Population averaging due to paracrine communication can arbitrarily reduce cellular response variability. Yet, variability is ubiquitously observed, suggesting limits to paracrine averaging. It remains unclear whether and how biological systems may be affected by such limits of paracrine signaling. To address this question, we quantify the signal and noise of Ca2+ and ERK spatial gradients in response to an in vitro wound within a novel microfluidics-based device. We find that while paracrine communication reduces gradient noise, it also reduces the gradient magnitude. Accordingly we predict the existence of a maximum gradient signal to noise ratio. Direct in vitro measurement of paracrine communication verifies these predictions and reveals that cells utilize optimal levels of paracrine signaling to maximize the accuracy of gradient-based positional information. Our results demonstrate the limits of population averaging and show the inherent tradeoff in utilizing paracrine communication to regulate cellular response fidelity.
- Sarah A Teichmann, EMBL-European Bioinformatics Institute & Wellcome Trust Sanger Institute, United Kingdom
© 2015, Handly et al.
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Cerebellar climbing fibers convey diverse signals, but how they are organized in the compartmental structure of the cerebellar cortex during learning remains largely unclear. We analyzed a large amount of coordinate-localized two-photon imaging data from cerebellar Crus II in mice undergoing 'Go/No-go' reinforcement learning. Tensor component analysis revealed that a majority of climbing fiber inputs to Purkinje cells were reduced to only four functional components, corresponding to accurate timing control of motor initiation related to a Go cue, cognitive error-based learning, reward processing, and inhibition of erroneous behaviors after a No-go cue. Changes in neural activities during learning of the first two components were correlated with corresponding changes in timing control and error learning across animals, indirectly suggesting causal relationships. Spatial distribution of these components coincided well with boundaries of Aldolase-C/zebrin II expression in Purkinje cells, whereas several components are mixed in single neurons. Synchronization within individual components was bidirectionally regulated according to specific task contexts and learning stages. These findings suggest that, in close collaborations with other brain regions including the inferior olive nucleus, the cerebellum, based on anatomical compartments, reduces dimensions of the learning space by dynamically organizing multiple functional components, a feature that may inspire new-generation AI designs.
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