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

Abstract

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.T he neocortical sheet is a layered structure with a thickness that varies by a factor of two to three, whereas its surface area varies by 50,000 between the small smoky shrew and the massive blue whale. A unique hallmark of mammals, neocortex is a highly versatile, scalable, ∼2D computational tissue that excels at real time sensory processing across modalities and making and storing associations as well as planning and producing complex motor patterns. Neocortex consists of smaller modular units (columnar circuits that reach across the depth of cortex) broadly repeated iteratively across the cortical sheet. These modules vary considerably in their connectivity and properties between regions, with some controversy whether there is, indeed, a single canonical function performed by any and all neocortical columns.A deep understanding of cortex necessitates measuring relevant biophysical variables, such as recording action and membrane potentials, and relating them to genetically identified cell types. Mapping, observing, and intervening in widespread but highly specific cellular activity are more readily accomplished in the mouse, Mus musculus, than in the human brain. The brain of the laboratory mouse is more than three orders of magnitude smaller than the human brain in weight (0.4 vs. 1,350 g) and contains 71 million vs. 86 billion nerve cells for the entire brain and 14 million vs. 16 billion nerve cells for neocortex (1).The Allen Institute for Brain Science is engaged in a 10-y, highthroughput, milestone-driven effort to characterize all cortical cell types for the mouse cortex to build a small number of distinct experimental and computational platforms, called brain observatories, for studying behaving mice and to construct abstract and biophysically realisti...

A better way to crack the brain

“…Of all the current big-neuroscience initiatives, perhaps the most effective has been that of the Allen Institute for Brain Science, a private non-profit organization in Seattle, Washington. More than 100 scientists working together at the institute have produced useful resources, including brain-wide maps of gene expression in mouse and human and, most recently, maps of neural activity in the mouse visual cortex 3 . But it is not clear how the Allen Institute's model -industrial processes in a centralized corporate organizational structure -could be applied to geographically distributed collaborations targeting more complex problems.…”

Open Source Brain: a collaborative resource for visualizing, analyzing, simulating and developing standardized models of neurons and circuits

“…For example, reconstructed neuronal morphologies from NeuroMorpho.Org and the Janelia MouseLight project ( http://mouselight.janelia.org ) can be automatically converted to NeuroML and visualized through OSB, and these morphologies can become the basis for new models when combined with the complement of membrane conductances for that cell type already in NeuroML. The Allen Institute Cell Types Database 19 provides electrophysiological recordings and morphological reconstructions from cells in mouse visual cortex. Biophysically detailed cell models and point neuron models based on these data are present on OSB, as are cell models from the Blue Brain Project's reconstruction of the microcircuitry of rat somatosensory cortex 8 , and a reduced version of a cortical column used in the Human Brain Project 20 (HBP).…”

“…Model implementation Link Allen Institute Cell Types DB (Hawrylycz et al, 2016) Morphologically detailed and point neuron models based on electrophysiological recordings from visual cortex neurons Multicompartmental and Generalized Linear Integrate and Fire (GLIF) neuron models URL Brunel (2000) Spiking network illustrating balance between excitation and inhibition …”

“…Data-driven models have played a central role in elucidating the mechanisms underlying synaptic transmission 4 , the action potential 5 and dendritic integration 6 , and have been used more recently to investigate circuit function [7][8][9][10][11][12] . Such approaches are likely to become increasingly powerful as the amount of information available on the structure and dynamics of specific circuits increases, as a result of advances in connectomics 13,14 , functional activity mapping 15 and multi-cell and robotic patch clamping 16,17 , together with datasets from large-scale brain initiatives [18][19][20] . Developing more accurate, data-driven computer simulations of neurons and circuits [7][8][9]21 is increasingly important for integrating such multi-scale datasets into physico-chemically consistent models, and for helping to identify the key mechanisms involved in information processing and storage in health and disease.…”

“…These include single cell models from the Allen Institute Cell Types Database 19 and the Blue Brain Project 8 , which have been converted to NeuroML, to enable visualization and simulation on OSB. A number of invertebrate and abstract network models have also been converted to standardized formats 5,[46][47][48] .…”