Robust Resting-State Dynamics in a Large-Scale Spiking Neural Network Model of Area CA3 in the Mouse Hippocampus.

Hippocampal area CA3 performs the critical auto-associative function underlying pattern completion in episodic memory. Without external inputs, the electrical activity of this neural circuit reflects the spontaneous spiking interplay among glutamatergic pyramidal neurons and GABAergic interneurons. However, the network mechanisms underlying these resting-state firing patterns are poorly understood. Leveraging the Hippocampome.org knowledge base, we developed a data-driven, large-scale spiking neural network (SNN) model of mouse CA3 with 8 neuron types, 90,000 neurons, 51 neuron-type specific connections, and 250,000,000 synapses. We instantiated the SNN in the CARLsim4 multi-GPU simulation environment using the Izhikevich and Tsodyks-Markram formalisms for neuronal and synaptic dynamics, respectively. We analyzed the resultant population activity upon transient activation. The SNN settled into stable oscillations with a biologically plausible grand-average firing frequency, which was robust relative to a wide range of transient activation. The diverse firing patterns of individual neuron types were consistent with existing knowledge of cell type-specific activity in vivo. Altered network structures that lacked neuron- or connection-type specificity were neither stable nor robust, highlighting the importance of neuron type circuitry. Additionally, external inputs reflecting dentate mossy fibers shifted the observed rhythms to the gamma band. We freely released the CARLsim4-Hippocampome framework on GitHub to test hippocampal hypotheses. Our SNN may be useful to investigate the circuit mechanisms underlying the computational functions of CA3. Moreover, our approach can be scaled to the whole hippocampal formation, which may contribute to elucidating how the unique neuronal architecture of this system subserves its crucial cognitive roles.

Quantification of neuron types in the rodent hippocampal formation by data mining and numerical optimization.

Quantifying the population sizes of distinct neuron types in different anatomical regions is an essential step towards establishing a brain cell census. Although estimates exist for the total neuronal populations in different species, the number and definition of each specific neuron type are still intensively investigated. Hippocampome.org is an open-source knowledge base with morphological, physiological and molecular information for 122 neuron types in the rodent hippocampal formation. While such framework identifies all known neuron types in this system, their relative abundances remain largely unknown. This work quantitatively estimates the counts of all Hippocampome.org neuron types by literature mining and numerical optimization. We report the number of neurons in each type identified by main neurotransmitter (glutamate or GABA) and axonal-dendritic patterns throughout 26 subregions and layers of the dentate gyrus, Ammon's horn, subiculum and entorhinal cortex. We produce by sensitivity analysis reliable numerical ranges for each type and summarize the amounts across broad neuronal families defined by biomarkers expression and firing dynamics. Study of density distributions indicates that the number of dendritic-targeting interneurons, but not of other neuronal classes, is independent of anatomical volumes. All extracted values, experimental evidence and related software code are released on Hippocampome.org.

Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture.

Operations Research Methods for Estimating the Population Size of Neuron Types.

Understanding brain computation requires assembling a complete catalog of its architectural components. Although the brain is organized into several anatomical and functional regions, it is ultimately the neurons in every region that are responsible for cognition and behavior. Thus, classifying neuron types throughout the brain and quantifying the population sizes of distinct classes in different regions is a key subject of research in the neuroscience community. The total number of neurons in the brain has been estimated for multiple species, but the definition and population size of each neuron type are still open questions even in common model organisms: the so called "cell census" problem. We propose a methodology that uses operations research principles to estimate the number of neurons in each type based on available information on their distinguishing properties. Thus, assuming a set of neuron type definitions, we provide a solution to the issue of assessing their relative proportions. Specifically, we present a three-step approach that includes literature search, equation generation, and numerical optimization. Solving computationally the set of equations generated by literature mining yields best estimates or most likely ranges for the number of neurons in each type. While this strategy can be applied towards any neural system, we illustrate its usage on the rodent hippocampus.

Cell numbers, distribution, shape, and regional variation throughout the murine hippocampal formation from the adult brain Allen Reference Atlas.

Quantifying the distribution of cells in every brain region is fundamental to attaining a comprehensive census of distinct neuronal and glial types. Until recently, estimating neuron numbers involved time-consuming procedures that were practically limited to stereological sampling. Progress in open-source image recognition software, growth in computing power, and unprecedented neuroinformatics developments now offer the potentially paradigm-shifting alternative of comprehensive cell-by-cell analysis in an entire brain region. The Allen Brain Atlas provides free digital access to complete series of raw Nissl-stained histological section images along with regional delineations. Automated cell segmentation of these data enables reliable and reproducible high-throughput quantification of regional variations in cell count, density, size, and shape at whole-system scale. While this strategy is directly applicable to any regions of the mouse brain, we first deploy it here on the closed-loop circuit of the hippocampal formation: the medial and lateral entorhinal cortices; dentate gyrus (DG); areas Cornu Ammonis 3 (CA3), CA2, and CA1; and dorsal and ventral subiculum. Using two independent image processing pipelines and the adult mouse reference atlas, we report the first cellular-level soma segmentation in every sub-region and non-principal layer of the left hippocampal formation through the full rostral-caudal extent. It is important to note that our techniques excluded the layers with the largest number of cells, DG granular and CA pyramidal, due to dense packing. The numerical estimates for the remaining layers are corroborated by traditional stereological sampling on a data subset and well match sparse published reports.