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A theoretical framework for optogenetic perturbations in the oculomotor integrator Nuno Calaim*, David Barrett*, Pedro J. Goncalves*, Sophie Deneve, Christian K. Machens Computational and Systems Neuroscience (CoSyNe), 2015 How do neural networks respond to instantaneous perturbations of their activity? This question has been the subject of intense investigation ever since the advent of optogenetic perturbation techniques, which allow us to instantaneously perturb neural activity and record the response. We do not yet have a theoretical framework to adequately describe the neural response to such optogenetic perturbations, nor do we understand how neural networks can perform computations amid a background of on-going natural perturbations. In this work, we develop a framework to describe the impact of optogenetic perturbations on the oculomotor integrator (OI). The OI is a neural structure in the hindbrain which is responsible for controlling eye position by integrating eye movement signals to produce eye position signals. We build a spiking network model of the OI from first principles, following the approach of Boerlin et al. 2013. Specifically, we postulate that the connectivity and dynamics of neurons in OI are optimized to represent eye movement signals using a linear decoder (analogous to a dendritic summation). The resulting spiking network replicates key properties of the OI, such as the typical distribution of tuning curves and accurate eye position representation (Aksay et al. 2000, 2004). We can now do simulated optogenetics in our model: we artificially perturb membrane voltages and record the impact of these perturbations. We find that changes in eye position in our model are consistent with recent optogenetic experiments in which the OI was perturbed with Halorhodopsin and Channelrhodopsin (Goncalves et al. 2014). This indicates that the OI acts to instantaneously adjust the activities of the unperturbed neurons in order to compensate for any error in the computation performed by the OI. More generally, these results suggest that our framework may provide a useful and timely tool for characterizing the impact of optogenetic manipulations. (* authors contributed equally)