Ningxia Key Laboratory of Craniocerebral Diseases, Department of Anatomy, Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia, China.
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
CNS Neurosci Ther. 2023 Jun;29(6):1602-1614. doi: 10.1111/cns.14123. Epub 2023 Feb 16.
We often experience dreams of strong irrational and negative emotional contents with postural muscle paralysis during rapid eye movement (REM) sleep, but how REM sleep is generated and its function remain unclear. In this study, we investigate whether the dorsal pontine sub-laterodorsal tegmental nucleus (SLD) is necessary and sufficient for REM sleep and whether REM sleep elimination alters fear memory.
To investigate whether activation of SLD neurons is sufficient for REM sleep induction, we expressed channelrhodopsin-2 (ChR2) in SLD neurons by bilaterally injecting AAV1-hSyn-ChR2-YFP in rats. We next selectively ablated either glutamatergic or GABAergic neurons from the SLD in mice in order to identify the neuronal subset crucial for REM sleep. We finally investigated the role of REM sleep in consolidation of fear memory using rat model with complete SLD lesions.
We demonstrate the sufficiency of the SLD for REM sleep by showing that photo-activation of ChR2 transfected SLD neurons selectively promotes transitions from non-REM (NREM) sleep to REM sleep in rats. Diphtheria toxin-A (DTA) induced lesions of the SLD in rats or specific deletion of SLD glutamatergic neurons but not GABAergic neurons in mice completely abolish REM sleep, demonstrating the necessity of SLD glutamatergic neurons for REM sleep. We then show that REM sleep elimination by SLD lesions in rats significantly enhances contextual and cued fear memory consolidation by 2.5 and 1.0 folds, respectively, for at least 9 months. Conversely, fear conditioning and fear memory trigger doubled amounts of REM sleep in the following night, and chemo-activation of SLD neurons projecting to the medial septum (MS) selectively enhances hippocampal theta activity in REM sleep; this stimulation immediately after fear acquisition reduces contextual and cued fear memory consolidation by 60% and 30%, respectively.
SLD glutamatergic neurons generate REM sleep and REM sleep and SLD via the hippocampus particularly down-regulate contextual fear memory.
我们在快速眼动 (REM) 睡眠期间经常经历强烈的非理性和负面情绪内容的梦境，并伴有姿势性肌肉瘫痪，但 REM 睡眠是如何产生的及其功能仍不清楚。在这项研究中，我们调查了脑桥背外侧 SL 区（SLD）是否是 REM 睡眠所必需且充分的，以及 REM 睡眠的消除是否会改变恐惧记忆。
为了研究 SLD 神经元的激活是否足以诱导 REM 睡眠，我们通过双侧注射 AAV1-hSyn-ChR2-YFP 在大鼠中表达通道视紫红质-2（ChR2）。接下来，我们在小鼠中选择性地消融 SLD 中的谷氨酸能或 GABA 能神经元，以确定对 REM 睡眠至关重要的神经元亚群。最后，我们使用完全 SLD 损伤的大鼠模型研究 REM 睡眠在恐惧记忆巩固中的作用。
我们通过证明 ChR2 转染的 SLD 神经元的光激活选择性地促进大鼠从非快速眼动 (NREM) 睡眠向 REM 睡眠的转变，证明了 SLD 对 REM 睡眠的充分性。在大鼠中用白喉毒素-A（DTA）诱导 SLD 损伤或特异性缺失 SLD 谷氨酸能神经元但不缺失 GABA 能神经元可完全消除 REM 睡眠，表明 SLD 谷氨酸能神经元对 REM 睡眠的必要性。然后我们发现，通过 SLD 损伤消除 REM 睡眠会使大鼠的情境和线索恐惧记忆巩固分别显著增强 2.5 倍和 1.0 倍，至少持续 9 个月。相反，恐惧条件反射和恐惧记忆会在随后的夜间引发 REM 睡眠量增加一倍，而化学刺激投射到内侧隔核（MS）的 SLD 神经元会选择性地增强 REM 睡眠中的海马θ活动；这种刺激在恐惧获得后立即进行，会使情境和线索恐惧记忆的巩固分别减少 60%和 30%。
SLD 谷氨酸能神经元产生 REM 睡眠，通过海马体特别是下调情境恐惧记忆。
