Department of Neurohumoral Regulations, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
J Biol Rhythms. 2019 Jun;34(3):307-322. doi: 10.1177/0748730419835360. Epub 2019 Mar 11.
The adult circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is resilient to glucocorticoids (GCs). The fetal rodent SCN resembles that of the adult in its organization of GC-sensitive peripheral tissues. We tested the hypothesis that the fetal SCN clock is sensitive to changes in GC levels. Maternal GCs must pass through the placenta to reach the fetal SCN. We show that the maternal but not the fetal part of the placenta harbors the autonomous circadian clock, which is reset by dexamethasone (DEX) and rhythmically expresses Hsd11b2. The results suggest the presence of a mechanism for rhythmic GC passage through the placental barrier, which is adjusted according to actual GC levels. GC receptors are expressed rhythmically in the laser-dissected fetal SCN samples. We demonstrate that hypothalamic explants containing the SCN of the mPer2 mouse prepared at embryonic day (E)15 spontaneously develop rhythmicity within several days of culture, with dynamics varying among fetuses from the same litter. Culturing these explants in media enriched with DEX accelerates the development. At E17, treatment of the explants with DEX induces phase advances and phase delays of the rhythms depending on the timing of treatments, and the shifts are completely blocked by the GC receptor antagonist, mifepristone. The DEX-induced phase-response curve differs from that induced by the vehicle. The fetal SCN is sensitive to GCs in vivo because DEX administration to pregnant rats acutely downregulates c-fos expression specifically in the laser-dissected fetal SCN. Our results provide evidence that the rodent fetal SCN clock may respond to changes in GC levels.
下丘脑视交叉上核（SCN）中的成人昼夜节律对糖皮质激素（GCs）具有弹性。胎儿啮齿动物 SCN 在其组织 GC 敏感的外周组织方面与成人相似。我们检验了这样一个假设，即胎儿 SCN 时钟对 GC 水平的变化敏感。母体 GCs 必须穿过胎盘才能到达胎儿 SCN。我们表明，胎盘的母体部分而不是胎儿部分具有自主昼夜节律时钟，该时钟被地塞米松（DEX）重置，并节律性地表达 Hsd11b2。结果表明存在一种通过胎盘屏障进行节律性 GC 传递的机制，该机制根据实际 GC 水平进行调整。GC 受体在激光分离的胎儿 SCN 样本中呈节律性表达。我们证明，在胚胎日（E）15 制备的包含 mPer2 小鼠 SCN 的下丘脑外植体在培养几天内自发地发展出节律性，来自同一窝的胎儿之间的动力学变化。在富含 DEX 的培养基中培养这些外植体可加速其发育。在 E17 时，用 DEX 处理外植体可根据处理时间诱导节律的相位提前和相位延迟，而 GC 受体拮抗剂米非司酮完全阻断了这些变化。DEX 诱导的相位反应曲线与载体诱导的曲线不同。DEX 给药会急性地下调激光分离的胎儿 SCN 中 c-fos 的表达，这表明体内胎儿 SCN 对 GCs 敏感。我们的结果提供了证据，表明啮齿动物胎儿 SCN 时钟可能对 GC 水平的变化做出反应。
