Structural and functional changes in the suprachiasmatic nucleus following chronic circadian rhythm perturbation

Abstract

Circadian rhythms, generated in the suprachiasmatic nucleus (SCN), are synchronized to the ambient light/dark (LD) cycle. Long-term disruptions in circadian rhythms are associated with many health problems. However, the underlying mechanisms for such pathologies are not well understood. In the present study, we utilized a chronic jet lag paradigm consisting of weekly 6 h phase shifts in the LD cycle to investigate the circadian responses in behavior and in the functioning of the SCN following long-term circadian perturbation, and to explore the duration and direction dependent changes of the SCN using rats subjected to weekly phase advances or delays. Wheel-running activity was monitored over four weekly phase advances. The nocturnal activity pattern was re-established by the end of each shift, and the rate for recovering the nocturnality appeared to accelerate following multiple shifts. SCN function was assessed by the expressions of the protein product of clock gene PER1 and of two putative SCN output signals, arginine vasopressin (AVP) and prokineticin2 (Pk2). At the end of the 4th weekly advance, the amplitude of the PER1 rhythm in the SCN decreased, and this reduction was more prominent in the dorsomedial SCN than in the ventrolateral SCN. The levels of AVP and Pk2 expression were also attenuated in the SCN and in targets of its efferent projections. Comparing rats subjected to four or eight shifts of either delay or advance, the results revealed that the responses of the SCN depended on both duration and direction of the shifts, such that the level of PER1 expression further decreased at the end of the 8th compared to the 4th phase advance, but did not change significantly following phase delays. Taken together, the results suggest that rhythm perturbation could compromise the time-keeping function of the SCN, which could contribute to the associated health issues.