We previously showed that different populations of cells in the monkey hippocampus monitored information about trial outcome including both success (correct up cells) and failure (error up cells) (Wirth et al., 2009). Here we confirm that this trial outcome signal is also present at the level of the LFP in monkeys and show for the first time that this signal is also seen at the level of BOLD fMRI signals in humans. We also show prominent trial outcome signals in the human striatum including the caudate, putamen, and nucleus accumbens. Previous studies in monkeys have shown associative learning signals in the anterior

caudate and putamen using tasks very similar to the one used here (Pasupathy and Miller, 2005 and Williams and Eskandar, 2006). How might the trial outcome and associative learning signals seen in both the medial temporal lobe (Wirth et al., 2003 and Wirth et al., 2009) and striatum (Pasupathy and Miller, 2005; present findings; Neratinib order PD0332991 Williams and Eskandar, 2006) interact? Lisman and Grace (2005) hypothesized that activity in a hippocampal-VTA loop, connected via projections through the nucleus accumbens, may control the entry of new information into long-term

memory. Our findings suggest that a similar functional loop may also underlie the development of new conditional motor associations. Future studies recording both single-units and LFP activity simultaneously in the medial temporal lobe and striatum during new conditional motor learning in monkeys will be a powerful model system to test important unanswered questions about the nature, timing, and direction of the learning signals across these areas suggested by the Lisman and Grace (2005) model. Another striking feature of the trial outcome signal was that the polarity of the LFP signals seen in monkeys (error trials > correct trials) was opposite to the BOLD fMRI pattern observed in humans (correct trials > error trials). Florfenicol Polarity differences were also seen in some of the areas and bandwidths for the new versus reference comparison (Figure 2B) and the novelty response (Figure 3B). There are

a number of possible explanations for these polarity differences. One possibility is that the underlying differential neural signals across species are equivalent and the polarity differences reflect the complex translation between LFP measures in monkeys and BOLD fMRI signals in humans. Alternatively, the polarity differences may reflect differences in behavioral strategy across species. For example, in the case of trial outcome, although both species use trial outcome data to solve the task, humans may focus on correct trials whereas monkeys may focus more on error trials. Further studies will be needed to differentiate between these possibilities. Our previous study in humans reported clear increases in BOLD fMRI signals across the medial temporal lobe as humans gradually learned new conditional motor associations (Law et al., 2005).