Elucidating Central Neural Mechanisms in an Apnea Model

项目总结:

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.