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Threshold-Free Population Analysis Identifies Larger DRG Neurons to Respond Stronger to NGF Stimulation

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  • Christine Andres
  • Jan Hasenauer
  • Frank Allgower
  • Tim Hucho

Abstract

Sensory neurons in dorsal root ganglia (DRG) are highly heterogeneous in terms of cell size, protein expression, and signaling activity. To analyze their heterogeneity, threshold-based methods are commonly used, which often yield highly variable results due to the subjectivity of the individual investigator. In this work, we introduce a threshold-free analysis approach for sparse and highly heterogeneous datasets obtained from cultures of sensory neurons. This approach is based on population estimates and completely free of investigator-set parameters. With a quantitative automated microscope we measured the signaling state of single DRG neurons by immunofluorescently labeling phosphorylated, i.e., activated Erk1/2. The population density of sensory neurons with and without pain-sensitizing nerve growth factor (NGF) treatment was estimated using a kernel density estimator (KDE). By subtraction of both densities and integration of the positive part, a robust estimate for the size of the responsive subpopulations was obtained. To assure sufficiently large datasets, we determined the number of cells required for reliable estimates using a bootstrapping approach. The proposed methods were employed to analyze response kinetics and response amplitude of DRG neurons after NGF stimulation. We thereby determined the portion of NGF responsive cells on a true population basis. The analysis of the dose dependent NGF response unraveled a biphasic behavior, while the study of its time dependence showed a rapid response, which approached a steady state after less than five minutes. Analyzing two parameter correlations, we found that not only the number of responsive small-sized neurons exceeds the number of responsive large-sized neurons—which is commonly reported and could be explained by the excess of small-sized cells—but also the probability that small-sized cells respond to NGF is higher. In contrast, medium-sized and large-sized neurons showed a larger response amplitude in their mean Erk1/2 activity.

Suggested Citation

  • Christine Andres & Jan Hasenauer & Frank Allgower & Tim Hucho, 2012. "Threshold-Free Population Analysis Identifies Larger DRG Neurons to Respond Stronger to NGF Stimulation," PLOS ONE, Public Library of Science, vol. 7(3), pages 1-14, March.
  • Handle: RePEc:plo:pone00:0034257
    DOI: 10.1371/journal.pone.0034257
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    References listed on IDEAS

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    1. Avigdor Eldar & Michael B. Elowitz, 2010. "Functional roles for noise in genetic circuits," Nature, Nature, vol. 467(7312), pages 167-173, September.
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    1. Jan Hasenauer & Christine Hasenauer & Tim Hucho & Fabian J Theis, 2014. "ODE Constrained Mixture Modelling: A Method for Unraveling Subpopulation Structures and Dynamics," PLOS Computational Biology, Public Library of Science, vol. 10(7), pages 1-17, July.

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