Regulation of Locomotor activity in fed, fasted, and food-restricted mice lacking tissue-type plasminogen activator

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.Electronic supplementary materialThe online version of this article (10.1186/s12899-018-0036-0) contains supplementary material, which is available to authorized users.

Hypothalamic mTORC2 is essential for metabolic health and longevity

“…Rictor Nkx2.1−/− mice exhibited a major decrease in voluntary wheel running when fed ad libitum (Figure h). Upon food deprivation, running wheel activity was partly restored during the dark phase in Rictor Nkx2.1−/− mice (Figure i), but the expected increase in activity during the light period relative to ad libitum fed mice was largely blunted (Krizo et al, ). These data support the conclusion that Rictor Nkx2.1−/− mice have a reduced intrinsic drive to be physically active.…”

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease

“…Muscles analyses were performed on Ocrl Y/+ versus Ocrl Y/− male mice aged 24 weeks. Lean mass/body weight ratio was determined in six pairs of live mice by using the whole body composition analyzer EchoMRI™ (Zinsser Analytic, Frankfurt, Germany) (56). Five pairs of mice were used for muscle and blood sampling.…”

Circadian rhythm and sleep-wake systems share the dynamic extracellular synaptic milieu

“…Similar to tPA, BDNF levels are higher in the SCN at night and lower during the day (Liang et al, 1998). Moreover, tPA -/- mice have less mBDNF in the SCN than wildtype mice (Cooper et al, 2017, Krizo et al, 2018). Blocking TrkB receptors inhibits light- and glutamate-induced phase shifts (Liang et al, 2000, Michel et al, 2006), and light-induced phase shifts are attenuated in BDNF heterozygous mice (Liang et al, 2000).…”

“…Given the data presented above, it is somewhat surprising that tPA -/- mice entrain normally to LD cycles and exhibit minimal changes in sensitivity to light-induced phase-shifts in vivo or glutamate-induced phase shifts in vitro . The only discernable deficiency in light entrainment is that tPA knockout mice re-entrain to either an inverted light cycle or to a 6 h advance in the light cycle more slowly than wildtype litter mates (Cooper et al, 2017, Krizo et al, 2018). It is also interesting to note that tPA modulates food anticipatory behavior driven by a food-entrainable circadian oscillator that functions independently of the SCN clock (Krizo et al, 2018).…”

“…The only discernable deficiency in light entrainment is that tPA knockout mice re-entrain to either an inverted light cycle or to a 6 h advance in the light cycle more slowly than wildtype litter mates (Cooper et al, 2017, Krizo et al, 2018). It is also interesting to note that tPA modulates food anticipatory behavior driven by a food-entrainable circadian oscillator that functions independently of the SCN clock (Krizo et al, 2018). This study found that tPA knockout mice have reduced wheel running activity compared to wildtype mice and altered behavioral activity patterns in response to fasting and temporally restricted food availability.…”