Departments of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Departments of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Psychiatry. 2021 Jul;26(7):3152-3168. doi: 10.1038/s41380-020-00921-1. Epub 2020 Oct 22.
Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic drug use. Notably, rapid eye movement (REM) sleep regulates emotional memory, and persistent REM sleep impairment after cocaine withdrawal negatively impacts relapse-like behaviors in rats. However, it is not understood how cocaine experience may alter REM sleep regulatory machinery, and what may serve to improve REM sleep after withdrawal. Here, we focus on the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH), which regulate REM sleep initiation and maintenance. Using adult male Sprague-Dawley rats trained to self-administer intravenous cocaine, we did transcriptome profiling of LH MCH neurons after long-term withdrawal using RNA-sequencing, and performed functional assessment using slice electrophysiology. We found that 3 weeks after withdrawal from cocaine, LH MCH neurons exhibit a wide range of gene expression changes tapping into cell membrane signaling, intracellular signaling, and transcriptional regulations. Functionally, they show reduced membrane excitability and decreased glutamatergic receptor activity, consistent with increased expression of voltage-gated potassium channel gene Kcna1 and decreased expression of metabotropic glutamate receptor gene Grm5. Finally, chemogenetic or optogenetic stimulations of LH MCH neural activity increase REM sleep after long-term withdrawal with important differences. Whereas chemogenetic stimulation promotes both wakefulness and REM sleep, optogenetic stimulation of these neurons in sleep selectively promotes REM sleep. In summary, cocaine exposure persistently alters gene expression profiles and electrophysiological properties of LH MCH neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhances REM sleep quality and quantity after long-term withdrawal.
睡眠异常通常是慢性药物使用后戒断症状的一个突出贡献者。值得注意的是，快速眼动 (REM) 睡眠调节情绪记忆，可卡因戒断后持续的 REM 睡眠损害会对大鼠的类似复发行为产生负面影响。然而，目前尚不清楚可卡因经历如何改变 REM 睡眠调节机制，以及什么可以改善戒断后的 REM 睡眠。在这里，我们专注于外侧下丘脑 (LH) 中的黑色素浓缩激素 (MCH) 神经元，它调节 REM 睡眠的启动和维持。使用经过训练的雄性 Sprague-Dawley 大鼠进行静脉内可卡因自我给药，我们使用 RNA 测序对长期戒断后的 LH MCH 神经元进行了转录组分析，并使用切片电生理学进行了功能评估。我们发现，从可卡因戒断 3 周后，LH MCH 神经元表现出广泛的基因表达变化，涉及细胞膜信号转导、细胞内信号转导和转录调控。从功能上讲，它们表现出膜兴奋性降低和谷氨酸能受体活性降低，这与电压门控钾通道基因 Kcna1 的表达增加和代谢型谷氨酸受体基因 Grm5 的表达降低一致。最后，LH MCH 神经元的化学遗传或光遗传刺激在长期戒断后增加 REM 睡眠，具有重要差异。化学遗传刺激促进觉醒和 REM 睡眠，而这些神经元在睡眠中的光遗传刺激选择性地促进 REM 睡眠。总之，可卡因暴露会持续改变 LH MCH 神经元的基因表达谱和电生理特性。在睡眠中选择性地对抗这些神经元的可卡因诱导的活性降低可增强长期戒断后的 REM 睡眠质量和数量。
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