P250 A computational study of the influence of circadian adaptive mechanisms on signal processing in retinal circuits
Laetitia Raison-Aubry*1, Nange Jin2, Christophe P. Ribelayga2, Laure Buhry1
1Université de Lorraine, CNRS, LORIA, F-54000 Nancy, France
2Vision Sciences, University of Houston, Houston, Texas, United-Stats
*Email: laetitia.raison-aubry@loria.fr
Introduction
Rod-mediated signals reach retinal ganglion cells (RGCs) via three major pathways with distinct sensitivities and operating ranges [1,2,3]. These pathways interact with the cone pathway to ensure seamless processing over >9 log units of light intensity [1]. Gap junctions (GJs) between rod and cone terminals, the entry point of the secondary rod pathway (SRP), exhibit circadian plasticity--stronger at night--directly modulating rod signal flow into cones, and thereby SRP influence on retinal output [4,5]. However, experimentally isolating this effect is challenging due to the non-specificity of pharmacological interventions. Biophysical modeling provides a precise and reversible alternative to selectively manipulate rod/cone coupling while preserving other synaptic conductances. Using a recent mathematical model of a retinal microcircuit [6], we investigate how circadian modulation shapes rod and cone signal integration.
Methods
Our simulated network consists of ~40,000 retinal cells presynaptic to a single transient OFF alpha (tOFF a) RGC [6], arranged on a circular grid approximating the RGC’s receptive field [7] and interconnected with >100,000 synaptic connections, including chemical and electrical synapses. Each retinal cell type is implemented using conductance-based models that follow the Hodgkin-Huxley formalism. Light-induced photocurrent waveforms, whose amplitude and kinetics vary nonlinearly with stimulus intensity [8], serve as input stimuli [6].
Measurements of transjunctional conductance between adjacent mouse rod/cone pairs reveal dynamic changes, ranging over 1000 pS [4,9]. To simulate circadian modulation of rod/cone coupling, we define three states for the GJ channels conductance: uncoupled (0 pS), resting/dark-adapted (300 pS), and maximally coupled (1,200 pS), in line with experimental data [4,9]. Simulations are conducted using Brian 2 [10].
Results
To evaluate the impact of circadian adaptation on retinal signal processing and RGC light responses, we compare normalized intensity-response profiles of the tOFF aRGC across rod/cone coupling states. Stimulus intensity spans the activation threshold of the primary (0.01 R*/rod/s) to the tertiary (60 R*/rod/s) rod pathways [3]. We find that, relative to the SRP resting dark-adapted range (1-60 R*/rod/s) [3], inhibiting rod/cone coupling lowers the sensitivity threshold by ~0.5 log unit, while increasing coupling shifts the tOFF aRGC activation threshold ~1 log unit to the right.
Discussion
Our results support a circadian shift in the threshold and relative contribution of the SRP to the retinal output. This computational approach circumvents experimental limitations, allowing precise investigation of rod/cone coupling modulation. By clarifying mechanistic links between circadian modulation and retinal sensitivity, we demonstrate that our model can be used as a theoretical framework to reconcile previous experimental inconsistencies [5].
Acknowledgements
Research in the Ribelayga lab is supported by National Institutes of Health Grants EY032508, EY029408, and MH127343, National Institutes of Health Vision Core Grant P30EY007551, and The Foundation for Education and Research in Vision (FERV).
References
● https://doi.org/http://dx.doi.org/10.1016/S1350-9462(00)00031-8
● https://doi.org/https://doi.org/10.1146/annurev.physiol.67.031103.151256
● https://doi.org/https://doi.org/10.1126/sciadv.aba7232
● https://doi.org/https://doi.org/10.1126/sciadv.abm4491
● https://doi.org/10.1016/j.preteyeres.2022.101119
● https://doi.org/https://doi.org/10.1109/NER52421.2023.10123863
● https://doi.org/https://doi.org/10.1371/journal.pone.0180091
● https://doi.org/10.1113/jphysiol.2014.284919
● https://doi.org/https://doi.org/10.7554/eLife.73039
● https://doi.org/https://doi.org/10.7554/eLife.47314
