Direction-dependent effects of chronic “jet-lag” on hippocampal neurogenesis

Abstract

Disruptions in circadian rhythms, as seen in human shift workers, are often associated with many health consequences including impairments in cognitive functions. However, the mechanisms underlying these affects are not well understood. The objective of the present study is to explore the effects of circadian disruption on hippocampal neurogenesis, which has been implicated in learning and memory and could serve as a potential pathway mediating the cognitive consequences associated with rhythm disruption. Circadian rhythm disruptions were introduced using a weekly 6h phase shifting paradigm, in which male Wistar rats were subjected to either 6h phase advances (i.e. traveling eastbound from New York to Paris) or 6h phase delays (i.e. traveling westbound from Paris to New York) in their light/dark schedule every week. The effects of chronic phase shifts on hippocampal neurogenesis were assessed using doublecortin (DCX), a microtubule binding protein expressed in immature neurons. The results revealed that chronic disruption in circadian rhythms inhibits hippocampal neurogenesis, and the degree of reduction in neurogenesis depends upon the direction and duration of the shifts. In two cohorts of animals that experienced phase shifts for either 4 or 8 weeks, a greater decrease in neurogenesis was observed when the phase was advanced versus delayed in both groups. The direction-dependent effect mirrors the findings on clock gene expression in the SCN, suggesting a causal link between the reduction in hippocampal neurogenesis and a disrupted SCN circadian clock.