神经肽S对睡眠觉醒的调节

The role of neuropeptide S in sleep-wake regulation

新发现神经肽S （NPS）及其受体（NPSR）构成一新的内源性神经调节系统,NPS-NPSR系统被认为是中枢新的觉醒系统参与睡眠觉醒周期的生理与病理过程.近期研究证明侧脑室注射NPS引起大鼠脑电高频（14.5～60 Hz）活动增强为特征的觉醒时间增加,同时抑制脑电δ波和θ波为特征的慢波睡眠（SWS）和异相睡眠或称为快动眼睡眠（PS/REMS）;NPSR拮抗剂[D-Cys（tBu）5] NPS引起大鼠觉醒减少,SWS增加,而不影响PS/REMS. NPSR rs324981单核苷酸多态性和Asn/Ile 107 NPSR多态性与人类的生理性睡眠调节密切相关.机制研究揭示下丘脑结节乳头体核（TMN）91.5％组胺能神经元表达NPSR,TMN注射0.1 nmoL NPS引起大鼠觉醒时间,比侧脑室注射1nmoL NPS引起大鼠觉醒时间显著延长,该作用可分别被NPSR、组胺受体H1R和组胺受体H2R拮抗剂所拮抗,提示NPS神经元投射TMN经NPSR介导激活组胺能神经元是NPS-NPSR调节睡眠觉醒的重要通路.另外,证据表明NPS抗焦虑与抑郁引起睡眠紊乱.为此,揭示NPS能神经元投射途径、作用靶点与突触后神经元作用模式,发现NPSR高效激动剂及拮抗剂将成为今后工作重点.

Neuropeptide S （NPS） and cognate receptor （NPSR） identified recently have contributed to a new endogenous regulation system in central nervous system.The NPS-NPSR system is proposed as a new arousal system involved in the physiological and pathological sleep-wake regulation.Several new evidences have demonstrated that intracerebroventricular （ICV） injection of NPS increases wakefulness,accompanied by an increase in EEG high frequency activities （14.5-60 Hz） in rats.Meanwhile,slow wave sleep （SWS） and paradoxical sleep,also called rapid eye movement sleep （PS/REMS）,decrease it significantly.The wakefulness is decreased following [D-Cys （tBu）5] NPS,a selective NPSR agonist,ICV administration,whereas SWS is increased without PS/REMS alteration.Recent genetic epidemiology studies have found a clear association between the single nucleotide polymorphism rs324981 in NPSR and Asn/Ile 107 NPSR polymorphism and physiological sleep regulation in human.The mechanism of NPS-NPSR system in sleepwake regulation has recently demonstrated that the 91.5％ histaminergic tuberomammillary （TMN） neurons bear MPSR,0.1 nmoL NPS （1/10 dose of NPS ICV injection） microinjected into the TMN induces waking time more than 1 nmoL NPS ICV injection does.The effects of NPS on sleepwake states induced by the TMN microinjection are blocked by NPSR antagonists,H1R and H2R antagonists,respectively.These data indicate that the pathway of NPS neurons projecting to the TMN through NPSR to activate histaminergic neurons and enhance wakefulness plays a key role in NPS-NPSR system that regulates sleep-wake cycle.In addition,several studies show that NPS counteracts anxiety-and depression-like behaviors and sleep disorders.These results suggest that our future studies should be to reveal the NPS projection,innervations,targets and the pattern of postsynaptic action,and to find more powerful agonists and antagonists of NPSR.