Gizowski Claire, Bourque Charles W
Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
Nature. 2020 Jul;583(7816):421-424. doi: 10.1038/s41586-020-2471-x. Epub 2020 Jul 8.
The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle. For example, the SCN opposes overnight adipsia by driving water intake before sleep, and by driving the secretion of anti-diuretic hormone and lowering body temperature to reduce water loss during sleep. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCN (vasopressin) neurons are inactive-excited SCN neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCN neurons and mimicked by optogenetic stimulation of SCN neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLT) relay this information to SCN neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLT neuron axon terminals excited SCN neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLT neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLT→ SCN pathway and was prevented by chemogenetic inhibition of OVLT neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.
视交叉上核（SCN）作为人体的主生物钟，在24小时昼夜循环中，能根据不断变化的需求，适应性地协调生理和行为的变化。例如，SCN通过在睡眠前促进饮水，并通过促进抗利尿激素的分泌和降低体温以减少睡眠期间的水分流失，来对抗夜间烦渴。这些反应也可由中枢渗透压 - 钠传感器驱动，以对抗活动期渗透压的意外升高。然而，尚不清楚渗透压 - 钠传感器是否需要生物钟输出网络来驱动稳态反应。在此，我们表明在时间标记19（此时SCN（加压素）神经元不活跃）给予系统性盐注射（高渗盐水）会兴奋SCN神经元，并降低非颤抖性产热（NST）和体温。高渗盐水对NST和体温的影响可通过化学遗传学抑制SCN神经元来预防，并可通过体内对SCN神经元的光遗传学刺激来模拟。解剖学和电生理学实验相结合表明，表达谷氨酸脱羧酶的渗透压 - 钠传感终板血管器（OVLT）神经元通过γ - 氨基丁酸（GABA）的兴奋作用将此信息传递给SCN神经元。OVLT神经元轴突终末的光遗传学激活在体外兴奋SCN神经元，并在体内模拟高渗盐水对NST和体温的影响。此外，化学遗传学抑制OVLT神经元可减弱系统性高渗盐水对NST和体温的影响。最后，我们表明高渗盐水显著提前了小鼠昼夜运动活动的开始时间。这种效应可通过OVLT→SCN通路的光遗传学激活来模拟，并可通过化学遗传学抑制OVLT神经元来预防。总的来说，我们的研究结果证明生物钟时间可由非光生理性相关线索调节，并且这些线索可通过生物钟输出网络驱动意外的稳态反应。
