Background Alterations in environmental light and intrinsic circadian function have strong associations with mood disorders. The neural origins underpinning these changes remain unclear, although genetic deficits in the molecular clock regularly render mice with altered mood-associated phenotypes. Methods A detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase α3 Myshkin (Myk/+) mouse model of mania was performed. Na+/K+-ATPase α3 does not reside within the core circadian molecular clockwork, but Myk/+ mice exhibit concomitant disruption in circadian rhythms and mood. The neural basis of this phenotype was investigated through molecular and electrophysiological dissection of the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Light input and glutamatergic signaling to the SCN were concomitantly assessed through behavioral assays and calcium imaging. Results In vivo assays revealed several circadian abnormalities including lengthened period and instability of behavioral rhythms, and elevated metabolic rate. Grossly aberrant responses to light included accentuated resetting, accelerated re-entrainment, and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PERIOD2) output from ex vivo SCN revealed no deficits in Myk/+ molecular clock function. Optic nerve crush rescued the circadian period of Myk/+ behavior, highlighting that afferent inputs are critical upstream mediators. Electrophysiological and calcium imaging SCN recordings demonstrated changes in the response to glutamatergic stimulation as well as the electrical output indicative of altered retinal input processing. Conclusions The Myshkin model demonstrates profound circadian and light-responsive behavioral alterations independent of molecular clock disruption. Afferent light signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.

中文翻译：

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Myshkin 小鼠躁狂模型中的昼夜节律紊乱与视交叉上分子钟功能缺陷无关


背景环境光和内在昼夜节律功能的改变与情绪障碍密切相关。尽管分子钟的遗传缺陷经常使小鼠的情绪相关表型发生改变，但支撑这些变化的神经起源仍不清楚。方法对 Na+/K+-ATPase α3 Myshkin (Myk/+) 小鼠躁狂模型进行详细的昼夜节律和光相关行为表征。 Na+/K+-ATPase α3 并不存在于核心昼夜节律分子时钟结构中，但 Myk/+ 小鼠表现出昼夜节律和情绪的伴随破坏。通过对主要昼夜节律起搏器——视交叉上核（SCN）进行分子和电生理学解剖，研究了这种表型的神经基础。通过行为测定和钙成像同时评估 SCN 的光输入和谷氨酸信号。结果体内检测显示了一些昼夜节律异常，包括行为节律延长和不稳定以及代谢率升高。对光的严重异常反应包括加剧的重置、加速的重新夹带和缺乏运动抑制。离体 SCN 输出的昼夜节律时钟蛋白 (PERIOD2) 的生物发光记录显示 Myk/+ 分子时钟功能没有缺陷。视神经挤压挽救了 Myk/+ 行为的昼夜节律周期，强调传入输入是关键的上游介质。电生理学和钙成像 SCN 记录显示对谷氨酸能刺激的反应以及表明视网膜输入处理改变的电输出的变化。 结论 Myshkin 模型表现出深刻的昼夜节律和光响应行为改变，与分子钟破坏无关。传入光信号驱动行为变化，并对情感障碍的昼夜节律破坏提出新的机制影响。