喘的相关因素和机制调节 PTSD 相关 PFC 缺陷的机制仍然未知。我们使用独特的鼠标发布和最近的数据空气过敏原屋尘螨（HDM）引起的炎症范例，表现出恐惧感仅在 Th17/IL17A 扩增的小鼠中灭绝，该效应依赖于 IL17A 受体信号传导和外周IL17A。重要的是，这伴随着 1) PFC 中神经元激活的减少和消退- 调节区和 2) 穹窿下器官 (SFO)（缺乏 BBB）内的小胶质细胞/T 细胞/内皮细胞改变投影到 PFC 的区域。总的来说，这些观察结果为我们的假设提供了依据：严重哮喘相关的 IL- 17A 激活 SFO 内复杂的多细胞信号级联，该级联使 PFC 参与调节害怕。该假设将在 3 个目标中得到检验。目标 1 将确定 IL-17A 信号传导和 Th17 细胞活性是否对于 HDM-Th17/IL17A 驱动的恐惧消退缺陷来说是必要且充分的 IL-17A 的能力阻断（中和单克隆抗体）或 Th17 拮抗（小分子抑制剂）可逆转恐惧消退 Th2/Th17 反应小鼠的缺陷/神经免疫改变，或重组 IL17A 诱导恐惧将评估具有 Th2 反应的小鼠的消退缺陷/神经免疫改变。目标 2 将决定 SFO？IL 预测对于 HDM-Th17/IL17A 驱动的恐惧消退缺陷是否必要且充分使用依赖于retroCre的化学遗传学策略，我们将抑制或激活SFO？IL预测来评估 Th2 与 Th2/Th17A 治疗的 HDM 小鼠对恐惧消退的影响目标 3 将鉴定转录组 SFO 和 PFC 中与 HDM-Th2/Th17 效应和恐惧相关的概况使用单细胞 RNAseq， SFO 和 PFC 衍生细胞的转录谱将通过免疫细胞特异性特征生成细胞、神经胶质细胞、内皮细胞和神经元，以识别 HDM 中独特激活的 DEG 和信号通路 TH2 与 Th2/Th17 小鼠。将使用 HDM-Th2/Th17 对恐惧的影响进行验证和关联瞄准 1/瞄准 2 组织。影响：我们的数据揭示了适应性免疫介质独特的核心机制与慢性肺部炎症相关的调节皮质缺陷和恐惧，与心理健康相关。这些研究的完成将拓宽我们对外周炎症介质如何调节的理解大脑功能和行为，并确定与恐惧相关的病理的新危险因素和治疗目标。