Visual processing starts in the outer retina where photoreceptors transform light into electrochemical signals. These signals are modulated by inhibition from horizontal cells and sent to the inner retina via excitatory bipolar cells. The outer retina is thought to play an important role in contrast invariant coding of visual information, but how the different cell types implement this computation together remains incompletely understood. To understand the role of each cell type, we developed a fully-differentiable biophysical model of a circular patch of mouse outer retina. The model includes 200 cone photoreceptors with a realistic phototransduction cascade and ribbon synapses as well as horizontal and bipolar cells, all with cell-type specific ion channels. Going beyond decades of work constraining biophysical models of neurons only by experimental data, we used a dual approach, constraining some parameters of the model with available measurements and others by a visual task: (1) We fit the parameters of the cone models to whole cell patch-clamp measurements of photocurrents and two-photon glutamate imaging measurements of synaptic release. (2) We then trained the spatiotemporal outer retina model with photoreceptors and the other cell types to perform a visual classification task with varying contrast and luminance levels. We found that our outer retina model could learn to solve the classification task despite contrast and luminance variance in the stimuli. Testing different cell type compositions and connectivity patterns, we found that feedback from horizontal cells did not further improve task performance beyond that of excitatory photoreceptors and bipolar cells. This is surprising given that horizontal cells are positioned to mediate communication across cones and that they add to the model's number of trainable parameters. Finally, we found that our model generalized better to out of distribution contrast levels than a linear classifier. Our work shows how the nonlinearities found in the outer retina can accomplish contrast invariant classification and teases apart the contributions of different cell types.

Identifying cell types and understanding their functional properties is crucial for unraveling the mechanisms underlying perception and cognition. In the retina, functional types can be identified by carefully selected stimuli, but this requires expert domain knowledge and biases the procedure towards previously known cell types. In the visual cortex, it is still unknown what functional types exist and how to identify them. Thus, for unbiased identification of the functional cell types in retina and visual cortex, new approaches are needed. Here we propose an optimization-based clustering approach using deep predictive models to obtain functional clusters of neurons using Most Discriminative Stimuli (MDS). Our approach alternates between stimulus optimization with cluster reassignment akin to an expectation-maximization algorithm. The algorithm recovers functional clusters in mouse retina, marmoset retina and macaque visual area V4. This demonstrates that our approach can successfully find discriminative stimuli across species, stages of the visual system and recording techniques. The resulting most discriminative stimuli can be used to assign functional cell types fast and on the fly, without the need to train complex predictive models or show a large natural scene dataset, paving the way for experiments that were previously limited by experimental time. Crucially, MDS are interpretable: they visualize the distinctive stimulus patterns that most unambiguously identify a specific type of neuron.

Neural population responses in sensory systems are driven by external physical stimuli. This stimulus-response relationship is typically characterized by receptive fields, which have been estimated by neural system identification approaches. Such models usually require a large amount of training data, yet, the recording time for animal experiments is limited, giving rise to epistemic uncertainty for the learned neural transfer functions. While deep neural network models have demonstrated excellent power on neural prediction, they usually do not provide the uncertainty of the resulting neural representations and derived statistics, such as most exciting inputs (MEIs), from in silico experiments. Here, we present a Bayesian system identification approach to predict neural responses to visual stimuli, and explore whether explicitly modeling network weight variability can be beneficial for identifying neural response properties. To this end, we use variational inference to estimate the posterior distribution of each model weight given the training data. Tests with different neural datasets demonstrate that this method can achieve higher or comparable performance on neural prediction, with a much higher data efficiency compared to Monte Carlo dropout methods and traditional models using point estimates of the model parameters. At the same time, our variational method provides us with an effectively infinite ensemble, avoiding the idiosyncrasy of any single model, to generate MEIs. This allows us to estimate the uncertainty of stimulus-response function, which we have found to be negatively correlated with the predictive performance at model level and may serve to evaluate models. Furthermore, our approach enables us to identify response properties with credible intervals and to determine whether the inferred features are meaningful by performing statistical tests on MEIs. Finally, in silico experiments show that our model generates stimuli driving neuronal activity significantly better than traditional models in the limited-data regime.

Neural system identification aims at learning the response function of neurons to arbitrary stimuli using experimentally recorded data, but typically does not leverage normative principles such as efficient coding of natural environments. Visual systems, however, have evolved to efficiently process input from the natural environment. Here, we present a normative network regularization for system identification models by incorporating, as a regularizer, the efficient coding hypothesis, which states that neural response properties of sensory representations are strongly shaped by the need to preserve most of the stimulus information with limited resources. Using this approach, we explored if a system identification model can be improved by sharing its convolutional filters with those of an autoencoder which aims to efficiently encode natural stimuli. To this end, we built a hybrid model to predict the responses of retinal neurons to noise stimuli. This approach did not only yield a higher performance than the "stand-alone" system identification model, it also produced more biologically plausible filters, meaning that they more closely resembled neural representation in early visual systems. We found these results applied to retinal responses to different artificial stimuli and across model architectures. Moreover, our normatively regularized model performed particularly well in predicting responses of direction-of-motion sensitive retinal neurons. The benefit of natural scene statistics became marginal, however, for predicting the responses to natural movies. In summary, our results indicate that efficiently encoding environmental inputs can improve system identification models, at least for noise stimuli, and point to the benefit of probing the visual system with naturalistic stimuli.

Integrating data from multiple experiments is common practice in systems neuroscience but it requires inter-experimental variability to be negligible compared to the biological signal of interest. This requirement is rarely fulfilled; systematic changes between experiments can drastically affect the outcome of complex analysis pipelines. Modern machine learning approaches designed to adapt models across multiple data domains offer flexible ways of removing inter-experimental variability where classical statistical methods often fail. While applications of these methods have been mostly limited to single-cell genomics, in this work, we develop a theoretical framework for domain adaptation in systems neuroscience. We implement this in an adversarial optimization scheme that removes inter-experimental variability while preserving the biological signal. We compare our method to previous approaches on a large-scale dataset of two-photon imaging recordings of retinal bipolar cell responses to visual stimuli. This dataset provides a unique benchmark as it contains biological signal from well-defined cell types that is obscured by large inter-experimental variability. In a supervised setting, we compare the generalization performance of cell type classifiers across experiments, which we validate with anatomical cell type distributions from electron microscopy data. In an unsupervised setting, we remove inter-experimental variability from the data which can then be fed into arbitrary downstream analyses. In both settings, we find that our method achieves the best trade-off between removing inter-experimental variability and preserving biological signal. Thus, we offer a flexible approach to remove inter-experimental variability and integrate datasets across experiments in systems neuroscience. Code available at https://github.com/eulerlab/rave.

Visual processing in the retina has been studied in great detail at all levels such that a comprehensive picture of the retina's cell types and the many neural circuits they form is emerging. However, the currently best performing models of retinal function are black-box CNN models which are agnostic to such biological knowledge. In particular, these models typically neglect the role of the many inhibitory circuits involving amacrine cells and the biophysical mechanisms underlying synaptic release. Here, we present a computational model of temporal processing in the inner retina, including inhibitory feedback circuits and realistic synaptic release mechanisms. Fit to the responses of bipolar cells, the model generalized well to new stimuli including natural movie sequences, performing on par with or better than a benchmark black-box model. In pharmacology experiments, the model replicated in silico the effect of blocking specific amacrine cell populations with high fidelity, indicating that it had learned key circuit functions. Also, more in depth comparisons showed that connectivity patterns learned by the model were well matched to connectivity patterns extracted from connectomics data. Thus, our model provides a biologically interpretable data-driven account of temporal processing in the inner retina, filling the gap between purely black-box and detailed biophysical modeling.

Variability, stochastic or otherwise, is a central feature of neural activity. Yet the means by which estimates of variation and uncertainty are derived from noisy observations of neural activity is often heuristic, with more weight given to numerical convenience than statistical rigour. For two-photon imaging data, composed of fundamentally probabilistic streams of photon detections, the problem is particularly acute. Here, we present a statistical pipeline for the inference and analysis of neural activity using Gaussian Process regression, applied to two-photon recordings of light-driven activity in ex vivo mouse retina. We demonstrate the flexibility and extensibility of these models, considering cases with non-stationary statistics, driven by complex parametric stimuli, in signal discrimination, hierarchical clustering and other inference tasks. Sparse approximation methods allow these models to be fitted rapidly, permitting them to actively guide the design of light stimulation in the midst of ongoing two-photon experiments.

[This corrects the article DOI: 10.1371/journal.pcbi.1007205.].

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.

Neuroscientists classify neurons into different types that perform similar computations at different locations in the visual field. Traditional methods for neural system identification do not capitalize on this separation of “what” and “where”. Learning deep convolutional feature spaces that are shared among many neurons provides an exciting path forward, but the architectural design needs to account for data limitations: While new experimental techniques enable recordings from thousands of neurons, experimental time is limited so that one can sample only a small fraction of each neuron's response space. Here, we show that a major bottleneck for fitting convolutional neural networks (CNNs) to neural data is the estimation of the individual receptive field locations – a problem that has been scratched only at the surface thus far. We propose a CNN architecture with a sparse readout layer factorizing the spatial (where) and feature (what) dimensions. Our network scales well to thousands of neurons and short recordings and can be trained end-to-end. We evaluate this architecture on ground-truth data to explore the challenges and limitations of CNN-based system identification. Moreover, we show that our network model outperforms current state-of-the art system identification models of mouse primary visual cortex.