Elucidating Central Neural Mechanisms in an Apnea Model

阐明呼吸暂停模型中的中枢神经机制

• 批准号: 10396465
• 负责人: Emma Catherine Janke
• 金额: $ 4.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396465
• 关键词: Ablation; Affect; Amygdaloid structure; Animal Model; Apnea; Attention; Autopsy; Behavior; Behavioral; Brain Stem; Breathing; Cardiovascular Diseases; Central Sleep Apnea; Cessation of life; Chronic; Clinical Data; Color; Congestive Heart Failure; Dependence; Disease; Dose; Epilepsy; Exhibits; Exposure to; FOS gene; Face; Freezing; Frequencies; Fright; Generations; Genetic Diseases; Genetic Recombination; Goals; Health; Heart failure; Human; Immunohistochemistry; In Situ Hybridization; Investigation; Knowledge; Life; Light; Literature; Methimazole; Modeling; Molecular Profiling; Monitor; Motor output; Mus; Neurons; Odors; Olfactory Epithelium; Olfactory Pathways; Opiate Addiction; Opsin; Output; Patients; Pattern; Phenotype; Play; Population; Primates; Production; Research; Respiration; Respiratory Center; Respiratory Signs and Symptoms; Risk; Rodent; Role; Saimiri; Seizures; Stimulus; Sudden Death; Sudden infant death syndrome; System; Testing; Trigeminal System; Trigeminal nerve structure; behavioral response; cell type; central pattern generator; clinically relevant; experimental study; improved; in vivo; motor control; mouse model; neural circuit; neuromechanism; novel; opioid overdose; optogenetics; photoactivation; pre-clinical; pressure; promoter; rare genetic disorder; relating to nervous system; respiratory; response; somatosensory

Project summary: Central apnea plays a predominant role in death in a range of disorders including congestive heart failure, opioid addiction, sudden infant death syndrome, and epilepsy; however, robust preclinical animal models to study central apnea and the underlying neural circuitry are lacking. We found that upon exposure to a synthetic predator odor, mice exhibit a unique breathing pattern consisting of increased apnea frequency. This proposal will establish this novel apnea model through predator odor exposure and uncover a neural circuit for central apnea generation in mice. Aim 1 will rigorously determine how the stimulus intensity (i.e., dose of the predator odor) affects both central apnea and behavioral output such as freezing. In addition to olfactory activation, odorants activate the somatosensory system in a concentration dependent manner which may initiate protective apnea; thus, we will probe the olfactory requirement for predator odor apnea induction. We will then evaluate whether an odor with similar aversive quality, that fails to induce freezing, also induces apnea in a concentration- dependent manner. These fundamental experiments will further develop our understanding of how apnea relates to various stimulus qualities of predator odor. Furthermore, existing literature in animal models focuses on the brainstem central pattern generator that coordinates the motor output for breathing, but currently research lacks investigation of top-down modulation of breathing from circuits involved in behavior. Clinical data consistently show that the amygdala drives apnea in humans and likely contributes to sudden death in epilepsy in temporal seizures; however, the amygdala’s role in apnea is unknown in mice. The central amygdala is involved in behavioral responses to fearful stimuli such as predator odor and sends direct projections to ponto-medullary respiratory regions. Aim 2 will isolate the functional role of neurons in the central amygdala that are activated and genetically tagged by predator odor to determine their involvement in apnea generation. Given the advantages of a genetically tractable mouse model, we will elaborate this mechanism by identifying the predominant cell type(s) responsible in the central amygdala and their downstream targets. Completion of these aims will enrich our understanding of apnea induced by predator odor while providing a novel limbic mechanism for a central apnea model in mice.

项目概要： 中枢性呼吸暂停在一系列疾病的死亡中起主要作用，包括充血性心力衰竭、阿片类药物 成瘾、婴儿猝死综合症和癫痫；然而，需要研究稳健的临床前动物模型 缺乏中枢性呼吸暂停和潜在的神经回路。我们发现，当接触合成物时 由于捕食者的气味，小鼠表现出一种独特的呼吸模式，包括呼吸暂停频率增加。这个提议 将通过捕食者气味暴露建立这种新颖的呼吸暂停模型，并揭示中枢神经回路 小鼠呼吸暂停的发生。目标 1 将严格确定刺激强度（即捕食者的剂量）如何 气味）影响中枢性呼吸暂停和行为输出（例如冻结）。除了激活嗅觉之外， 气味剂以浓度依赖性方式激活体感系统，这可能会启动保护作用 呼吸暂停；因此，我们将探讨捕食者气味呼吸暂停感应的嗅觉要求。然后我们将评估 具有类似厌恶性质的气味，不能引起冻结，是否也会在一定浓度下引起呼吸暂停—— 依赖方式。这些基础实验将进一步加深我们对呼吸暂停如何关联的理解 捕食者气味的各种刺激品质。此外，现有的动物模型文献重点关注 协调呼吸运动输出的脑干中枢模式发生器，但目前研究缺乏 研究行为相关回路对呼吸的自上而下调节。临床数据一致 表明杏仁核会导致人类呼吸暂停，并可能导致颞叶癫痫猝死 癫痫发作；然而，杏仁核在小鼠呼吸暂停中的作用尚不清楚。中央杏仁核参与 对捕食者气味等可怕刺激的行为反应，并向脑桥髓质发送直接投射 呼吸区域。目标 2 将分离中央杏仁核中被激活的神经元的功能作用 并通过捕食者气味进行基因标记，以确定它们参与呼吸暂停的发生。鉴于 由于遗传易驯化小鼠模型的优点，我们将通过识别 负责中央杏仁核及其下游目标的主要细胞类型。完成这些 目标将丰富我们对捕食者气味引起的呼吸暂停的理解，同时提供一种新颖的边缘机制 用于小鼠中枢性呼吸暂停模型。