Aging of the circadian system in zebrafish and the effects of melatonin on sleep and cognitive performance

Abstract

Aging is a complex process involving intracellular changes and, notably, modifications in intercellular communications, required for coordinated responses to internal and external events. One of the potential reasons for such changes is an age-dependent failure of the integrating systems, including the circadian clock. Here we demonstrate that aging in a diurnal vertebrate, zebrafish (Danio rerio), is associated with major but selective circadian alterations. By 3-5 years of age, zebrafish have reduced amplitude and increased fragmentation of entrained circadian rhythms of activity, with fast desynchronization of the rhythms in the absence of environmental time cues. Aging in zebrafish is also associated with a reduction in the overall duration of nighttime sleep, followed by lower activity levels and a higher arousal threshold during the day. The production of the principal circadian hormone, melatonin, progressively declines during zebrafish aging. However, the ability of melatonin to acutely promote sleep and entrain circadian rhythms of activity remains robust until at least 4-5-years of age, consistent with the preserved levels of mRNA expression for melatonin receptors. Aged zebrafish have altered expression of the circadian genes zBmal1 and zPer1 but not zClock1. A lack of circadian time cues alters cognitive performance in aged more than in young zebrafish and this can be partially attenuated by daily melatonin administration. The advantages of zebrafish as a diurnal, small, prolific and genetically well-characterized vertebrate model provide new opportunities to clarify the intrinsic circadian factors involved in human aging and promote the search for prophylactic and treatment strategies.

Towards a Comprehensive Catalog of Zebrafish Behavior 1.0 and Beyond

“…Sleep (sleep-like behavior): Activity characterized in zebrafish by rest behavior, including reversible immobility/ hypolocomotion, elevated arousal threshold, reduced respiratory rate (e.g., opercular movements) and mouth opening frequency, and a compensatory rebound in response to sleep deprivation. 107,122,144,145,[153][154][155][156] In adult zebrafish, includes brief periods of inactivity, often with a drooping caudal fin (see Droopy tail), alternated with active periods of swimming; can be easily reversed by startling stimuli, such as tapping, sound, or weak electric field. 1.149.…”

Zebrafish as a Genetic Model in Biological and Behavioral Gerontology: Where Development Meets Aging in Vertebrates – A Mini-Review

“…3 ). They can be documented starting at 2 years of age and are associated with the gradual onset of melatonin deficiency and a decline in the expression of core clock genes [14,16] . An especially prominent decline was found in bmal1 mRNA abundance in aged zebrafish.…”

“…Following the initial behavioral characterization of the sleep process in zebrafish and its modulation by melatonin, which we conducted in larvae [25] , we extensively investigated changes in sleep and circadian rhythms in aged zebrafish [14,26] . We found that in spite of the relatively long life span of this vertebrate, and its gradual senescence, sleep and circadian rhythmicity changes occur relatively early in life ( fig.…”

Melatonin and Peripheral Circuitries: Insights on Appetite and Metabolism in Danio Rerio

“…Two groups of zebrafish (n = 10 fish per group), in triplicate, maintained with the photoperiod previously described, were exposed via water to two different doses of melatonin (Sigma Aldrich), 100 nM and 1 lM, following previous studies. 9,38 Briefly, for stock solution, melatonin was directly dissolved to 100 lM concentration in water. The actual levels of melatonin were confirmed by highperformance liquid chromatography with fluorescence detection using serial dilutions, in three independent experiments.…”