Dissecting the Interoception Circuit that Controls Airway Constriction

剖析控制气道收缩的内感受回路

• 批准号: 10689241
• 负责人: Xin Sun
• 金额: $ 53.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689241
• 关键词: Ablation; Address; Adult; Aerosols; Afferent Neurons; Air; Airway Disease; Allergens; Alveolus; Anxiety; Asthma; Back; Brain; Brain Stem; Brain region; Breathing; Cell Nucleus; Central Nervous System; Child; Chronic; Data; Dementia; Disease; Efferent Neurons; Electrophysiology (science); Epithelium; Experimental Genetics; Foundations; Ganglia; Gases; Genetic; Health system; Human; Hypothalamic structure; Imaging Device; In Situ; Individual; Injections; Interoception; Irritants; Knowledge; Label; Light; Link; Lung; Maps; Meditation; Mental Depression; Molecular; Mus; Nerve; Nervous System; Neuroanatomy; Neuroendocrine Cell; Neurons; Nucleus solitarius; Organ; Peripheral; Physiology; Property; Psyche structure; Qi Gong; RNA; Recombinant adeno-associated virus (rAAV); Respiration; Sensory; Side; Signal Induction; Signal Transduction; Smooth Muscle; Spinal; Spinal Cord; Spinal cord posterior horn; Stress; Synapses; Techniques; Testing; Three-Dimensional Imaging; Toxin; Tube; Vagotomy; Vertebral column; Viral; airway hyperresponsiveness; asthma exacerbation; attenuation; cell type; constriction; dorsal motor nucleus; expectation; functional loss; improved; in vivo; in vivo calcium imaging; insight; mouse model; neural; neural circuit; neuronal cell body; neurotransmission; novel therapeutics; optical imaging; optogenetics; paraventricular nucleus; prevent; pulmonary function; respiratory; response; sensor; spatial relationship; tool; transmission process

PROJECT SUMMARY/ABSTRACT Lung is one of the largest internal sensory organs. Chronic exposure of the lung to allergens or other irritants has been shown to influence stress, anxiety, depression, and dementia. On the other hand, practices that modulate respiration including deep breathing in meditation or Qi Gong are linked to improved central nervous system (CNS) health. However, the functional neuroanatomical connections between brain and lung at the molecular and cellular level remain largely unknown. This R01 application proposes to test the hypothesis, using mouse models, that allergen-induced signals detected by interoceptors in the lung are transmitted via vagal afferent neurons to nucleus tractus solitarius (NTS) (aim 1), and then from NTS to other central integrators in the brain, potentially including paraventricular nucleus (PVH) in the hypothalamus (aim 2), and lastly from dorsal motor nucleus of the vagus (DMV) to descending spinal cord efferents that project back to the lung (aim 3) to sense and regulate airway hyperresponsiveness. The aims will incorporate cutting-edge cell-type specific circuit and viral tracing techniques, lightsheet 3-D imaging, and candidate multiplex RNA in situ and unbiased snRNAseq approaches to map the neural circuits and identify the signature of signal-activated neurons in peripheral ganglia, NTS and other brain regions. In addition, they will combine chemogenetic, optogenetic and toxin-based approaches with neural activity readouts including cFOS, in vivo calcium imaging, electrophysiology, and lung physiology to assess gain and loss of functional effects of key lung, vagal, spinal and brain connections.

项目总结/摘要 肺是人体最大的内部感觉器官之一。 肺长期暴露于过敏原或其他刺激物已被证明会影响压力，焦虑，抑郁和痴呆。 另一方面，调节呼吸的练习，包括冥想或气功中的深呼吸，与改善中枢神经系统（CNS）健康有关。 然而，在分子和细胞水平上，脑和肺之间的功能性神经解剖学联系仍然在很大程度上未知。 该R01申请提出使用小鼠模型来检验以下假设，即由肺中的内感受器检测到的过敏原诱导的信号经由迷走传入神经元传递到孤束核（NTS）（目的1），然后从NTS传递到大脑中的其他中枢整合器，可能包括下丘脑中的室旁核（PVH）（目的2），最后从迷走神经背侧运动核（DMV）到脊髓下行传出神经，脊髓下行传出神经投射回肺（目的3）以感知和调节气道高反应性。 这些目标将结合尖端的细胞类型特异性电路和病毒追踪技术、光片3D成像、候选多重RNA原位和无偏snRNAseq方法，以绘制神经回路并识别外周神经节、NTS和其他大脑区域中信号激活神经元的特征。 此外，他们将结合联合收割机化学遗传学，光遗传学和基于毒素的方法与神经活动读数，包括cFOS，体内钙成像，电生理学和肺生理学，以评估关键肺，迷走神经，脊髓和大脑连接的功能效应的获得和损失。