Department of Biology, University of Washington, Seattle, WA 98195-1800.
Molecular and Cellular Biology in Seattle, University of Washington and Fred Hutch, Seattle, WA 98195-7275.
Proc Natl Acad Sci U S A. 2023 Dec 5;120(49):e2314857120. doi: 10.1073/pnas.2314857120. Epub 2023 Nov 29.
The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian timekeeping requires intercellular communication among SCN neurons, and multiple signaling pathways contribute to SCN network coupling. Gamma-aminobutyric acid (GABA) is produced by virtually all SCN neurons, and previous work demonstrates that this transmitter regulates coupling in the adult SCN but is not essential for the nucleus to sustain overt circadian rhythms. Here, we show that the deletion of the gene that codes for the GABA vesicular transporter from neuromedin-S (NMS) neurons-a subset of neurons critical for SCN function-causes arrhythmia of locomotor activity and sleep. Further, NMS- deletion impairs intrinsic clock gene rhythms in SCN explants cultured ex vivo. Although vasoactive intestinal polypeptide (VIP) is critical for SCN function, deletion from VIP-expressing neurons did not lead to circadian arrhythmia in locomotor activity rhythms. Likewise, adult SCN-specific deletion of led to mild impairment of behavioral rhythms. Our results suggest that while the removal of GABA release from the adult SCN does not affect the pacemaker's ability to sustain overt circadian rhythms, its removal from a critical subset of neurons within the SCN throughout development removes the nucleus ability to sustain circadian rhythms. Our findings support a model in which SCN GABA release is critical for the developmental establishment of intercellular network properties that define the SCN as a central pacemaker.
视交叉上核（SCN）是下丘脑的一个中央生物钟部位，协调生理和行为的明显节律。昼夜节律计时需要 SCN 神经元之间的细胞间通讯，并且多种信号通路有助于 SCN 网络耦合。γ-氨基丁酸（GABA）几乎由所有 SCN 神经元产生，先前的工作表明该递质调节成年 SCN 中的耦合，但对于核维持明显的昼夜节律并非必需。在这里，我们表明编码神经肽 S（NMS）神经元中 GABA 囊泡转运蛋白的基因的缺失-对于 SCN 功能至关重要的神经元子集-导致运动活动和睡眠的节律性紊乱。此外，NMS-缺失会损害体外培养的 SCN 外植体中的固有时钟基因节律。尽管血管活性肠肽（VIP）对于 SCN 功能至关重要，但从 VIP 表达神经元中删除 VIP 并没有导致运动活动节律中的昼夜节律性紊乱。同样，成年 SCN 特异性删除 也导致行为节律的轻度损害。我们的结果表明，虽然从成年 SCN 中去除 GABA 释放不会影响起搏器维持明显昼夜节律的能力，但从发育过程中 SCN 内的关键神经元子集去除 GABA 释放会去除核维持昼夜节律的能力。我们的研究结果支持这样一种模型，即 SCN GABA 释放对于定义 SCN 为中央起搏器的细胞间网络特性的发育建立至关重要。
