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Hypothesis-driven structural connectivity analysis supports network over hierarchical model of brain architecture
Contributed by Larry W. Swanson, June 30, 2010 (sent for review May 14, 2010)

Abstract
The brain is usually described as hierarchically organized, although an alternative network model has been proposed. To help distinguish between these two fundamentally different structure-function hypotheses, we developed an experimental circuit-tracing strategy that can be applied to any starting point in the nervous system and then systematically expanded, and applied it to a previously obscure dorsomedial corner of the nucleus accumbens identified functionally as a “hedonic hot spot.” A highly topographically organized set of connections involving expected and unexpected gray matter regions was identified that prominently features regions associated with appetite, stress, and clinical depression. These connections are arranged as a longitudinal series of circuits (closed loops). Thus, the results do not support a rigidly hierarchical model of nervous system organization but instead indicate a network model of organization. In principle, the double-coinjection circuit tracing strategy can be applied systematically to the rest of the nervous system to establish the architecture of the global structural wiring diagram, and its abstraction, the connectome.
Footnotes
- 1To whom correspondence should be addressed. E-mail: lswanson{at}usc.edu.
Author contributions: R.H.T. and L.W.S. designed research; R.H.T. performed research; R.H.T. and L.W.S. analyzed data; and R.H.T. and L.W.S. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1009112107/-/DCSupplemental.
*Structural evidence here for functional interactions consists of confocal microscopy images of direct appositions. Proof of functional synaptic interactions requires a combination of electron microscopy observation of synaptic specializations (presynaptic and postsynaptic densities) and electrophysiological evidence of functional interaction (changes in membrane potential).