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.

项目摘要： 中央呼吸暂停在死亡中起主要作用，包括充血性心力衰竭，阿片类药物 此外，婴儿猝死综合征和癫痫 中央呼吸暂停和底座神经回路缺乏暴露于合成的情况下。 捕食者气味，小鼠表现出呼吸呼吸量的呼吸呼吸模式。 将通过捕食气味暴露建立这种新颖的呼吸暂停模型。 小鼠的呼吸暂停1将严格确定刺激强度（即捕食者的剂量） 气味）会影响中央呼吸暂停和行为输出，例如嗅觉激活。 气味剂以浓度依赖性方式激活体感系统，该系统可能会初始保护器 因此，我们将探究捕食者气味呼吸暂停的嗅觉要求。 是否具有类似厌恶质量的气味，无法诱导冻结，也会引起呼吸措施。 这些基本实验将进一步发展我们对呼吸 对于捕食气味的各种刺激品质。 脑干中央模式生成器可以协调呼吸的电动机输出，但目前研究缺乏 对临床数据涉及的电路的自上而下调节 表明杏仁核在人类中驱动呼吸暂停，并有可能导致暂时性癫痫的突然死亡 癫痫发作； 对恐惧的行为反应，例如捕食者气味和直接proyect AIM 2的呼吸区域将隔离神经元在中央杏仁核的功能 并在遗传上被捕食者气味标记，以确定其在呼吸暂停产生中的涉及。 遗传障碍小鼠模型的优点，我们将通过识别该机制来阐述这种机制 中央杏仁核和下游靶标的主要细胞类型 目的将丰富我们对捕食者气味引起的呼吸暂停的理解，同时提供一种新型的边缘机制 用于小鼠中央呼吸暂停模型。