An update to Hippocampome.org by integrating single-cell phenotypes with circuit function in vivo.

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org. We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.

A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology.

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal is to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters from Hippocampome.org. The software (version 1.0) is released as open source to enable broad community reuse and encourage novel applications.

Comprehensive Estimates of Potential Synaptic Connections in Local Circuits of the Rodent Hippocampal Formation by Axonal-Dendritic Overlap.

A quantitative description of the hippocampal formation synaptic architecture is essential for understanding the neural mechanisms of episodic memory. Yet the existing knowledge of connectivity statistics between different neuron types in the rodent hippocampus only captures a mere 5% of this circuitry. We present a systematic pipeline to produce first-approximation estimates for most of the missing information. Leveraging the www.Hippocampome.org knowledge base, we derive local connection parameters between distinct pairs of morphologically identified neuron types based on their axonal-dendritic overlap within every layer and subregion of the hippocampal formation. Specifically, we adapt modern image analysis technology to determine the parcel-specific neurite lengths of every neuron type from representative morphologic reconstructions obtained from either sex. We then compute the average number of synapses per neuron pair using relevant anatomic volumes from the mouse brain atlas and ultrastructurally established interaction distances. Hence, we estimate connection probabilities and number of contacts for >1900 neuron type pairs, increasing the available quantitative assessments more than 11-fold. Connectivity statistics thus remain unknown for only a minority of potential synapses in the hippocampal formation, including those involving long-range (23%) or perisomatic (6%) connections and neuron types without morphologic tracings (7%). The described approach also yields approximate measurements of synaptic distances from the soma along the dendritic and axonal paths, which may affect signal attenuation and delay. Overall, this dataset fills a substantial gap in quantitatively describing hippocampal circuits and provides useful model specifications for biologically realistic neural network simulations, until further direct experimental data become available.SIGNIFICANCE STATEMENT The hippocampal formation is a crucial functional substrate for episodic memory and spatial representation. Characterizing the complex neuron type circuit of this brain region is thus important to understand the cellular mechanisms of learning and navigation. Here we present the first numerical estimates of connection probabilities, numbers of contacts per connected pair, and synaptic distances from the soma along the axonal and dendritic paths, for more than 1900 distinct neuron type pairs throughout the dentate gyrus, CA3, CA2, CA1, subiculum, and entorhinal cortex. This comprehensive dataset, publicly released online at www.Hippocampome.org, constitutes an unprecedented quantification of the majority of the local synaptic circuit for a prominent mammalian neural system and provides an essential foundation for data-driven, anatomically realistic neural network models.

Spiking Neural Networks and Hippocampal Function: A Web-Accessible Survey of Simulations, Modeling Methods, and Underlying Theories.

Computational modeling has contributed to hippocampal research in a wide variety of ways and through a large diversity of approaches, reflecting the many advanced cognitive roles of this brain region. The intensively studied neuron type circuitry of the hippocampus is a particularly conducive substrate for spiking neural models. Here we present an online knowledge base of spiking neural network simulations of hippocampal functions. First, we overview theories involving the hippocampal formation in subjects such as spatial representation, learning, and memory. Then we describe an original literature mining process to organize published reports in various key aspects, including: (i) subject area (e.g., navigation, pattern completion, epilepsy); (ii) level of modeling detail (Hodgkin-Huxley, integrate-and-fire, etc.); and (iii) theoretical framework (attractor dynamics, oscillatory interference, self-organizing maps, and others). Moreover, every peer-reviewed publication is also annotated to indicate the specific neuron types represented in the network simulation, establishing a direct link with the Hippocampome.org portal. The web interface of the knowledge base enables dynamic content browsing and advanced searches, and consistently presents evidence supporting every annotation. Moreover, users are given access to several types of statistical reports about the collection, a selection of which is summarized in this paper. This open access resource thus provides an interactive platform to survey spiking neural network models of hippocampal functions, compare available computational methods, and foster ideas for suitable new directions of research.

Spatial periodicity in grid cell firing is explained by a neural sequence code of 2-D trajectories.

Spatial periodicity in grid cell firing has been interpreted as a neural metric for space providing animals with a coordinate system in navigating physical and mental spaces. However, the specific computational problem being solved by grid cells has remained elusive. Here, we provide mathematical proof that spatial periodicity in grid cell firing is the only possible solution to a neural sequence code of 2-D trajectories and that the hexagonal firing pattern of grid cells is the most parsimonious solution to such a sequence code. We thereby provide a teleological cause for the existence of grid cells and reveal the underlying nature of the global geometric organization in grid maps as a direct consequence of a simple local sequence code. A sequence code by grid cells provides intuitive explanations for many previously puzzling experimental observations and may transform our thinking about grid cells.

A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology.

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal was to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters from Hippocampome.org. The software is released as open source to enable broad community reuse and encourage novel applications.

Hippocampome.org v2.0: a knowledge base enabling data-driven spiking neural network simulations of rodent hippocampal circuits.

Hippocampome.org is a mature open-access knowledge base of the rodent hippocampal formation focusing on neuron types and their properties. Hippocampome.org v1.0 established a foundational classification system identifying 122 hippocampal neuron types based on their axonal and dendritic morphologies, main neurotransmitter, membrane biophysics, and molecular expression. Releases v1.1 through v1.12 furthered the aggregation of literature-mined data, including among others neuron counts, spiking patterns, synaptic physiology, in vivo firing phases, and connection probabilities. Those additional properties increased the online information content of this public resource over 100-fold, enabling numerous independent discoveries by the scientific community. Hippocampome.org v2.0, introduced here, besides incorporating over 50 new neuron types, now recenters its focus on extending the functionality to build real-scale, biologically detailed, data-driven computational simulations. In all cases, the freely downloadable model parameters are directly linked to the specific peer-reviewed empirical evidence from which they were derived. Possible research applications include quantitative, multiscale analyses of circuit connectivity and spiking neural network simulations of activity dynamics. These advances can help generate precise, experimentally testable hypotheses and shed light on the neural mechanisms underlying associative memory and spatial navigation.

Hippocampome.org 2.0 is a knowledge base enabling data-driven spiking neural network simulations of rodent hippocampal circuits.

Hippocampome.org is a mature open-access knowledge base of the rodent hippocampal formation focusing on neuron types and their properties. Previously, Hippocampome.org v1.0 established a foundational classification system identifying 122 hippocampal neuron types based on their axonal and dendritic morphologies, main neurotransmitter, membrane biophysics, and molecular expression (Wheeler et al., 2015). Releases v1.1 through v1.12 furthered the aggregation of literature-mined data, including among others neuron counts, spiking patterns, synaptic physiology, in vivo firing phases, and connection probabilities. Those additional properties increased the online information content of this public resource over 100-fold, enabling numerous independent discoveries by the scientific community. Hippocampome.org v2.0, introduced here, besides incorporating over 50 new neuron types, now recenters its focus on extending the functionality to build real-scale, biologically detailed, data-driven computational simulations. In all cases, the freely downloadable model parameters are directly linked to the specific peer-reviewed empirical evidence from which they were derived. Possible research applications include quantitative, multiscale analyses of circuit connectivity and spiking neural network simulations of activity dynamics. These advances can help generate precise, experimentally testable hypotheses and shed light on the neural mechanisms underlying associative memory and spatial navigation.