Dissecting the Interoception Circuit that Controls Airway Constriction

剖析控制气道收缩的内感受回路

基本信息

批准号：
10320714
负责人：
Xin Sun
金额：
$ 55.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10320714
关键词：
Ablation Address Adult Aerosols Afferent Neurons Air Airway Disease Allergens Anxiety Asthma Back Brain Brain Stem Brain region Breathing Cell Nucleus Child Chronic Data Dementia Disease Efferent Neurons Electrophysiology (science)Epithelial Foundations Ganglia Gases Genetic Health system Human Hypothalamic structure Imaging Device In Situ Individual Injections Interoception Irritants Knowledge Label Link Lung Maps Meditation Mental Depression Molecular Nerve Nervous system structure Neuraxis Neuroendocrine Cell Neurons Nucleus solitarius Organ Peripheral Physiology Property Psyche structure Qi Gong RNA Recombinant adeno-associated virus (rAAV)Respiration Sensory Side Signal Transduction Smooth Muscle Spinal Spinal Cord Spinal cord posterior horn Stress Suggestion Synapses Techniques Testing Three-Dimensional Imaging Toxin Tube Vagotomy Viral airway hyperresponsiveness asthma exacerbation attenuation base cell type constriction dorsal motor nucleus expectation experimental study functional loss improved in vivo in vivo calcium imaging insight mouse allergen mouse model neural circuit neuronal cell body novel therapeutics optical imaging optogenetics paraventricular nucleus prevent pulmonary function relating to nervous system respiratory response sensor spatial relationship tool

项目摘要

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.

项目概要/摘要肺是最大的内部感觉器官之一。肺部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，大脑和肺之间在分子和细胞水平上的功能性神经解剖学联系仍然很大程度上未知。该 R01 应用提出使用小鼠模型来测试这一假设，即肺部内感受器检测到的过敏原诱导信号通过迷走神经传入神经元传输至孤束核 (NTS)（目标 1），然后从 NTS 传输至其他中央积分器在大脑中，可能包括下丘脑的室旁核 (PVH)（目标 2），最后来自迷走神经的背运动核(DMV) 到投射回肺部的下行脊髓传出神经（目标 3），以感知和调节气道高反应性。目标将结合尖端的细胞类型特异性电路和病毒追踪技术、lightsheet 3-D 成像以及候选多重 RNA 原位和无偏 snRNAseq 方法来绘制神经电路图并识别周围神经节中信号激活神经元的特征、NTS 和其他大脑区域。此外，他们还将化学遗传学、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）相结合，以评估关键肺、迷走神经、脊柱和大脑连接的功能影响的获得和丧失。