Morgado et al. Stress affects pavlovian-to-instrumental transfer While the excitatory response of lateral OFC neurons may sig- nify a positive motivational signal associated with the expected reward (Tremblay and Schultz, 1999; Schoenbaum et al., 2003), the inhibitory response of mPFC neurons evokes their pattern of activity in goal-directed actions (Homayoun and Moghaddam, 2006; Moghaddam and Homayoun, 2008). The fact that there is a re-emergence of inhibitory pattern in prelimbic mPFC neurons re- activates its representation of instrumental action under the inﬂu- ence of the Pavlovian incentives (Homayoun and Moghaddam, 2009). This integration of Pavlovian and instrumental processes, where cue-evoked incentives recruit instrumental representations, may provide a mechanism for the prelimbic mPFC, to execute motivational control over goal-directed behavior; importantly, this re-activation is likely to be compromised after chronic stress as the present results demonstrate. Of course, other regions tar- geted by stress, such as the striatum, could also be implicated in the stress-induced PIT impairment; in fact, there are stud- ies demonstrating that the dorsolateral striatum is critical for the formation of speciﬁc stimulus-outcome associations, whereas the dorsomedial striatum is involved in the formation of spe- ciﬁc response-outcome associations. Disruption of either form of learning impairs PIT (Corbit and Janak, 2010) and stress is known to inﬂuence the structure and function of both divisions of the dorsal striatum (Dias-Ferreira et al., 2009). In the same vein, ven- tral striatal areas could also play an important role in the observed impairments as integrity of NAc shell was found to be critical to the transfer effect (Corbit et al., 2001). In fact, previous stud- ies of our lab showed that stress reduces the total volume of this region, impairing its function (Leão et al., 2007). These reported alterations could underlie impairments we have found. Additionally, current evidence suggests that BLA is involved in the formation of stimulus-reward associations by assigning an affective value to associated rewards (Everitt et al., 1991) and in the production and direction of instrumental actions (Everitt and Robbins, 1992). Although BLA lesions completely abolish both outcome-selective PIT and outcome devaluation, this area integrates different circuits that connect differently with other rel- evant brain structures. Anterior BLA connects with OFC and shell NAc and posterior BLA connects with prelimbic cortex, medial accumbens core, and key components of instrumental condition- ing circuitry (Balleine, 2005). Structural stress-induced alterations described by Vyas et al. (2002) could conﬁgure an interesting possibility to explain our results. Stress has a strong impact in hippocampal structure and func- tion, impairing the learning and storage of newly acquired infor- mation (Sousa et al., 2000). In this regard, the herein observed PIT deﬁcits could be due to a disruption of these hippocampal functions, interfering with the consolidation of stimulus-outcome associations. Alternatively, the stress-induced hippocampal dys- function could also interfere with the hippocampal role in appet- itive Pavlovian conditioning (Ito et al., 2005). However, neither of these hypotheses is supported by the fact that chronic stress did not impair Pavlovian conditioning. Importantly, the stress-induced impairment of PIT was no longer evident after a stress-free period. This reversibility of stress effects is in accordance with previous studies showing the recov- ery of other stress-induced deﬁcits, including spatial memory (Sousa et al., 2000), and behavioral ﬂexibility (Bloss et al., 2010), after similar stress-free periods. Of note, recovery of these func- tions is paralleled by synaptic regrowth and reorganization on the hippocampus and the mPFC, which are also involved in PIT. Alto- gether, these results highlight the extreme plastic capabilities of areas involved in PIT and explain why most stress-induced deﬁcits, including those described in the present paper, are, at least in part, reversible. A better knowledge of the mechanisms underlying these events, to be pursued in future studies, is crucial to optimize therapeutic interventions in altered cue-controlled behaviors, par- ticularly in those situations in which spontaneous recovery is not likely. ACKNOWLEDGMENTS The authors acknowledge the discussions with Osborne Almeida. Pedro Morgado is supported by a fellowship “SFRH/SINTD/60129/2009”funded by FCT – Foundation for Science and Technology. 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