Department of Cell Biology and Physiology and the UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Sleep. 2022 Aug 11;45(8). doi: 10.1093/sleep/zsac083.
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.
睡眠是一种基本行为，通过作用于神经元突触，支持大脑功能和认知能力在整个生命周期中的发挥。介导睡眠恢复益处的突触信号通路尚未完全了解，尤其是在发育过程中。内源性大麻素（eCBs）包括 2-花生四烯酰甘油（2-AG）和花生四烯酸乙醇酰胺（AEA），是生物活性脂质，可激活大麻素受体 CB1，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测量了幼鼠和青少年雌雄小鼠睡眠/觉醒周期中大脑前突触 eCB 的变化。我们发现 eCB 在幼鼠中没有昼夜节律，而在青少年中，AEA 和相关的油酰基乙醇酰胺以昼夜节律的方式在睡眠阶段增加。接下来，我们使用选择性药理学来操纵 eCB 系统，并使用非侵入性压电式家庭笼记录装置测量了发育中和成年雌雄小鼠睡眠行为的影响。通过抑制 2-AG 或 AEA 降解增强 eCB 信号，可增加发育中和成年雄性小鼠的暗期睡眠时间和时长，但对雌性小鼠没有影响。通过注射拮抗剂 AM251 抑制 CB1 会减少发育中和成年雄性和雌性小鼠的睡眠时间并导致睡眠碎片化。我们的数据表明，雄性对增强的 eCB 促进睡眠的作用更为敏感，但紧张的 eCB 信号通过两性的多个发育阶段支持睡眠行为。这项工作为基于大麻素的治疗睡眠障碍的进一步发展提供了信息。
