NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions
NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions
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DOI：
10.1073/pnas.0602006103
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发表时间：
2006-05-02
影响因子：
11.1
通讯作者：
McKnight, SL
中科院分区：
文献类型：
--
作者：
Franken, P;Dudley, CA;McKnight, SL
由于转录因子神经元Per - Arnt - Sim型信号传感器蛋白结构域蛋白2（NPAS2）既是细胞内能量平衡的传感器又是效应器，并且由于睡眠被认为是纠正清醒时产生的能量失衡，我们利用npas2基因敲除（npas2^{-/-}）小鼠研究了NPAS2在睡眠稳态中的作用。我们发现，在睡眠需求增加的条件下，即活动期结束时或睡眠剥夺（SD）后，NPAS2使得睡眠能够在小鼠通常清醒的时间发生。npas2的缺失影响了丘脑皮质起源的脑电图活动；在非快速眼动睡眠（NREMS）期间，纺锤波频段（10 - 15Hz）的活动减少，并且在δ频段（1 - 4Hz）内，活动向更高频率偏移。此外，SD后NPAS2靶基因period2（per2）的皮质表达增加在npas2^{-/-}小鼠中减弱。这意味着NPAS2对先前记录的皮质per2表达的觉醒依赖性增加有重要贡献。数据还揭示了睡眠中的许多性别差异；在雌性中，睡眠需求积累的速度较慢，并且SD后快速眼动睡眠（REMS）的损失没有恢复。相反，SD后NREMS时间的反弹仅在npas2^{-/-}雄性中受损。我们得出结论，NPAS2在睡眠稳态中起作用，很可能在丘脑和皮质水平起作用，因为NPAS2在丘脑和皮质中大量表达。
Because the transcription factor neuronal Per-Arnt-Sim-type signal-sensor protein-domain protein 2 (NPAS2) acts both as a sensor and an effector of intracellular energy balance, and because sleep is thought to correct an energy imbalance incurred during waking, we examined NPAS2's role in sleep homeostasis using npas2 knockout (npas2(-/-)) mice. We found that, under conditions of increased sleep need, i.e., at the end of the active period or after sleep deprivation (SD), NPAS2 allows for sleep to occur at times when mice are normally awake. Lack of npas2 affected electroencephalogram activity of thalamocortical origin; during non-rapid eye movement sleep (NREMS), activity in the spindle range (10-15 Hz) was reduced, and within the delta range (1-4 Hz), activity shifted toward faster frequencies. In addition, the increase in the cortical expression of the NPAS2 target gene period2 (pert) after SD was attenuated in npas2(-/-) mice. This implies that NPAS2 importantly contributes to the previously documented wake-dependent increase in cortical per2 expression. The data also revealed numerous sex differences in sleep; in females, sleep need accumulated at a slower rate, and REMS loss was not recovered after SD. In contrast, the rebound in NREMS time after SD was compromised only in npas2(-/-) males. We conclude that NPAS2 plays a role in sleep homeostasis, most likely at the level of the thalamus and cortex, where NPAS2 is abundantly expressed.