Kostin Andrey, Siegel Jerome M, Alam Md Noor
Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA.
Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA ; Department of Psychiatry and Brain Research Institute, University of California, Los Angeles, CA.
Sleep. 2014 May 1;37(5):1011-20. doi: 10.5665/sleep.3680.
The hypocretins (HCRTs) are two hypothalamic peptides predominantly localized to neurons in the perifornical, dorsomedial, and lateral hypothalamic area (PF-LHA). Evidence suggests that HCRT signaling is critical for the promotion and stabilization of active-arousal and its loss or malfunction leads to symptoms of narcolepsy. In the PF-LHA, HCRT neurons are intermingled with glutamate-expressing neurons and also co-express glutamate. Evidence suggests that HCRT-glutamate interactions within the PF-LHA may play a critical role in maintaining behavioral arousal. However, the relative contributions of the glutamate and HCRT in sleep-wake regulation are not known.
We determined whether a lack of HCRT signaling in the prepro-orexin-knockout (HCRT-KO) mouse attenuates/compromises the wake-promoting ability of glutamatergic activation of the PF-LHA region. We used reverse microdialysis to deliver N-methyl-D-aspartate (NMDA) into the HCRT zone of the PF-LHA in HCRT-KO and wild-type (WT) mice to evaluate the contributions of glutamatergic vs. HCRT signaling in sleep-wake regulation.
As compared to respective controls, local perfusion of NMDA into the PF-LHA, dose-dependently increased active-waking with concomitant reductions in nonREM and REM sleep in spontaneously sleeping WT as well as HCRT-KO mice. However, compared to WT, the NMDA-induced behavioral changes in HCRT-KO mice were significantly attenuated, as evidenced by the higher dose of NMDA needed and lower magnitude of changes induced in sleep-wake parameters. Although not observed in WT mice, the number of cataplectic events increased significantly during NMDA-induced behavioral arousal in HCRT-KO mice.
The findings of this study are consistent with a hypothesis that synergistic interactions between hypocretin and glutamatergic mechanisms within the perifornical, dorsomedial, and lateral hypothalamic area are critical for maintaining behavioral arousal, especially arousal involving elevated muscle tone.
下丘脑泌素（HCRTs）是两种下丘脑肽，主要定位于穹窿周、背内侧和下丘脑外侧区（PF-LHA）的神经元。有证据表明，HCRT信号传导对于主动觉醒的促进和稳定至关重要，其缺失或功能异常会导致发作性睡病症状。在PF-LHA中，HCRT神经元与表达谷氨酸的神经元相互交织，并且也共同表达谷氨酸。有证据表明，PF-LHA内的HCRT-谷氨酸相互作用可能在维持行为觉醒中起关键作用。然而，谷氨酸和HCRT在睡眠-觉醒调节中的相对作用尚不清楚。
我们确定了前阿立新原基因敲除（HCRT-KO）小鼠中HCRT信号的缺失是否会减弱/损害PF-LHA区域谷氨酸能激活促进觉醒的能力。我们使用反向微透析将N-甲基-D-天冬氨酸（NMDA）注入HCRT-KO和野生型（WT）小鼠的PF-LHA的HCRT区，以评估谷氨酸能与HCRT信号在睡眠-觉醒调节中的作用。
与各自的对照组相比，将NMDA局部灌注到PF-LHA中，剂量依赖性地增加了自发睡眠的WT以及HCRT-KO小鼠的主动觉醒，同时非快速眼动睡眠和快速眼动睡眠减少。然而，与WT相比，HCRT-KO小鼠中NMDA诱导的行为变化明显减弱，所需的NMDA剂量更高以及睡眠-觉醒参数诱导的变化幅度更低就证明了这一点。虽然在WT小鼠中未观察到，但在HCRT-KO小鼠中，NMDA诱导的行为觉醒期间猝倒事件的数量显著增加。
本研究结果与以下假设一致，即穹窿周、背内侧和下丘脑外侧区内的下丘脑泌素和谷氨酸能机制之间的协同相互作用对于维持行为觉醒至关重要，尤其是涉及肌张力升高的觉醒。
