Generation and Description of Neuronal Morphology and Connectivity - Dendritic and axonal morphologies play fundamental roles in physiological brain function and pathological dysfunction by affecting synaptic integration, spiking dynamics, and circuit connectivity. Incorporating published experimental data into accurate, full-scale, biologically plausible neural network simulations is important for quantitatively linking the sub-cellular and systems-levels. With NeuroMorpho.Org, we successfully designed, implemented, and freely distributed databases and software to reconstruct, visualize, analyze, simulate, and share the 3D tree-like shape of neurons and glia collected from any labeling techniques, animal species, brain regions, developmental stages, and experimental conditions. We microscopically imaged, digitally traced, and shared new data, and we provided our peers with the electronic means of freely doing the same. Moreover, we combined those data with computational models of membrane biophysics and network connectivity to investigate the neuronal structure-activity relationship with a special focus on the hippocampus and entorhinal cortex due to their central role in spatial representation and episodic memory. We additionally annotated a massive amount of cellular and circuit data in an open-source knowledge base of the rodent hippocampal formation. We now propose to advance this research program with three specific aims. The first is to expand the scientific scope, research utility, and long-term sustainability of NeuroMorpho.Org. We plan to more than double the number of shared reconstructions and to introduce a new morphometric quantification of branching geometry in its anatomical context. We will also future-proof the digital lifespan of these valuable datasets by distributing community mirror sites over both physical and cloud servers. The second aim is to augment Hippocampome.org with a novel formulation of neural mass action, relating neural population activity to neuron type-specific excitability, connectomics, and synaptic signaling. This will enable the implementation of computationally efficient yet powerful multi-scale simulations, spanning from a large portion of the mammalian brain (the cortical-hippocampal system) to detailed models of individual ionic channels, to test, refine, and constrain functional theories against experimental measurements. The third aim is to use data-driven modeling and neuronal reconstructions to test two novel hypotheses relating ubiquitous connectivity motifs in neural circuits to (i) network synchrony and information processing, and (ii) morphological similarity of long-range axonal projections. Together, these three aims will advance neuroscience both through new discoveries and by continuing to develop and provide widely used community resources that are solely supported by this grant. The focus of this application on neural morphology and connectivity is relevant to all neuropathologies marked by aberrant cellular structure, including epilepsy and Alzheimer’s. Our proposed computational approach, bridging theory and experiments to investigate the neuron type circuit function of the hippocampal formation, will shed light on the mechanisms underlying impairments of episodic memory formation and retrieval.
