Abstract
BackgroundCircadian rhythms of physiology and behavior are driven by a circadian clock located in the suprachiasmatic nucleus of the hypothalamus. This clock is synchronized to environmental day/night cycles by photic input, which is dependent on the presence of mature brain-derived neurotrophic factor (BDNF) in the SCN. Mature BDNF is produced by the enzyme plasmin, which is converted from plasminogen by the enzyme tissue-type plasminogen activator (tPA). In this study, we evaluate circadian function in mice lacking functional tPA.ResultstPA−/− mice have normal circadian periods, but show decreased nocturnal wheel-running activity. This difference is eliminated or reversed on the second day of a 48-h fast. Similarly, when placed on daily cycles of restricted food availability the genotypic difference in total wheel-running activity disappears, and tPA−/− mice show equivalent amounts of food anticipatory activity to wild type mice.ConclusionsThese data suggest that tPA regulates nocturnal wheel-running activity, and that tPA differentially affects SCN-driven nocturnal activity rhythms and activity driven by fasting or temporal food restriction.
Highlights
Circadian rhythms of physiology and behavior are driven by a circadian clock located in the suprachiasmatic nucleus of the hypothalamus
Assessment of mBDNF/proBDNF ratio in the suprachiasmatic nucleus of the hypothalamus (SCN) First, we established whether there was a reduction in mBDNF levels in the SCN of type plasminogen activator (tPA)−/− mice
SCN tissue was isolated from tPA+/+ and tPA −/− mice at zeitgeber time (ZT) 4 and ZT 12 and immediately transferred into extraction buffer for protein analysis
Summary
Circadian rhythms of physiology and behavior are driven by a circadian clock located in the suprachiasmatic nucleus of the hypothalamus This clock is synchronized to environmental day/night cycles by photic input, which is dependent on the presence of mature brain-derived neurotrophic factor (BDNF) in the SCN. The production of the mature form of BDNF in the brain is at least partly dependent on the extracellular activity of tissue-type plasminogen activator (tPA), which converts plasminogen to plasmin, which in turn catalyzes the conversion of proBDNF to mBDNF [7] Both BDNF and trkB are found in the SCN [6, 8, 9]. Mice that lack tPA have normal free-running periods and normal phase-shifting responses to light pulses, though they do show slower entrainment to a large shift of the light-dark cycle [12]. Mice that lack BDNF in adulthood are hyperactive [13], suggesting the possibility that depressed activity in tPA−/− mice occurs via a BDNF-independent mechanism
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