Elucidating Central Neural Mechanisms in an Apnea Model

项目总结： 中枢性呼吸暂停在包括充血性心力衰竭、阿片类药物在内的一系列疾病的死亡中起主导作用 成瘾、婴儿猝死综合征和癫痫；然而，可以用强大的临床前动物模型进行研究 中枢性呼吸暂停和潜在的神经回路缺失。我们发现，当接触到一种合成的 捕食者气味，小鼠表现出一种独特的呼吸模式，包括呼吸暂停频率增加。这项建议 将通过捕食者气味暴露建立这种新型的呼吸暂停模型，并揭示中枢神经回路 在小鼠中产生呼吸暂停。目标1将严格确定刺激强度(即捕食者的剂量 气味)既会影响中枢性呼吸暂停，也会影响行为输出，如冰冻。除了嗅觉激活之外， 气味以浓度依赖的方式激活体感系统，这可能会启动保护 因此，我们将探讨嗅觉对捕食性气味呼吸暂停诱导的要求。然后我们将评估 如果一种气味具有类似的令人厌恶的品质，但不能导致冰冻，是否也会在一定程度上导致呼吸暂停- 依赖的态度。这些基础实验将进一步加深我们对呼吸暂停与呼吸暂停之间关系的理解 各种刺激性的捕食者气味。此外，现有的动物模型文献主要集中在 脑干中枢模式发生器，协调呼吸的运动输出，但目前缺乏研究 研究涉及行为的回路对呼吸的自上而下的调制。临床数据一致 表明杏仁核导致人类呼吸暂停，并可能导致癫痫患者在颞叶猝死。 癫痫发作；然而，杏仁核在小鼠呼吸暂停中的作用尚不清楚。中央杏仁核参与了 对捕食者气味等可怕刺激的行为反应，并向延髓桥脑发送直接投射 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 并用捕食者气味进行基因标记，以确定它们是否参与了呼吸暂停的生成。给定 基因易驯化的小鼠模型的优势，我们将通过识别 优势细胞类型(S)，负责中央杏仁核及其下游靶点。完成这些工作 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 用于小鼠的中枢性呼吸暂停模型。

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.