Wakefulness and Forebrain Activation by Orexin Neurons

阻塞性睡眠呼吸暂停唤醒(OSA)起到了挽救生命的作用，我们假设它是由在正常清醒时产生唤醒的相同回路支持的。下丘脑外侧的食欲素神经元在产生觉醒过程中起着关键作用，缺乏食欲素神经传递会导致慢性的低觉醒状态。这些研究将为该计划项目的一个重要方面提供关键的见解：确定增食欲素神经元最终激活皮质的机制。 我们提出了一个可测试的模型，在该模型中，食欲素神经元通过兴奋基底前脑来促进觉醒。 激活大脑皮层的神经元。除了食欲素以外，食欲素神经元可能还共同释放抑制性神经肽强啡肽，我们推测强啡肽和食欲素在基底前脑协同作用以促进完全觉醒。 我们将使用强大的遗传学、解剖学和生理学技术来识别食欲素神经元促进觉醒的神经回路。为了确定食欲素促进觉醒的大脑区域，我们将研究仅在基底前脑、丘脑或皮质表达食欲素受体的小鼠的睡眠/醒来行为。使用切片记录，我们将确定食欲素和强啡肽对神经化学定义的基底前脑神经元，包括投射到前额叶皮质的突触前和突触后的影响。我们还将绘制食欲素和强啡肽促进觉醒的基础前脑通路。 总的来说，这些多学科的实验将定义食欲素，在 与强啡肽结合，促进皮质激活，从而提供解剖学和生理学 框架，以更好地了解觉醒的神经生物学和嗜睡的临床问题。

Arousal from obstructive sleep apnea (OSA) plays a life-saving role, and we hypothesize that it is supported by the same circuitry that produces arousal during normal wakefulness. The orexin neurons in the lateral hypothalamus play a critical role in producing arousal, and lack of orexin neurotransmission produces a chronic state of hypoarousal. These studies will provide key insights into an important aspect of this Program Project: Defining the mechanisms through which the orexin neurons ultimately activate the cortex. We present a testable model in which the orexin neurons promote arousal by exciting basal forebrain neurons that activate the cortex. In addition to the orexin peptides, the orexin neurons probably co-release the inhibitory neuropeptide dynorphin, and we hypothesize that dynorphin and orexin act synergistically in the basal forebrain to promote full arousal. We will use powerful genetic, anatomic, and physiologic techniques to identify the neural circuits through which the orexin neurons promote arousal. To define the brain regions through which orexin promotes arousal, we will study sleep/wake behavior in mice that express orexin receptors only in the basal forebrain, thalamus, or cortex. Using slice recordings, we will determine the pre- and postsynaptic effects of orexin and dynorphin on neurochemically-defined basal forebrain neurons, including those projecting to prefrontal cortex. We will also map the basal forebrain pathways through which orexin and dynorphin promote wakefulness. Collectively, these multidisciplinary experiments will define the pathways through which orexin, in combination with dynorphin, promotes cortical activation, thus providing an anatomic and physiologic framework to better understand the neurobiology of arousal and the clinical problem of sleepiness.