Introduction

1. Introduction to Neurophysiome

Understanding the fundamental relationship between neuron structure and function has long been an important goal in neuroscience. At all scales of analysis, the roles that geometric shapes and spatial interrelationships play in determining the functional abilities and constraints on brain activity are of paramount consideration. Currently most modeling and simulations of the electrical properties of neurons and their dendrites are carried out at a relatively coarse scale, reflecting numerous simplifying assumptions about the structure of dendrites. Such studies do not account for the small-scale heterogeneity in dendritic structure and composition that are apparent at the level of electron microscopy. Even our understanding of the electrical differences between spiny and non-spiny dendrites may be incomplete due to an over-reliance on simplified models.

The goal of this project is to bring together an interdisciplinary collaboration comprised of computer scientists, mathematicians, and neurobiologists to bring new reconstruction and computational tools to bear on some of the most fundamental, outstanding questions in cellular neuroscience. Specific goals include:

  • Constructing a scalable software framework for conducting multiscale and spatially realistic electrical simulations of neuronal activity.
  • Analyze how differences in head size, neck construction, surface area, and intracellular organelles impact spine electrical activity.
  • Investigate the role of active conductances both within spines and along dendritic shafts and examine how heterogeneity in the distribution of ion channels impacts dendritic signaling.
  • Use 3-D electrodiffusion models to determine the significance of variable ionic concentration gradients, especially in thin processes like spines and also in non-uniform geometries. This is largely overlooked in simpler models of spiny dendrites.
  • Enhance our understanding of the role of dendritic spines. Many roles have been proposed, including increasing axonal connectivity, electrical compartmentalization, and biochemical and calcium compartmentalization. We also seek to understand the functional consequences of heterogeneity and plasticity in spine geometries.
Figure: scales of neuronal modeling. Black arrowheads indicate synaptic input sites. Blue arrows indicate output sites.

  1. Model of a neuron as a single compartment.
  2. Ball-and-stick neuron model represents dendritic tree as long 1-D cable.
  3. 1-D, branched multi-compartment model of a CA1 pyramidal neuron with entire dendritic tree (hundreds of microns long).
  4. Realistic 3-D dendritic segment with spines reconstructed from serial section electron microscopy (5-6 microns long).
  5. Cube of fully reconstructed neuropil (~6 microns on a side). Axons in red; dendrites in gray.