Suprachiasmatic Nuclei Possess Glucocorticoid Receptors That Activate Downstream Signaling Pathways but Do Not...

The circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) is resistant to glucocorticoids (GC) in adults but responds to dexamethasone (DEX) during the fetal stage. Previously, this resistance of the adult SCN clock was attributed to a developmental loss of the glucocorticoid receptor (GR). The aim of our study was to re-examine the mechanism underlying SCN clock resistance.

We detected GR in the adult SCN at the mRNA level (Nr3c1) using RT-qPCR and at the protein level by immunohistochemistry, and examined the effects of DEX on the SCN clock of mPer2^Luc mice ex vivo at embryonic day E17, postnatal days P1-2, P3, P5, P10, and adulthood.

Surprisingly, we found that Nr3c1 expression gradually increases from the fetal stage to postnatal day (P)28. In the adult SCN, GR immunoreactivity is present in both neurons and glia. The effect of DEX on the SCN clock disappears shortly after birth. Although DEX does not entrain the adult SCN clock, it acutely increases the expression of Gilz and Sgk1, indicating that GRs in the adult SCN can activate downstream signaling pathways. Inhibition of glial metabolism by fluorocitrate had no effect on resistance to DEX, but treatment with tetrodotoxin sensitized the clock to DEX and induced phase shifts similar to those observed at the fetal stage.

These results indicate that the adult SCN possesses GRs capable of activating GC-signaling pathways, but the clock is resistant to GC in part due to coupling between individual cellular oscillators.