Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics
Abstract
While multicompartment models have long been used to study the biophysics of neurons, it is still challenging to infer the parameters of such models from data including uncertainty estimates. Here, we performed Bayesian inference for the parameters of detailed neuron models of a photoreceptor and an OFF- and an ON-cone bipolar cell from the mouse retina based on two-photon imaging data. We obtained multivariate posterior distributions specifying plausible parameter ranges consistent with the data and allowing to identify parameters poorly constrained by the data. To demonstrate the potential of such mechanistic data-driven neuron models, we created a simulation environment for external electrical stimulation of the retina and optimized stimulus waveforms to target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprosthetics.
Data availability
All code and data will be made available upon publication on https://github.com/berenslab.
Article and author information
Author details
Funding
Bundesministerium für Bildung und Forschung (01GQ1601)
- Philipp Berens
Bundesministerium für Bildung und Forschung (01IS18052)
- Philipp Berens
Deutsche Forschungsgemeinschaft (EXC 2064 - 390727645)
- Philipp Berens
Deutsche Forschungsgemeinschaft (BE5601/4-1)
- Philipp Berens
Baden-Württemberg Stiftung (NEU013)
- Günther Zeck
- Philipp Berens
National Institutes of Health (EY022070)
- Robert G Smith
National Institutes of Health (EY023766)
- Robert G Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Alexander Borst, Max Planck Institute of Neurobiology, Germany
Ethics
Animal experimentation: All animal procedures were approved by the governmental review board (Regierungspräsidium Tübingen, Baden-Württemberg, Konrad-Adenauer-Str. 20, 72072 Tübingen, Germany) and performed according to the laws governing animal experimentation issued by the German Government.All procedures were approved by the governmental review board (Regierungspräsidium Tübingen, Baden-Württemberg, Konrad-Adenauer-Str. 20, 72072 Tübingen, Germany, AZ 35/9185.82-7) and performed according to the laws governing animal experimentation issued by the German Government.
Version history
- Received: January 8, 2020
- Accepted: October 26, 2020
- Accepted Manuscript published: October 27, 2020 (version 1)
- Version of Record published: November 18, 2020 (version 2)
Copyright
© 2020, Oesterle et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,848
- views
-
- 288
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Computational and Systems Biology
- Neuroscience
Mechanistic modeling in neuroscience aims to explain observed phenomena in terms of underlying causes. However, determining which model parameters agree with complex and stochastic neural data presents a significant challenge. We address this challenge with a machine learning tool which uses deep neural density estimators—trained using model simulations—to carry out Bayesian inference and retrieve the full space of parameters compatible with raw data or selected data features. Our method is scalable in parameters and data features and can rapidly analyze new data after initial training. We demonstrate the power and flexibility of our approach on receptive fields, ion channels, and Hodgkin–Huxley models. We also characterize the space of circuit configurations giving rise to rhythmic activity in the crustacean stomatogastric ganglion, and use these results to derive hypotheses for underlying compensation mechanisms. Our approach will help close the gap between data-driven and theory-driven models of neural dynamics.
-
- Cell Biology
- Computational and Systems Biology
Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2-STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation.