Astrocytes in the mouse suprachiasmatic nuclei respond directly to glucocorticoids feedback

The circadian timing system anticipates daily recurring changes in the environment to synchronize physiology. In mammals, the master pacemaker is the hypothalamic suprachiasmatic nuclei (SCN), which synchronizes “wake” functions by inducing the circadian release of Glucocorticoids (GCs) from the adrenal gland. GCs peak right before the active phase and set the time of peripheral clocks, however, it is still unclear whether the SCN respond to GCs feedback. While GCs influence directly the SCN during the perinatal period, the adult circuit is considered to be resistant to them, suggesting a reduction of GCs-sensitivity along development. To understand this mechanism, we followed the expression of GC receptor (GR) along mouse SCN development with single cell resolution and show that GR is up-regulated in astrocytes as the circuit matures. We provide in vivo and in vitro evidence that the adult SCN stays responsive to circulating GCs through the activation of GR in astrocytes. Astrocytes' communication is necessary to induce the GC-dependent shift on the SCN clock. Our data provides insight into the development of the SCN and highlight a new role of astrocytes as time-keepers in the adult. This finding might shed light on how the circadian system adapts to jetlag or shift work. Overall design: We have assessed the mRNA expression profile of the developing mouse SCN at single-cell resolution at three key developmental time points (gestational day (GD) 17.5, postnatal day (PND) 2, PND10) and at PND30 when the SCN circuit is fully mature. At GD17.5 a substantial increase in the synchrony of clock genes' oscillations in SCN cells has been observed concurrent to the neurogenic-gliogenic switch. At PND02 neurons are differentiated and the first peak of astrocytes' proliferation happens. At PND10 the maturation of the RHT and the innervation of the ventral SCN is complete and the eyes open, light entrainment would promote the final development of the circuit. At PND30, the SCN circuit architecture has reached the maturity of the adult nuclei.