ドーパミンＤ２受容体による覚醒調節分子機構

在过去的一年里，我们明确了多巴胺D2受体（D2R）在维持清醒中的神经解剖学位置。我们设计了由腺相关病毒（AAV）携带的D2R短发夹RNA，用于敲低尾壳核（CPU）、伏隔核核心（NAc core）和NAc壳（shell）中的D2R。运动活动生物测定采用基础传感器。进行脑电图记录，并通过SleepSign自动离线评分，每10秒为清醒、非快速眼动（non-REM， NREM）和快速眼动睡眠。此外，我们还设计了携带人D2R基因的AAV （AAV- hd2r）来局部拯救D2R KO小鼠的D2R。在NAc核心敲除D2R后，小鼠在基础条件下白天和夜间的运动活动都比对照组小鼠减少。在睡眠-觉醒方面，核心D2R敲除小鼠的清醒程度显著降低，同时非快速眼动和快速眼动睡眠增加。当D2R获救时，小鼠的运动活动有所增加。在WT小鼠NAc壳D2R敲除或KO小鼠D2R抢救组，运动和睡眠-觉醒特征无明显变化。敲除中央处理器中的D2R后，小鼠表现出运动活动减少，而睡眠-觉醒特征没有显著变化。综上所述，NAc核心的D2R在维持清醒状态中起着至关重要的作用。然而，中央处理器中的D2R在控制运动中起重要作用，而NAc壳中的D2R不介导觉醒和运动。

During the last year, we clarified neuroanatomical location of dopamine D2 receptor (D2R) in maintaining wakefulness.We designed short-hairpin RNA of D2R carried by adeno-associated virus (AAV) to knockdown D2R in caudate-putamen (CPU), core of nucleus accumbens (NAc core) and shell of NAc (shell). The locomotor activity bioassay was performed using the infra sensors. EEG recordings were performed and automatically scored off-line by 10-s epochs as wakefulness, non-rapid eye movement (non-REM, NREM), and REM sleep by SleepSign. In addition, we also designed the AAV carrying human D2R gene (AAV-hD2R) to focally rescue the D2R in D2R KO mice.After knockdown of D2R in the NAc core, the mice showed decreased locomotor activity during both day and night periods under the basal conditions, compared to the control mice. For the sleep-wake profile, core D2R knockdown mice exhibited a significant decrease in wakefulness, with a concomitant increase in NREM and REM sleep. While the D2R were rescued, mice showed an increase in locomotor activity. In mice with knockdown of D2R in NAc shell in WT or rescue of D2R in the KO mice, there were no significant changes in locomotion and sleep-wake profiles.After knockdown of D2R in the CPU, the mice exhibited decreased locomotor activity, whereas there were no significant changes in sleep-wake profiles.In conclusion, D2R in the NAc core plays an essential role in the maintenance of wakefulness. However, D2R in the CPU is important in controlling movement whereas D2R in NAc shell does not mediate the arousal and locomotion.