Choi Ashley, Kim Bowon, Labriola Eleanor, Wiest Alyssa, Wang Yingqi, Smith Jennifer, Shin Hyunsoo, Jin Xi, An Isabella, Hong Jiso, Antila Hanna, Thomas Steven, Bhattarai Janardhan P, Beier Kevin, Ma Minghong, Weber Franz, Chung Shinjae
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
iScience. 2024 Oct 28;27(12):111285. doi: 10.1016/j.isci.2024.111285. eCollection 2024 Dec 20.
Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine consolidate sleep. Furthermore, inhibiting LC-NE neurons restores memory. Finally, rabies-mediated screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory-regulatory regions in 16p11.2 deletion mice. Our findings identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.
睡眠障碍在自闭症谱系障碍（ASD）儿童中很普遍。令人惊讶的是，睡眠问题与ASD症状的严重程度呈正相关，如记忆障碍。然而，ASD中睡眠障碍和认知缺陷背后的神经机制在很大程度上尚未得到探索。在这里，我们表明，在ASD的16p11.2缺失小鼠模型中，非快速眼动睡眠（NREM）是碎片化的。睡眠碎片化程度反映在NREM期间蓝斑去甲肾上腺素能（LC-NE）神经元活动中钙瞬变数量的增加。相比之下，对LC-NE神经元的光遗传学抑制和使用可乐定对去甲肾上腺素能传递的药理学阻断可巩固睡眠。此外，抑制LC-NE神经元可恢复记忆。最后，狂犬病介导的突触前神经元筛选显示，16p11.2缺失小鼠中LC-NE神经元与睡眠和记忆调节区域的连接性发生了改变。我们的研究结果确定了LC-NE系统在调节ASD睡眠稳定性和记忆方面的关键作用。
