Endogenous opioid signaling in the retina modulates sleep/wake activity in mice.
Endogenous opioid signaling in the retina modulates sleep/wake activity in mice.
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DOI：
10.1016/j.nbscr.2022.100078
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发表时间：
2022-11
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昼夜睡眠/觉醒节律与环境光/暗周期同步，这一过程称为光诱导。我们先前已经表明，β-内啡肽偏好μ-阿片受体（MORs）的激活抑制了光诱发的内在光敏视网膜神经节细胞（ipRGC）的放电，ipRGC是光夹带的唯一通道。虽然我们已经证明β-内啡肽在成年小鼠视网膜中表达，但β-内啡肽表达的条件尚不清楚。此外，还不清楚ipRGC表达的MORs的内源性激活是否调节睡眠/觉醒周期的光夹带。为了阐明这一点，我们首先通过定量逆转录PCR在一天中的不同时间测量β-内啡肽的前体阿黑皮素原（POMC）的mRNA表达。POMC mRNA似乎在小鼠视网膜中具有周期性表达。然后我们用免疫组织化学研究了β-内啡肽的表达，发现视网膜β-内啡肽在黑暗/夜间表达更高。最后，我们使用遥测技术测量自由活动动物的活动、EEG和EMG，以比较野生型和转基因小鼠的睡眠/觉醒周期，其中只有ipRGC缺乏功能性MORs。来自这些实验的结果表明，由ipRGC表达的M0 R通过促进觉醒和抑制慢波睡眠而有助于诱导和维持夜间小鼠中暗相的活动。总之，这些数据表明，内源性β-内啡肽激活ipRGC表达的M0 R以通过光夹带途径调节睡眠/觉醒活动。β-内啡肽在小鼠视网膜中的表达在黑暗/夜间更高。内源性β-内啡肽通过黑视素神经节细胞调节睡眠/觉醒。由黑视素神经节细胞表达的μ-阿片受体影响睡眠/觉醒。
Circadian sleep/wake rhythms are synchronized to environmental light/dark cycles in a process known as photoentrainment. We have previously shown that activation of β-endorphin-preferring μ-opioid receptors (MORs) inhibits the light-evoked firing of intrinsically photosensitive retinal ganglion cells (ipRGCs), the sole conduits of photoentrainment. Although we have shown that β-endorphin is expressed in the adult mouse retina, the conditions under which β-endorphin is expressed are unknown. Moreover, it is unclear whether endogenous activation of the MORs expressed by ipRGCs modulates the photoentrainment of sleep/wake cycles. To elucidate this, we first measured the mRNA expression of β-endorphin's precursor, proopiomelanocortin (POMC), at various times of day by quantitative reverse-transcription PCR. POMC mRNA appears to have cyclic expression in the mouse retina. We then studied β-endorphin expression with immunohistochemistry and found that retinal β-endorphin is more highly expressed in the dark/at night. Finally, we used telemetry to measure activity, EEG and EMG in freely moving animals to compare sleep/wake cycles in wild-type and transgenic mice in which only ipRGCs lack functional MORs. Results from these experiments suggest that the MORs expressed by ipRGCs contribute to the induction and maintenance of activity in the dark phase in nocturnal mice, via the promotion of wakefulness and inhibition of slow-wave sleep. Together, these data suggest that endogenous β-endorphin activates MORs expressed by ipRGCs to modulate sleep/wake activity via the photoentrainment pathway. β-endorphin expression in the mouse retina is higher in the dark/at night. Endogenous β-endorphin modulates sleep/wake through melanopsin ganglion cells. μ-opioid receptors expressed by melanopsin ganglion cells influence sleep/wake.