On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Survey of spiking in the mouse visual system reveals functional hierarchy.

The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically1. However, direct observation of cellular-level functional interactions across this hierarchy is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory2-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area functional connectivity during visual stimulation mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas3. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.

Contextual Integration in Cortical and Convolutional Neural Networks.

It has been suggested that neurons can represent sensory input using probability distributions and neural circuits can perform probabilistic inference. Lateral connections between neurons have been shown to have non-random connectivity and modulate responses to stimuli within the classical receptive field. Large-scale efforts mapping local cortical connectivity describe cell type specific connections from inhibitory neurons and like-to-like connectivity between excitatory neurons. To relate the observed connectivity to computations, we propose a neuronal network model that approximates Bayesian inference of the probability of different features being present at different image locations. We show that the lateral connections between excitatory neurons in a circuit implementing contextual integration in this should depend on correlations between unit activities, minus a global inhibitory drive. The model naturally suggests the need for two types of inhibitory gates (normalization, surround inhibition). First, using natural scene statistics and classical receptive fields corresponding to simple cells parameterized with data from mouse primary visual cortex, we show that the predicted connectivity qualitatively matches with that measured in mouse cortex: neurons with similar orientation tuning have stronger connectivity, and both excitatory and inhibitory connectivity have a modest spatial extent, comparable to that observed in mouse visual cortex. We incorporate lateral connections learned using this model into convolutional neural networks. Features are defined by supervised learning on the task, and the lateral connections provide an unsupervised learning of feature context in multiple layers. Since the lateral connections provide contextual information when the feedforward input is locally corrupted, we show that incorporating such lateral connections into convolutional neural networks makes them more robust to noise and leads to better performance on noisy versions of the MNIST dataset. Decomposing the predicted lateral connectivity matrices into low-rank and sparse components introduces additional cell types into these networks. We explore effects of cell-type specific perturbations on network computation. Our framework can potentially be applied to networks trained on other tasks, with the learned lateral connections aiding computations implemented by feedforward connections when the input is unreliable and demonstrate the potential usefulness of combining supervised and unsupervised learning techniques in real-world vision tasks.

Systematic Integration of Structural and Functional Data into Multi-scale Models of Mouse Primary Visual Cortex.

Structural rules underlying functional properties of cortical circuits are poorly understood. To explore these rules systematically, we integrated information from extensive literature curation and large-scale experimental surveys into a data-driven, biologically realistic simulation of the awake mouse primary visual cortex. The model was constructed at two levels of granularity, using either biophysically detailed or point neurons. Both variants have identical network connectivity and were compared to each other and to experimental recordings of visual-driven neural activity. While tuning these networks to recapitulate experimental data, we identified rules governing cell-class-specific connectivity and synaptic strengths. These structural constraints constitute hypotheses that can be tested experimentally. Despite their distinct single-cell abstraction, both spatially extended and point models perform similarly at the level of firing rate distributions for the questions we investigated. All data and models are freely available as a resource for the community.

Visual physiology of the layer 4 cortical circuit in silico.

Despite advances in experimental techniques and accumulation of large datasets concerning the composition and properties of the cortex, quantitative modeling of cortical circuits under in-vivo-like conditions remains challenging. Here we report and publicly release a biophysically detailed circuit model of layer 4 in the mouse primary visual cortex, receiving thalamo-cortical visual inputs. The 45,000-neuron model was subjected to a battery of visual stimuli, and results were compared to published work and new in vivo experiments. Simulations reproduced a variety of observations, including effects of optogenetic perturbations. Critical to the agreement between responses in silico and in vivo were the rules of functional synaptic connectivity between neurons. Interestingly, after extreme simplification the model still performed satisfactorily on many measurements, although quantitative agreement with experiments suffered. These results emphasize the importance of functional rules of cortical wiring and enable a next generation of data-driven models of in vivo neural activity and computations.

Generalized leaky integrate-and-fire models classify multiple neuron types.

There is a high diversity of neuronal types in the mammalian neocortex. To facilitate construction of system models with multiple cell types, we generate a database of point models associated with the Allen Cell Types Database. We construct a set of generalized leaky integrate-and-fire (GLIF) models of increasing complexity to reproduce the spiking behaviors of 645 recorded neurons from 16 transgenic lines. The more complex models have an increased capacity to predict spiking behavior of hold-out stimuli. We use unsupervised methods to classify cell types, and find that high level GLIF model parameters are able to differentiate transgenic lines comparable to electrophysiological features. The more complex model parameters also have an increased ability to differentiate between transgenic lines. Thus, creating simple models is an effective dimensionality reduction technique that enables the differentiation of cell types from electrophysiological responses without the need for a priori-defined features. This database will provide a set of simplified models of multiple cell types for the community to use in network models.

Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma.

Currently, molecular markers are not used when determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). In the present study, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT) and adjacent non-malignant tissues (AT) typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods. We developed a 24-ribosomal gene-based HCC classifier (RGC), which is prognostically significant in both PT and AT. The RGC gene overexpression in PT was associated with a poor prognosis in the training (hazard ratio = 8.2, P = 9.4 × 10-6 ) and cross-cohort validation (hazard ratio = 2.63, P = 0.004) datasets. The multivariate survival analysis demonstrated the significant and independent prognostic value of the RGC. The RGC displayed a significant prognostic value in AT of the training (hazard ratio = 5.0, P = 0.03) and cross-validation (hazard ratio = 1.9, P = 0.03) HCC groups, confirming the accuracy and robustness of the RGC. Our experimental and bioinformatics analyses suggested a key role for c-MYC in the pro-oncogenic pattern of ribosomal biogenesis co-regulation in PT and AT. Microarray, quantitative RT-PCR and quantitative immunohistochemical studies of the PT showed that DKK1 in PT is the perspective biomarker for poor HCC outcomes. The common co-transcriptional pattern of ribosome biogenesis genes in PT and AT from HCC patients suggests a new scalable prognostic system, as supported by the model of tumor-like metabolic redirection/assimilation in non-malignant AT. The RGC, comprising 24 ribosomal genes, is introduced as a robust and reproducible prognostic model for stratifying HCC patient risks. The adjacent non-malignant liver tissue alone, or in combination with HCC tissue biopsy, could be an important target for developing predictive and monitoring strategies, as well as evidence-based therapeutic interventions, that aim to reduce the risk of post-surgery relapse in HCC patients.

A Comparison of Visual Response Properties in the Lateral Geniculate Nucleus and Primary Visual Cortex of Awake and Anesthetized Mice.

The cerebral cortex of the mouse has become one of the most important systems for studying information processing and the neural correlates of behavior. Multiple studies have examined the first stages of visual cortical processing: primary visual cortex (V1) and its thalamic inputs from the dorsal lateral geniculate nucleus (dLGN), but more rarely in the lateral posterior nucleus (LP) in mice. Multiple single-unit surveys of dLGN and V1, both with electrophysiology and two-photon calcium imaging, have described receptive fields in anesthetized animals. Increasingly, awake animals are being used in physiological studies, so it is important to compare neuronal responses between awake and anesthetized state. We have performed a comprehensive survey of spatial and temporal response properties in V1, dLGN, and lateral posterior nucleus of both anesthetized and awake animals, using a common set of stimuli: drifting sine-wave gratings spanning a broad range of spatial and temporal parameters, and sparse noise stimuli consisting of flashed light and dark squares. Most qualitative receptive field parameters were found to be unchanged between the two states, such as most aspects of spatial processing, but there were significant differences in several parameters, most notably in temporal processing. Compared with anesthetized animals, the temporal frequency that evoked the peak response was shifted toward higher values in the dLGN of awake mice and responses were more sustained. Further, the peak response to a flashed stimulus was earlier in all three areas. Overall, however, receptive field properties in the anesthetized animal remain a good model for those in the awake animal. SIGNIFICANCE STATEMENT: The primary visual cortex (V1) of the mouse and its inputs from visual thalamus (dLGN), have become a dominant model for studying information processing in the brain. Early surveys of visual response properties (receptive fields) were performed in anesthetized animals. Although most recent studies of V1 have been performed in awake animals to examine links between vision and behavior, there have been few comprehensive studies of receptive field properties in the awake mouse, especially in dLGN and lateral posterior nucleus. We have performed a comparative survey of receptive fields in dLGN, lateral posterior nucleus, and V1 in anesthetized and awake mice. We found multiple differences in processing of time-varying stimuli, whereas the spatial aspects of receptive fields remain comparatively unchanged.

The Computational Properties of a Simplified Cortical Column Model.

The mammalian neocortex has a repetitious, laminar structure and performs functions integral to higher cognitive processes, including sensory perception, memory, and coordinated motor output. What computations does this circuitry subserve that link these unique structural elements to their function? Potjans and Diesmann (2014) parameterized a four-layer, two cell type (i.e. excitatory and inhibitory) model of a cortical column with homogeneous populations and cell type dependent connection probabilities. We implement a version of their model using a displacement integro-partial differential equation (DiPDE) population density model. This approach, exact in the limit of large homogeneous populations, provides a fast numerical method to solve equations describing the full probability density distribution of neuronal membrane potentials. It lends itself to quickly analyzing the mean response properties of population-scale firing rate dynamics. We use this strategy to examine the input-output relationship of the Potjans and Diesmann cortical column model to understand its computational properties. When inputs are constrained to jointly and equally target excitatory and inhibitory neurons, we find a large linear regime where the effect of a multi-layer input signal can be reduced to a linear combination of component signals. One of these, a simple subtractive operation, can act as an error signal passed between hierarchical processing stages.

Inferring cortical function in the mouse visual system through large-scale systems neuroscience.

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

The influence of synaptic weight distribution on neuronal population dynamics.

The manner in which different distributions of synaptic weights onto cortical neurons shape their spiking activity remains open. To characterize a homogeneous neuronal population, we use the master equation for generalized leaky integrate-and-fire neurons with shot-noise synapses. We develop fast semi-analytic numerical methods to solve this equation for either current or conductance synapses, with and without synaptic depression. We show that its solutions match simulations of equivalent neuronal networks better than those of the Fokker-Planck equation and we compute bounds on the network response to non-instantaneous synapses. We apply these methods to study different synaptic weight distributions in feed-forward networks. We characterize the synaptic amplitude distributions using a set of measures, called tail weight numbers, designed to quantify the preponderance of very strong synapses. Even if synaptic amplitude distributions are equated for both the total current and average synaptic weight, distributions with sparse but strong synapses produce higher responses for small inputs, leading to a larger operating range. Furthermore, despite their small number, such synapses enable the network to respond faster and with more stability in the face of external fluctuations.