A developmental shift in glucocorticoid receptor expression preserves glucocorticoid sensitivity in the adult...

The circadian system synchronizes physiology, improving the adaptation to daily environmental changes. In mammals, the central pacemaker, in the suprachiasmatic nuclei (SCN) of the hypothalamus, coordinates "wake" functions by inducing the circadian release of glucocorticoids (GCs). GCs entrain the clocks of a wide variety of tissues through GC receptor (GR) activation, however, the influence of GCs on the SCN is unclear and seems to depend on the maturity of the circuit. During the perinatal period, the mouse SCN express GR and respond directly to GCs while the adult SCN express low GR and have been traditionally considered resistant to GCs. To understand the change of sensitivity to GCs we followed the developmental trajectory of the mouse SCN, and found that while GR is expressed in all SCN cells early in life, it remains expressed mainly in astrocytes in the adult. Using a model of prenatal exposure to GCs, we found that offspring from treated mothers, adapt slower to shifted light-dark cycle and shows reduced expression of GR in SCN astrocytes. The adult SCN astrocytes can indeed sense and respond to GCs with rapid astrocytic Ca2+ events that propagate across neighboring cells, an effect that is prevented by the specific inhibition of astrocyte-astrocyte communication. Our findings provide a conceptual advance on how the mouse clock develops and on the influence that GCs have on the SCN. This might be relevant to understand how circadian synchrony is restored in conditions of temporal misalignment, such as jet lag.