Central Nervous System Plasticity in Airway Disease

气道疾病中的中枢神经系统可塑性

• 批准号: 10529342
• 负责人: Leah R Reznikov
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10529342
• 关键词: Ablation; Acute; Address; Airway Disease; Airway Resistance; Amygdaloid structure; Anatomy; Anti-Anxiety Agents; Anxiety; Asthma; Attention; Attenuated; Behavior; Brain; Brain region; Brain-Derived Neurotrophic Factor; Bronchoconstriction; Central Nervous System; Cessation of life; Cre lox recombination system; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dendritic Spines; Development; Excitatory Amino Acid Antagonists; Extrinsic asthma; FDA approved; Frequencies; Fright; Functional disorder; Gene Expression; Gene Transfer; Genes; Glutamate Receptor; Golgi Apparatus; Guidelines; Human; Impairment; Intervention; Link; MK801; Magnetic Resonance Imaging; Maintenance; Manganese; Measures; Mediating; Mediator; Mental disorders; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neuronal Plasticity; Neurons; Nose; Outcome; Ovalbumin; Pathologic; Patients; Peripheral; Pharmaceutical Preparations; Price; Quality of life; Receptor Signaling; Regulation; Risk Factors; Signaling Protein; Stains; Structure; Testing; Therapeutic Intervention; Transgenic Mice; Vertebral column; anxiety treatment; asthma exacerbation; asthmatic; comorbidity; density; excitatory neuron; experience; holistic approach; mRNA Expression; mortality; mouse model; optogenetics; overexpression; pharmacologic; prevent; targeted treatment; transcription factor

PROJECT SUMMARY Exacerbations (asthma attacks) account for nearly one-third of all asthma deaths. Despite psychiatric illness as a risk factor for death from asthma, and many connections between asthma exacerbations and anxiety, the brain region that initiates anxiety, the amygdala, has received limited attention as a driver of asthma exacerbations. This represents a considerable gap in the field, which, if addressed, may lead to new mechanism-based approaches to treat asthma exacerbations and reduce patient deaths. Exciting preliminary data from control mice suggest that acute optogenetic activation of the basolateral amygdala, a key input center essential for anxiety, reduces airway resistance. In asthmatic mice, which show anxiety, optogenetic activation of the basolateral amygdala fails to reduce airway resistance, suggesting amygdala dysfunction. Amygdala dysfunction is mechanistically linked to anxiety and characterized by heightened activity and spinogenesis (e.g., development of new dendritic spines). Asthmatic mice showed spinogenesis, heightened activity, and elevated expression of genes important for functional and structural remodeling in the basolateral amygdala. To investigate whether these changes were mechanistically linked to impaired regulation of airway resistance, we blocked NMDA glutamate receptors with MK-801, an anxiolytic drug that prevents anxiety-associated basolateral amygdala spinogenesis and in a class of drugs that reduce airway resistance in asthma. We found that MK-801 mitigated bronchoconstriction and diminished elevated gene expression in asthmatic mice. Broadly disrupting the cAMP- responsive element-binding protein (CREB), a transcription factor downstream of NMDA receptor signaling necessary for maintenance of amygdala neuroplasticity, also attenuated bronchoconstriction in asthmatic mice. These data guide our central hypothesis that the basolateral amygdala undergoes NMDA-CREB-dependent plasticity that disrupts airway regulation and promotes pathologic bronchoconstriction. To test this hypothesis, we propose 3 Specific Aims. In Aim 1, we will use optogenetic approaches to activate or inhibit excitatory neurons of the murine basolateral amygdala to test the hypothesis that the basolateral amygdala regulates airway resistance. In Aim 2, we use pharmacologic approaches, magnetic resonance imaging, RNAscope, and Golgi staining to test the hypothesis that experimental asthma structurally and functionally remodels the basolateral amygdala through NMDA receptor signaling. Finally, in Aim 3, we use CRE-lox technology and transgenic mice to test the hypothesis that ablation or overexpression of CREB in the basolateral amygdala alleviates or promotes, respectively, bronchoconstriction. Completion of this proposal will establish NMDA-CREB signaling in the basolateral amygdala as a key driver of asthma exacerbations and highlight NMDA receptor antagonists as a stand-alone or adjunct relief medications for asthma.

项目摘要 恶化（哮喘发作）占所有哮喘死亡的近三分之一。尽管精神病为 哮喘死亡的危险因素，以及哮喘加重与焦虑之间的许多联系，大脑 引发焦虑的地区，杏仁核，作为哮喘加重的驱动力受到了有限的关注。 这代表了该领域的一个很大的差距，如果解决的话，可能会导致新的基于机制 治疗哮喘加重并减少患者死亡的方法。来自控制小鼠的令人兴奋的初步数据 建议基底外侧杏仁核的急性光遗传激活，这是焦虑至关重要的关键输入中心， 降低气道阻力。在表现出焦虑的哮喘小鼠中，基底外侧的光遗传学激活 杏仁核无法降低气道阻力，表明杏仁核功能障碍。杏仁核功能障碍是 机械上与焦虑有关，以增强的活性和旋转生成的特征（例如，发展 新的树突状刺）。哮喘小鼠表现出旋转生成，活性的增强和升高的表达 基因对基底外侧杏仁核中功能和结构重塑很重要。调查是否 这些变化在机械上与气道阻力调节受损有关，我们阻止了NMDA MK-801的谷氨酸受体，一种抗焦虑药，可防止与焦虑相关的基底外侧杏仁核 旋转生成和一类降低哮喘气道耐药性的药物。我们发现MK-801缓解了 哮喘小鼠的支气管收缩和基因表达升高。广泛破坏了营地 - 响应元素结合蛋白（CREB），NMDA受体信号下游的转录因子 维持杏仁核神经可塑性所必需的，这也减弱了哮喘小鼠的支气管收缩。 这些数据指导了我们的中心假设，即基底外侧杏仁核经历了NMDA-CREB依赖性 破坏气道调节并促进病理支气管收缩的可塑性。为了检验这一假设， 我们提出了3个具体目标。在AIM 1中，我们将使用光遗传学方法激活或抑制兴奋性神经元 鼠的基底外侧杏仁核，以测试基底外侧杏仁核调节气道的假设 反抗。在AIM 2中，我们使用药理学方法，磁共振成像，rnascope和Golgi 染色以测试实验性哮喘在结构和功能上重塑基底外侧的假设 通过NMDA受体信号传导杏仁核。最后，在AIM 3中，我们使用Cre-Lox技术和转基因小鼠 测试以下假设：基底外侧杏仁核中CREB的消融或过表达 分别促进支气管收缩。该提案的完成将建立NMDA-CREB信号传导 基底外侧杏仁核是哮喘加重的关键驱动力，并突出了NMDA受体拮抗剂 哮喘的独立或辅助救济药物。