Neuroinformatics of the Hippocampus: From System-Level to Neuronal Arborizations

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DESCRIPTION (provided by applicant): Quantitative neuroanatomy is benefiting greatly from the integration of microscopy with increasingly powerful informatics. High resolution images of wide field histological preparations are captured and stored in the gigapixel range, while, at the cellular level, neuronal arborizations can be digitally reconstructed for morphometric analysis and computational modeling. The investigation of the cross-scale relation between system and cellular level neuroanatomy, however, has been so far largely limited to qualitative considerations. The present neurotechnology project will fill this gap and integrate the three-dimensional representation of brain regions and neuronal morphology focusing on the rat hippocampus as an exemplar structure of wide interest. In particular, a high resolution spatial map of all cytoarchitectural subregions of the hippocampal complex will be constructed from Nissl stained thin sections. Over one hundred digitally reconstructed neurons (including both excitatory and inhibitory cells) will be embedded and replicated throughout the full septotemporal extent of the hippocampus according to their appropriate location and orientation. Axonal and dendritic densities and volume occupancies will be calculated for each layer and along the transverse and longitudinal directions. Axodendritic overlaps will be measured for each pair of major cellular classes to estimate the matrix of potential synaptic connectivity for the complete hippocampal network. The maps for the whole hippocampal complex and full cellular detail will be made publicly available along with the underlying raw data and software source code. The hippocampus is intensely studied for its role in learning and memory and impairment in diseases such as epilepsy and Alzheimer's. A wealth of data is accumulating on its molecular and biophysical properties both in physiological and pathological conditions. This project will provide an anatomical framework to integrate hippocampal knowledge from the cellular to the system level for both experimental and computational neuroscientists. The techniques and research approach developed in this exploratory/developmental study will be extensible to other rat brain regions, and eventually to the whole mammalian central nervous system. PUBLIC HEALTH RELEVANCE The connection between the cellular and system levels of neuroanatomical analysis is a fundamental factor in the structure-function relationship of both the normal and diseased central nervous system. This cross-scale connection can seldom be quantitatively characterized because of the current lack of analytical tools and experimental preparations simultaneously suited for both single cells and entire brain regions. By virtually bridging this gap in a detailed digital montage of the mammalian hippocampus, we will demonstrate the feasibility of synthesizing vast amounts of neuroscience data while providing precise quantitative estimates for essential features of a structure involved in learning, memory, and devastating conditions such as epilepsy and Alzheimer's disease.