Behavioral and Brain Functions

The transitive inference (TI) task assesses the ability to generalize learned knowledge to new contexts, and is thought to depend on the hippocampus (Dusek & Eichenbaum, 1997). Animals or humans learn in separate trials to choose stimulus A over B, B over C, C over D and D over E, via reinforcement feedback. Transitive responding based on the hierarchical structure A > B > C > D > E is then tested with the novel BD pair. We and others have argued that successful BD performance by animals – and even humans in some implicit studies – can be explained by simple reinforcement learning processes which do not depend critically on the hippocampus, but rather on the striatal dopamine system. We recently showed that the benzodiazepene midazolam, which is thought to disrupt hippocampal function, profoundly impaired human memory recall performance but actually enhanced implicit TI performance (Frank, O'Reilly & Curran, 2006). We posited that midazolam biased participants to recruit striatum during learning due to dysfunctional hippocampal processing, and that this change actually supported generalization of reinforcement values. Greene (2007) questions the validity of our pharmacological assumptions and argues that our conclusions are unfounded. Here we stand by our original hypothesis, which remains the most parsimonious account of the data, and is grounded by multiple lines of evidence. Background Our interpretation of our findings was based on the following premises. When humans are prevented from becoming explicitly aware of the hierarchy they can still perform better than chance at the novel "inference" test using an implicit reinforcement learning system [1]. Several mathematical and neural models show that when trained with the TI task procedure, stimulus B develops a higher associative strength then stimulus D, and that transitive responding can be achieved simply by comparing these implicit values [1-5]. Thus although under some circumstances the hippocampus can play a subtle modulatory role in setting up these values [4] (and is likely critical for genuine, explicit logical inference), neural models suggest that the elemental associative learning process itself does not depend on the hippocampus, but rather on the striatal dopamine system [6,7]. Moreover, the striatal and hippocampal systems often compete, such that disruption of one system can lead to enhanced performance of tasks that depend on the other (for review: [8,9]). We therefore posited that midazolam would disrupt the hippocampus [10-18], thereby removing its normal inhibitory interaction with the striatum, and allowing that system to dominate. The resulting impaired hippocampal learning but enhanced implicit reinforcement encoding Published: 30 January 2008 Behavioral and Brain Functions 2008, 4:5 doi:10.1186/1744-9081-4-5 Received: 22 January 2008 Accepted: 30 January 2008 This article is available from: http://www.behavioralandbrainfunctions. com/content/4/1/5 © 2008 Frank et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.