Reentrainment of the circadian pacemaker through three distinct stages

Circadian rhythms are endogenously generated by a central pacemaker and are synchronized to the environmental LD cycle. The rhythms can be resynchronized, or reentrained, after a shift of the LD cycle, as in traveling across time zones. The authors have performed high-resolution mapping of the pacemaker to analyze the reentrainment process using rat pineal melatonin onset (MTon) and melatonin offset (MToff) rhythms as markers. Following LD (12:12) delays of 3, 6, and 12 h, MTon was phase locked immediately, whereas MToff shifted rapidly during the initial 1 through 3 cycles. In all animals, the MToff shifted beyond their expected phase positions in the new LD cycle, which resulted in a transient expansion of melatonin secretion duration for several cycles. It took MToff only 1, 2, or 3 cycles to complete most of the required phase shifts after 3, 6, or 12 h of the LD cycle delays, respectively. However, the final stabilization of phase relationships of both MTon and MToff required at least 6 cycles for rats experiencing a 3-h LD delay and much longer for the rest. These results reaffirmed the notion that both onset and offset phases of melatonin rhythms are important markers for the pacemaker and demonstrated that the reentrainment of the central pacemaker to a delay shift of the LD cycle is a 3-step process: an immediate phase lock of onset and a rapid delay shift of offset rhythms, overshoot of the offset, and, finally, a slow adjustment of both onset and offset phases. This study represents the 1st detailed analysis of the pacemaker behavior during reentrainment using melatonin and supports the notion that the eventual adaptation of the circadian pacemaker to a new time zone is a time-consuming process.