Biology subjects

Mihalas, S.

Publications and source records attributed to Mihalas, S..

10 recordsLinked to original sources

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

bioRxiv2018

A large-scale, standardized physiological survey reveals higher order coding throughout the mouse visual cortex

To understand how the brain processes sensory information to guide behavior, we must know how stimulus representations are transformed throughout the visual cortex. Here we report an open, large-scale physiological survey of neural activity in the awake mouse visual cortex: the Allen Brain Observatory Visual Coding dataset. This publicly available dataset includes cortical activity from nearly 60,000 neurons collected from 6 visual areas, 4 layers, and 12 transgenic mouse lines from 221 adult mice, in response to a systematic set of visual stimuli. Using this dataset, we reveal functional differences across these dimensions and show that visual cortical responses are sparse but correlated. Surprisingly, responses to different stimuli are largely independent, e.g. whether a neuron responds to natural scenes provides no information about whether it responds to natural movies or to gratings. We show that these phenomena cannot be explained by standard local filter-based models, but are consistent with multi-layer hierarchical computation, as found in deeper layers of standard convolutional neural networks.

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bioRxiv2018

Synchronization dependent on spatial structures of a mesoscopic whole-brain network

We study how the spatial structure of connectivity shapes synchronization in a system of coupled phase oscillators on a mammalian whole-brain network at the mesoscopic level. Complex structural connectivity of the mammalian brain is believed to underlie the versatility of neural computations. The Allen Mouse Brain Connectivity Atlas constructed from viral tracing experiments together with a new mapping algorithm reveals that the connectivity has a significant spatial dependence: the connection strength decreases with distance between the regions, following a power law. However, there are a number of residuals above the power-law fit, predominantly for long-range connections. We show how these strong connections between distal brain regions promote rapid transitions between highly localized synchronization and more global synchronization as the amount of dispersion in the frequency distribution changes. This may explain the brains ability to switch rapidly between global and modularized computations.

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bioRxiv2018

Sparse recurrent excitatory connectivity in the cortical microcircuit of the adult mouse and human

Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, the Allen Institute is engaged in a pipeline project using multipatch electrophysiology, supplemented with 2-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell types and layers we sampled, with the most sparse connections in layers 5 and 6. Almost all mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons; however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits.

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bioRxiv2018

The organization of intracortical connections by layer and cell class in the mouse brain

The mammalian cortex is a laminar structure composed of many cell types densely interconnected in complex ways. Recent systematic efforts to map the mouse mesoscale connectome provide comprehensive projection data on interareal connections, but not at the level of specific cell classes or layers within cortical areas. We present here a significant expansion of the Allen Mouse Brain Connectivity Atlas, with [~]1,000 new axonal projection mapping experiments across nearly all isocortical areas in 49 Cre driver lines. Using 13 lines selective for cortical layer-specific projection neuron classes, we identify the differential contribution of each layer/class to the overall intracortical connectivity patterns. We find layer 5 (L5) projection neurons account for essentially all intracortical outputs. L2/3, L4, and L6 neurons contact a subset of the L5 cortical targets. We also describe the most common axon lamination patterns in cortical targets. Most patterns are consistent with previous anatomical rules used to determine hierarchical position between cortical areas (feedforward, feedback), with notable exceptions. While diverse target lamination patterns arise from every source layer/class, L2/3 and L4 neurons are primarily associated with feedforward type projection patterns and L6 with feedback. L5 has both feedforward and feedback projection patterns. Finally, network analyses revealed a modular organization of the intracortical connectome. By labeling interareal and intermodule connections as feedforward or feedback, we present an integrated view of the intracortical connectome as a hierarchical network.

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bioRxiv2018

High resolution data-driven model of the mouse connectome

Knowledge of mesoscopic brain connectivity is important for understanding inter- and intra-region information processing. Models of structural connectivity are typically constructed and analyzed with the assumption that regions are homogeneous. We instead use the Allen Mouse Brain Connectivity Atlas to construct a model of whole brain connectivity at the scale of 100 {micro}m voxels. The dataset used consists of 366 anterograde tracing experiments in wild type C7BL/6 mice, mapping fluorescently-labeled neuronal projections brain-wide. Inferring spatial connectivity with this dataset remains underdetermined, since the approximately 2 x 105 source voxels outnumber the number of experiments. To address this, we assume that connection patterns and strengths vary smoothly across major brain divisions. We model the connectivity at each voxel as a radial basis kernel-weighted average of the projection patterns of nearby injections. The voxel model outperforms a previous regional model in predicting held-out experiments and compared to a human-curated dataset. This voxel-scale model of the mouse connectome permits researchers to extend their previous analyses of structural connectivity to unprecedented levels of resolution, and allows for comparison with functional imaging and other datasets.

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bioRxiv2018

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.\n\nAUTHOR SUMMARYHow can we capture the incredible complexity of brain circuits in quantitative models, and what can such models teach us about mechanisms underlying brain activity? To answer these questions, we set out to build extensive, bio-realistic models of brain circuitry employing systematic datasets on brain structure and function. Here we report the first modeling results of this project, focusing on the layer 4 of the primary visual cortex (V1) of the mouse. Our simulations reproduced a variety of experimental observations in a large battery of visual stimuli. The results elucidated circuit mechanisms determining patters of neuronal activity in layer 4 - in particular, the roles of feedforward thalamic inputs and specific patterns of intracortical connectivity in producing tuning of neuronal responses to the orientation of motion. Simplification of neuronal models led to specific deficiencies in reproducing experimental data, giving insights into how biological details contribute to various aspects of brain activity. To enable future development of more sophisticated models, we make the software code, the model, and simulation results publicly available.

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bioRxiv2017

Cortical circuits implement optimal context integration

Neurons in the primary visual cortex (V1) predominantly respond to a patch of the visual input, their classical receptive field. These responses are modulated by the visual input in the surround [2]. This reflects the fact that features in natural scenes do not occur in isolation: lines, surfaces are generally continuous, and the surround provides context for the information in the classical receptive field. It is generally assumed that the information in the near surround is transmitted via lateral connections between neurons in the same area [2]. A series of large scale efforts have recently described the relation between lateral connectivity and visual evoked responses and found like-to-like connectivity between excitatory neurons [16, 18]. Additionally, specific cell type connectivity for inhibitory neuron types has been described [11, 31]. Current normative models of cortical function relying on sparsity [27], saliency [4] predict functional inhibition between similarly tuned neurons. What computations are consistent with the observed structure of the lateral connections between the excitatory and diverse types of inhibitory neurons?\n\nWe combined natural scene statistics [24] and mouse V1 neuron responses [7] to compute the lateral connections and computations of individual neurons which optimally integrate information from the classical receptive field with that from the surround by directly implementing Bayes rule. This increases the accuracy of representation of a natural scene under noisy conditions. We show that this network has like-to-like connectivity between excitatory neurons, similar to the observed one [16, 18, 11], and has three types of inhibition: local normalization, surround inhibition and gating of inhibition from the surround - that can be attributed to three classes of inhibitory neurons. We hypothesize that this computation: optimal integration of contextual cues with a gate to ignore context when necessary is a general property of cortical circuits, and the rules constructed for mouse V1 generalize to other areas and species.

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bioRxiv2017

Generalized Leaky Integrate-And-Fire Models Classify Multiple Neuron Types

In the mammalian neocortex, there is a high diversity of neuronal types. 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 series of generalized integrate-and-fire (GLIF) models of increasing complexity aiming to reproduce the spiking behaviors of the recorded neurons. We test the performance of these GLIF models on data from 771 neurons from 14 transgenic lines, with increasing model performance for more complex models. To answer how complex a model needs to be to reproduce the number of electrophysiological cell types, we perform unsupervised clustering on the parameters extracted from these models. The number of clusters is smaller for individual model types, but when combining all GLIF parameters 18 clusters are obtained, while 11 clusters are obtained using 16 electrophysiological features. Therefore, these low dimensional models have the capacity to characterize the diversity of cell types without the need for a priori defined features.

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bioRxiv2016

Visual processing mode switching regulated by VIP cells

The responses of neurons in mouse primary visual cortex (V1) to visual stimuli depend on behavioral states. Specifically, surround suppression is reduced during locomotion. Although locomotion-induced vasoactive intestinal polypeptide positive (VIP) interneuron depolarization can account for the reduction of surround suppression, the functions of VIP cell depolarization are not fully understood. Here we utilize a firing rate model and a computational model to elucidate the potential functions of VIP cell depolarization during locomotion. Our analyses suggest 1) that surround suppression sharpens the visual responses in V1 to a stationary scene, 2) that depolarized VIP cells enhance V1 responses to moving objects by reducing self-induced surround suppression and 3) that during locomotion V1 neuron responses to some features of the moving objects can be selectively enhanced. Thus, VIP cells regulate surround suppression to allow pyramidal neurons to optimally encode visual information independent of behavioral state.

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