The present study reports the first comprehensive map of brain networks underlying latent inhibition learning and the first application of structural equation modeling to cytochrome oxidase data. In latent inhibition, repeated exposure to a stimulus results in a latent form of learning that inhibits subsequent associations with that stimulus. As neuronal energy demands to form learned associations changes, so does the induction of the respiratory enzyme cytochrome oxidase. Therefore, cytochrome oxidase can be used as an endpoint metabolic marker of the effects of experience on regional brain metabolic capacity. Quantitative cytochrome oxidase histochemistry was used to map brain regions in mice trained on a tone-footshock fear conditioning paradigm with either tone preexposure (latent inhibition), conditioning only (acquisition), conditioning followed by tone alone (extinction), or no handling or conditioning (naive). The ventral cochlear nucleus, medial geniculate, CA1 hippocampus, and perirhinal cortex showed modified metabolic capacity due to latent inhibition. Structural equation modeling was used to determine the causal influences in an anatomical network of these regions and others thought to mediate latent inhibition, including the accumbens and entorhinal cortex. An uncoupling of ascending influences between auditory regions was observed in latent inhibition. There was also a reduced influence on the accumbens from the perirhinal cortex in both latent inhibition and extinction. The results suggest a specific network with a neural mechanism of latent inhibition that appears to involve sensory gating, as evidenced by modifications in metabolic capacity and effective connectivity between auditory regions and reduced perirhinal cortex influence on the accumbens. © 2007 Elsevier Inc. All rights reserved.