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： 中枢性呼吸暂停在包括充血性心力衰竭、阿片类药物、 成瘾，婴儿猝死综合征和癫痫;然而，强大的临床前动物模型研究 中枢性呼吸暂停和潜在的神经回路缺乏。我们发现当接触到合成物 捕食者气味，小鼠表现出独特的呼吸模式，包括增加的呼吸暂停频率。这项建议 将通过捕食者气味暴露建立这种新的呼吸暂停模型，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 气味）影响中枢性呼吸暂停和行为输出如冻结。除了嗅觉激活， 气味剂以浓度依赖的方式激活躯体感觉系统， 呼吸暂停;因此，我们将探测捕食者气味呼吸暂停诱导的嗅觉要求。我们将评估 一种类似的令人厌恶的气味，不能引起冻结，是否也会引起呼吸暂停， 依赖的方式。这些基础实验将进一步发展我们对呼吸暂停如何与 不同的气味刺激特性。此外，动物模型中的现有文献集中于 脑干中央模式发生器，协调呼吸的运动输出，但目前的研究缺乏 从涉及行为的回路中研究自上而下的呼吸调节。临床数据一致 表明杏仁核驱动人类呼吸暂停，并可能导致颞叶癫痫猝死。 然而，杏仁核在小鼠呼吸暂停中的作用尚不清楚。中央杏仁核参与了 对可怕刺激的行为反应，如捕食者气味，并将直接投射到脑桥延髓 呼吸区目标2将分离中央杏仁核中被激活的神经元的功能作用 并通过捕食者的气味进行基因标记，以确定它们是否参与呼吸暂停的产生。鉴于 由于遗传学上易于处理的小鼠模型的优点，我们将通过鉴定 主要细胞类型负责中央杏仁核及其下游目标。完成这些 aims将丰富我们对捕食者气味引起的呼吸暂停的理解，同时提供一种新的边缘机制 用于小鼠中枢性呼吸暂停模型。