Age-related cognitive impairment, which affects the vast majority of elderly people worldwide, is accompanied by subtle changes in the geometry of dendritic arborizations, and reduced densities and distributions of dendritic spines. Understanding exactly how these structural changes might produce the observed cognitive deficits requires accurate 3D representations of neuronal morphology, and biophysical modeling that can relate structural changes to altered neuronal firing patterns. Recent experimental work indicates that the combined effects of these global (dendritic topology) and local (spine geometry) variations critically affect neuronal dynamic behavior and the extent of synapse-specific plasticity. To date however, no tools capable of resolving and simulating neuronal morphology and dynamics on both global and local scales have been available. This application directly addresses both of these needs. Existing methods of acquiring neuronal morphology for quantitative analysis or compartment modeling are limited in resolution, or are prohibitively time-consuming. The central goal of this project is to develop an automated software system for digitization, 3D reconstruction and biophysically-based simulation of detailed neuronal morphology, that reliably captures detail on spatial scales spanning several orders of magnitude and that avoids the subjective errors that arise during manual tracing. This system will be used to obtain a mechanistic understanding of the role of structural changes in age-related decrements in working memory and cognition.
Two specific aims will address this broad objective: 1) To develop an automated user interface for our prototype volume integration system and to extend the prototype to handle multiphoton image stacks that contain entire layer III pyramidal neurons; 2) To develop software tools for automatic parameter extraction from confocal and multiphoton imaged data, suitable for simulation with standard compartment modeling packages. By determining simple morphologic indices for altered efficacy of synaptic transmission, neural integration and action potential forward and backpropagation, the tools developed in this study will provide insight into fundamental mechanisms of memory induction and maintenance that underlie normal cognitive function. Such insight will lead to enhanced strategies for delaying and ameliorating the impairment of learning, memory and cognitive performance that accompanies normal aging and age-related pathologies. ? ?
| Radley, Jason J; Rocher, Anne B; Rodriguez, Alfredo et al. (2008) Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol 507:1141-50 |
