Bering Tenna, Blancas-Velazquez Aurea Susana, Rath Martin Fredensborg
Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
Neuroendocrinology. 2023;113(10):1076-1090. doi: 10.1159/000533151. Epub 2023 Jul 29.
In the hippocampus, clock gene expression is important for memory and mood; however, the signaling mechanism controlling clock gene expression in the hippocampus is unknown. Recent findings suggest that circadian glucocorticoid rhythms driven by the suprachiasmatic nucleus (SCN) control rhythmic clock gene expression in neurons; in addition, dexamethasone modulates hippocampal clock gene expression. We therefore hypothesized that oscillations of clock genes in the hippocampus could be driven by SCN-controlled circadian rhythms in glucocorticoids.
Temporal profiles of hippocampal clock gene expression were established by quantitative reverse-transcription real-time PCR on rat hippocampi, while cellular distribution was established by in situ hybridization. To determine the effect of rhythmic glucocorticoids on hippocampal clock gene expression, the SCN was lesioned, adrenal glands removed and a 24 h exogenous corticosterone rhythm at physiological levels was reestablished by use of a programmable infusion pump.
Daily rhythms were detected for Per1, Per2, Bmal1, Nr1d1, and Dbp, while clock gene products were confirmed in both the hippocampus proper and the dentate gyrus. In sham controls, differential hippocampal expression of Per1 and Dbp between ZT3 and ZT15 was detectable. This rhythm was abolished by SCN lesion; however, reestablishing the natural rhythm in corticosterone restored differential rhythmic expression of both Per1 and Dbp. Further, a 6 h phase delay in the corticosterone profile caused a predictable shift in expression of Nr1d1.
Our data show that rhythmic corticosterone can drive hippocampal clock gene rhythms suggesting that the SCN regulates the circadian oscillator of the hippocampus by controlling the circadian rhythm in circulating glucocorticoids.
在海马体中，生物钟基因的表达对记忆和情绪很重要；然而，控制海马体中生物钟基因表达的信号传导机制尚不清楚。最近的研究结果表明，由视交叉上核（SCN）驱动的昼夜糖皮质激素节律控制着神经元中有节奏的生物钟基因表达；此外，地塞米松可调节海马体生物钟基因的表达。因此，我们推测海马体中生物钟基因的振荡可能由SCN控制的糖皮质激素昼夜节律驱动。
通过对大鼠海马体进行定量逆转录实时PCR来确定海马体生物钟基因表达的时间模式，同时通过原位杂交确定细胞分布。为了确定有节奏的糖皮质激素对海马体生物钟基因表达的影响，损毁SCN，切除肾上腺，并使用可编程输液泵重建24小时生理水平的外源性皮质酮节律。
检测到Per1、Per2、Bmal1、Nr1d1和Dbp的每日节律，同时在海马体本身和齿状回中均证实了生物钟基因产物。在假手术对照组中，可检测到ZT3和ZT15之间海马体中Per1和Dbp的差异表达。这种节律在SCN损伤后消失；然而，重建皮质酮的自然节律可恢复Per1和Dbp的差异节律表达。此外，皮质酮谱中的6小时相位延迟导致Nr1d1表达出现可预测的变化。
我们的数据表明，有节奏的皮质酮可驱动海马体生物钟基因节律，这表明SCN通过控制循环糖皮质激素的昼夜节律来调节海马体的昼夜振荡器。
