, 1998) and hippocampus (Wirth et al., 2003), to cortical areas ranging from the frontal eye fields, supplementary eye fields and premotor cortex (Brasted and Wise, 2004, Chen and Wise, 1995a, Chen and Wise, 1995b, Chen and Wise, 1996 and Mitz et al., 1991) to various subregions of prefrontal cortex

(e.g., Pasupathy and Miller, 2005), including OFC (Tremblay and Schultz, 2000). The current work builds on these NVP-BGJ398 in vitro prior studies in several ways, including the addition of aversive stimuli and the use of a Pavlovian rather than instrumental task. In contrast to nearly all primate studies, studies in rodents have examined reversal learning in both the reward and aversive domains, and suggest that complex interactions between amygdala and OFC occur during reinforcement learning (Saddoris et al., 2005, Schoenbaum et al., 1999, Schoenbaum et al., 2009 and Stalnaker et al., 2007). For example, Schoenbaum and colleagues have shown that amygdala lesions impair the development of cue-selective activity in OFC that normally develops as rats learn about reversed reinforcement contingencies (Stalnaker Regorafenib mw et al., 2007). In a complementary study, the authors reported that OFC lesions impede the ability of the amygdala to adjust its firing to a CS after a reversal (Saddoris et al., 2005). These and other experiments have led the authors to suggest

that OFC plays a prominent role in representing reinforcement expectations, even when those expectations are no longer

correct (Schoenbaum et al., 2009). By retaining a representation of the prereversal outcome expectancies, OFC activity could provide inputs essential for the generation of prediction error signals in other brain areas—such as the ventral tegmental area—which could in turn direct flexible neural encoding in the amygdala and elsewhere. Our findings do not support the idea that OFC neurons, as a whole, encode prereversal outcome expectation for a longer period than their counterparts in the amygdala, as has been proposed (Schoenbaum et al., 2009). We showed that negative value-coding neurons—those that respond preferentially to stimuli that are linked with aversive events—are indeed slower either to shift their representation of stimulus-outcome contingencies in OFC than in the amygdala. On the other hand, positive value-coding neurons fully reverse their encoding more rapidly in OFC than in the amygdala. Thus, the question of which brain area is “in charge” during reversal learning is almost certainly the wrong question. Instead of a simple feed-forward process—one brain area learning about the reversal and sending instructive signals to another—these data suggest a more complex neural circuit, in which appetitive and aversive neural networks participate in a multipart interchange of information during learning.