Impact of Melatonin on Zeitgeber Time-Dependent Changes in Cell Proliferation and Apoptosis in the Adult Murine Hypothalamic-Hypophyseal System

Abstract

Background/Aims: Cell proliferation and apoptosis are known to adjust neuroendocrine circuits to the photoperiod. The latter is communicated by melatonin, the hormone secreted by the pineal organ. The present study investigated zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine neuroendocrine system and their regulation by melatonin. Methods: Adult melatonin-proficient (C3H/HeN) and melatonin-deficient (C57Bl/6J) mice, as well as melatonin-proficient (C3H/HeN) mice with targeted deletion of both melatonin receptor types (MT1 and MT2) were adapted to a 12-hour light, 12-hour dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 served to identify and quantify proliferating and apoptotic cells in the median eminence (ME), hypophyseal pars tuberalis, and pars distalis (PD). Results: ZT-dependent changes in cell proliferation and apoptosis were found exclusively in melatonin-proficient mice with functional MTs. Cell proliferation in the ME and PD showed ZT-dependent changes indicated by an increase at ZT12 (ME) and a decrease at ZT06 (PD). Apoptosis showed ZT-dependent changes in all regions analyzed, indicated by an increase at ZT06. Proliferating and apoptotic cells were found in nearly all cell types residing in the regions analyzed. Conclusions: Our results indicate that ZT-dependent changes in cell proliferation are counterbalanced by ZT-dependent changes in apoptosis exclusively in melatonin-proficient mice with functional MTs. Melatonin signaling appears to be crucial in both the generation and timing of proliferation and apoptosis that serve the high rate of physiological cell turnover in the adult neuroendocrine system.