Biology subjects

Ananthasubramaniam, B.

Publications and source records attributed to Ananthasubramaniam, B..

3 recordsLinked to original sources

bioRxiv2019

Ultradian regulation of rest and activity bouts in mice

The suprachiasmatic nucleus (SCN), which serves as the central pacemaker in mammals, regulates the 24-hour rhythm in behavioral activity. However, it is currently unclear whether and how bouts of activity and rest are regulated within the 24-hour cycle (i.e., over ultradian time scales). Therefore, we used passive infrared sensors to measure behavior in mice housed under either a light-dark (LD) cycle or continuous darkness (DD). We found that a probabilistic Markov model captures the ultradian changes in the behavioral state over a 24-hour cycle. In this model, the animals behavioral state in the next time interval is determined solely by the animals current behavioral state and by the "toss" of a proverbial "biased coin". We found that the bias of this "coin" is regulated by light input and by the phase of the clock. Moreover, the bias of this "coin" for an animal is related to the average length of rest and activity bouts in that animal. In LD conditions, the average length of rest bouts was greater during the day compared to during the night, whereas the average length of activity bouts was greater during the night compared to during the day. Importantly, we also found that day-night changes in the rest bout lengths were significantly greater than day-night changes in the activity bout lengths. Finally, in DD conditions, the activity and rest bouts also differed between subjective night and subjective day, albeit to a lesser extent compared to LD conditions. The persistent differences in bout length over the circadian cycle following loss of the external LD cycle indicate that the central pacemaker plays a role in regulating rest and activity bouts on an ultradian time scale.

physiology↗

bioRxiv2019

Amplitude effects allow short jetlags and large seasonal phase shifts in minimal clock models

Mathematical models of varying complexity have helped shed light on different aspects of circadian clock function. In this work, we question whether minimal clock models (Goodwin models) are sufficient to reproduce essential phenotypes of the clock: a small phase response curve (PRC), fast jetlag and seasonal phase shifts. Instead of building a single best model, we take an approach where we study the properties of a set of models satisfying certain constraints; here a one-hour pulse PRC with a range of three hours and clock periods between 22h and 26h. Surprisingly, almost all these randomly parameterized models showed a four hour change in phase of entrainment between long and short days and jetlag durations of three to seven days in advance and delay. Moreover, intrinsic clock period influenced jetlag duration and entrainment amplitude and phase. Fast jetlag was realized in this model by means of an interesting amplitude effect: the association between clock amplitude and clock period termed twist. This twist allows amplitude changes to speed up and slow down clocks enabling faster shifts. These findings were robust to the addition of positive feedback to the model. In summary, the known design principles of rhythm generation - negative feedback, long delay and switch-like inhibition (we review these in detail) - are sufficient to reproduce the essential clock phenotypes. Furthermore, amplitudes play a role in determining clock properties and must be always considered, although they are difficult to measure.

systems biology↗

bioRxiv2019

Susceptibility rhythm to bacterialendotoxin in myeloid clock-knockout mice

Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNF, MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffic of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell trafficking and cytokine expression.

immunology↗