ThompsonPNAS10 - Hypothesis-driven structural connectivity...

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Hypothesis-driven structural connectivity analysis supports network over hierarchical model of brain architecture Richard H. Thompson and Larry W. Swanson 1 Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 Contributed by Larry W. Swanson, June 30, 2010 (sent for review May 14, 2010) The brain is usually described as hierarchically organized, although an alternative network model has been proposed. To help distin- guish 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 identi fi ed functionally as a hedonic hot spot. A highly topographically organized set of connections involving expected and unexpected gray matter regions was identi fi ed 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 ab- straction, the connectome. brain systems | connectome | appetite | depression | stress T he starting point that we chose for neural systems analysis is a 1-mm 3 region of brain tissue in which injected μ -opioids in- crease ingestive behavior, possibly by increasing the hedonic im- pact of sweetness (1). The identi fi ed region, which has been called a hedonic hot spot, lies dorsomedially in the nucleus accumbens (ACB), a part of the basal ganglia s ventral striatum long thought to play a role in controlling foraging behavior and the rewarding properties of food or other natural rewards and substances of abuse (2, 3). This functional heterogeneity of the ACB suggested to us that the ACB s extrinsic axonal connectivity is also topo- graphically organized and specialized to a greater extent than demonstrated previously (4). Thus, we used the dorsomedial ACB (ACBdm) as a circumscribed, readily identi fi able anchor point for our hypothesis-driven structural connectivity analysis. Results We fi rst established differential extrinsic axonal inputs and outputs of the ACBdm dorsal tip (ACBdmt) with a new double-coinjection (COIN) network tracing strategy. In the same animal, two tiny, nonoverlapping anterograde/retrograde tracer COINs mixtures of biotinylated dextran amine/Fluorogold (BDA/FG) and Pha- seolus vulgaris leucoagglutinin/cholera toxin subunit b (PHAL/ CTb) were placed stereotaxically in the medial ACB ( Figs. 1 A C and Fig. S1 ). The sources of extrinsic axonal inputs speci fi cally to ACBdmt in these double-COIN topography experiments (Fig. 1 A ; the fi
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