Tonic endocannabinoid signaling supports sleep through development in both sexes.
Tonic endocannabinoid signaling supports sleep through development in both sexes.
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补品内源性大麻素信号传导通过两性的发育来支持睡眠。
DOI：
10.1093/sleep/zsac083
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发表时间：
2022
期刊：
影响因子：
5.6
通讯作者：
Diering,GrahamH
中科院分区：
文献类型：
--
作者：
Martin,ShenéeC;Gay,SeanM;Armstrong,MichaelL;Pazhayam,NilaM;Reisdorph,Nichole;Diering,GrahamH
睡眠是一种重要的行为，在整个生命过程中支持大脑功能和认知，部分原因是作用于神经元突触。介导睡眠恢复益处的突触信号传导途径尚未完全理解，特别是在发育的背景下。内源性大麻素（Endocannabinoids，eCB）包括2-花生四烯酸甘油（2-arachidonyl glycerol，2-AG）和大麻素酰胺（anandamide，AEA），是激活大麻素受体（cannabinoid receptor，CB 1）的生物活性脂质，以调节突触传递并介导认知功能和许多行为，包括睡眠。我们使用靶向质谱法来测量两种性别的幼年和青春期小鼠在睡眠/觉醒周期期间前脑突触eCB的变化。我们发现，eCBs缺乏一个每日的节奏在幼年小鼠，而在青少年AEA和相关的油酰乙醇酰胺增加在睡眠阶段的昼夜节律的方式。接下来，我们使用选择性药理学操纵eCB系统，并使用非侵入性压电家庭笼记录装置测量对发育和成年小鼠（两种性别）睡眠行为的影响。通过抑制2-AG或AEA降解增强eCB信号传导，增加发育中和成年雄性的暗相睡眠量和回合长度，但在雌性中不增加。通过注射拮抗剂AM 251抑制CB 1减少了睡眠时间，并导致发育中和成年男性和女性的睡眠片段化。我们的数据表明，男性对增强型eCB的睡眠促进作用更敏感，但在两性的多个发展阶段，紧张性eCB信号支持睡眠行为。这项工作为进一步开发基于大麻素的睡眠中断疗法提供了信息。
Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in juvenile and adolescent mice of both sexes. We find that eCBs lack a daily rhythm in juvenile mice, while in adolescents AEA and related oleoyl ethanolamide are increased during the sleep phase in a circadian manner. Next, we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a noninvasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark-phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep-promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.