Kirsten Meeker - Academia.edu (original) (raw)

Papers by Kirsten Meeker

Figure S1. Cry1 is required for sustained circadian mPer2Luc rhythmicity in liver and cornea expl... more Figure S1. Cry1 is required for sustained circadian mPer2Luc rhythmicity in liver and cornea explants. Figure S2. Cry1 is required for sustained circadian mPer2Luc rhythmicity in individual cells of liver explants. Figure S3. Oscillator network interactions provide system robustness but mask cell-autonomous phenotypes in mutant clock cells Supplemental Experimental Procedures. Lentiviral clock reporter construction Serum shock and quantitative PCR

Proceedings of the National Academy of Sciences, 2017

Many living organisms have evolved to anticipate daily circadian cycles and changing seasons of t... more Many living organisms have evolved to anticipate daily circadian cycles and changing seasons of their environment. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus, a brain region of about 20,000 neurons, serves as the master circadian clock coordinating timing throughout the body and entraining to daily external light cycles. The remarkable precision of the SCN clock relies on intercellular signaling. In its absence, each SCN neuron and the SCN as a whole have significantly less stable oscillations. Though there are candidate signaling We first validated the method on several model networks. After inferring connection networks of three SCN's, we modeled those networks in our stochastic SCN model and confirmed that we could re-infer the bio-inspired networks. We found that the SCN, at least for these experimental samples, appears to have a small-world network topology and is scale-free. We hope that our results have helped to illuminate how stochastic fluctuations in the SCN system contribute to

Proceedings of the National Academy of Sciences, 2016

Significance In mammals, circadian rhythms are controlled by a network of neurons in the brain. T... more Significance In mammals, circadian rhythms are controlled by a network of neurons in the brain. The structure of this network dictates organism-wide behavior and adaptation to the environment. We used a neurotoxin to desynchronize this circadian network and then used tools from information theory to determine which cells communicate to establish synchronization. Our results show that this functional network consists of two densely-connected cores, surrounded by sparsely connected shell regions. These findings represent the first time, to our knowledge, that this network has been examined at single cell resolution and show that the importance of these core network regions is independent of light input.

Real-Time PDE-Constrained Optimization, 2007

Proceedings of the National Academy of Sciences, 2013

Significance Daily rhythms in behavior depend on the coordinated cycling of circadian neurons in ... more Significance Daily rhythms in behavior depend on the coordinated cycling of circadian neurons in the brain. Here, we found that a neuropeptide that is required for synchrony among circadian neurons also, surprisingly, dose-dependently reduces synchrony among circadian cells. We find this allows the system to adjust how quickly it entrains to environmental cycles. We propose that treatments that enhance this signaling pathway could reduce jet lag associated with shift work and travel across time zones.

Journal of The Royal Society Interface, 2008

Systems theoretic tools (i.e. mathematical modelling, control, and feedback design) advance the u... more Systems theoretic tools (i.e. mathematical modelling, control, and feedback design) advance the understanding of robust performance in complex biological networks. We highlight phase entrainment as a key performance measure used to investigate dynamics of a single deterministic circadian oscillator for the purpose of generating insight into the behaviour of a population of (synchronized) oscillators. More specifically, the analysis of phase characteristics may facilitate the identification of appropriate coupling mechanisms for the ensemble of noisy (stochastic) circadian clocks. Phase also serves as a critical control objective to correct mismatch between the biological clock and its environment. Thus, we introduce methods of investigating synchrony and entrainment in both stochastic and deterministic frameworks, and as a property of a single oscillator or population of coupled oscillators.

Journal of Biological Rhythms, 2011

Cells in the suprachiasmatic nucleus (SCN) display remarkable precision, while either physically ... more Cells in the suprachiasmatic nucleus (SCN) display remarkable precision, while either physically or chemically decoupling these cells from each other leads to a dramatic increase in period-to-period variability. Where previous studies have classified cells as either arrhythmic or circadian, our wavelet analysis reveals that individual cells, when removed from network interactions, intermittently express circadian and/or longer infradian periods. We reproduce the characteristic period distribution of uncoupled SCN cells with a stochastic model of the uncoupled SCN cell near a bifurcation in Bmal1 transcription repression. This suggests that the uncoupled cells may be switching between 2 oscillatory mechanisms: the indirect negative feedback of protein complex PER-CRY on the expression of Per and Cry genes, and the negative feedback of CLOCK-BMAL1 on the expression of the Bmal1 gene. The model is particularly sensitive near this bifurcation point, with only a small change in Bmal1 tra...

Cell, 2007

Molecular mechanisms of the mammalian circadian clock have been studied primarily by genetic pert... more Molecular mechanisms of the mammalian circadian clock have been studied primarily by genetic perturbation and behavioral analysis. Here, we used bioluminescence imaging to monitor Per2 gene expression in tissues and cells from clock mutant mice. We discovered that Per1 and Cry1 are required for sustained rhythms in peripheral tissues and cells, and in neurons dissociated from the suprachiasmatic nuclei (SCN). Per2 is also required for sustained rhythms, whereas Cry2 and Per3 deficiencies cause only period length defects. However, oscillator network interactions in the SCN can compensate for Per1 or Cry1 deficiency, preserving sustained rhythmicity in mutant SCN slices and behavior. Thus, behavior does not necessarily reflect cell-autonomous clock phenotypes. Our studies reveal previously unappreciated requirements for Per1, Per2, and Cry1 in sustaining cellular circadian rhythmicity and demonstrate that SCN intercellular coupling is essential not only to synchronize component cellular oscillators but also for robustness against genetic perturbations.

Abstract: Systems theoretic tools, including mathematical modeling, control theoretic analysis, a... more Abstract: Systems theoretic tools, including mathematical modeling, control theoretic analysis, and feedback design, advance the understanding of the circadian clock: a set of noisy oscillators that communicate to ensure its function as a reliable pacemaker. The clock's ...