ORIGINAL RESEARCH ARTICLE published: 25 June 2012 doi: 10.3389/fnins.2012.00093 Stress transiently affects Pavlovian-to-instrumental transfer Pedro Morgado1,2, Miguel Silva1,2, Nuno Sousa1,2 and João J. Cerqueira1,2* 1 Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal 2 ICVS-3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal Edited by: Scott A. Huettel, Duke University, USA Reviewed by: Jack Van Honk, Utrecht University, Netherlands Mauricio R. Delgado, Rutgers-Newark: The State University of New Jersey, USA *Correspondence: João J. Cerqueira, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal. e-mail: jcerqueira@ecsaude.uminho.pt Stress has a strong impact in the brain, impairing decision-making processes as a result of changes in circuits involving the prefrontal and orbitofrontal cortices and the striatum. Given that these same circuits are key for action control and outcome encoding, we hypothesized that adaptive responses to which these are essential functions, could also be targeted by stress. To test this hypothesis we herein assessed the impact of chronic stress in a Pavlovian-to-instrumental transfer (PIT) paradigm, a model of an adaptive response in which a previously conditioned cue biases an instrumental goal-directed action. Data reveals that rats submitted to chronic unpredictable stress did not display deﬁcits in pavlovian condition- ing nor on the learning of the instrumental task, but were impaired in PIT; importantly, after a stress-free period the PIT deﬁcits were no longer observed. These results are relevant to understand how stress biases multiple incentive processes that contribute to instrumental performance. Keywords: stress, conditioning, pavlovian-to-instrumental transfer, choices INTRODUCTION Exposure to a stressful stimulus activates a physiological response intended to restore the organism’s homeostasis. However, when stressors are maintained for long periods of time, this response becomes maladaptive and results in several disruptions at the level of the regulatory systems, of which the brain is a key element. Thus, it is not surprising that chronic stress exposure is associated with signiﬁcant behavioral impairments such as deﬁcits in spatial reference and working memory (Mizoguchi et al., 2000; Cerqueira et al., 2007), behavioral ﬂexibility (Cerqueira et al., 2007), anxiety (Pêgo et al., 2006), and mood (Bessa et al., 2009). Such func- tional deﬁcits are paralleled by structural changes in several brain regions (Sousa and Almeida, 2002), that render chronic stress as an important risk-factor for the development of several neuropsychi- atric disorders. Importantly, several studies have also shown that the behavioral and structural effects of stress are transient, and important plastic phenomena take place after the removal of the stressful stimuli (Sousa et al., 2000; Bloss et al., 2010). Recent studies from our laboratory show that chronic stress bias decision-making processes, by favoring the shift from goal- directed actions to habit based behaviors (Dias-Ferreira et al., 2009). These alterations in instrumental behavior are correlated with changes in neuronal circuits involving different areas of the prefrontal cortex (PFC) [including the medial PFC (mPFC) and orbitofrontal cortex (OFC)] and dorsal striatum (Dias-Ferreira et al., 2009). Given that these regions are implicated in action control (Balleine and O’Doherty, 2010) and outcome encoding necessary for adaptive responses (Chudasama and Robbins, 2003; Hornak et al., 2004), we hypothesized that stress-induced changes in neuronal circuits involving the PFC and the striatum could lead to outcome encoding deﬁcits and to changes in the multiple incentive processes that contribute to instrumental performance. One of these processes is Pavlovian-to-instrumental transfer (PIT; Estes, 1948; Colwill and Rescorla, 1986). PIT encompasses three distinct components:(1) Pavlovian learning, in which stim- uli are associated with rewards; (2) instrumental conditioning, in which associations between actions and out comes are learned; and (3) a test phase, in which the impact of previous cues on instrumental response is assessed. The associative value of cue and its motivational signiﬁcance are determinants found crucial to proper transfer, a phenomenon which resembles cue-mediated increased drive seeking for drugs seen in drug abusers (Dickinson et al., 2000; Corbit and Janak, 2007). Because of that, PIT has been used as a useful model of maladaptive learning observed in several conditions, namely addictive disorders. The neural basis of PIT is not completely established but sev- eral studies implicate regions associated with emotional processing [amygdala and nucleus accumbens (NAc)], executive commands (dorsal striatum), and their integration (mPFC and OFC); impor- tantly, it is known that key regions involved in PIT operate in parallel. In fact, lesion studies in the amygdala and NAc have demonstrated that these brain regions are necessary for the behav- ioral expression of PIT (Corbit et al., 2001; Hall et al., 2001; de Borchgrave et al., 2002; Holland and Gallagher, 2004). Moreover, it is relevant to note that different regions of the amygdala and NAc display different roles in this process. While the amygdala baso- lateral nucleus (BLA) mediates the association between speciﬁc sensory and emotional features of stimulus and the responses that are elicited by each one (consummatory conditioning), the central nucleus (CN) mediates the association between cues and affective properties of stimuli (preparatory conditioning; Killcross et al., 1997; Balleine and Killcross, 2006). In what concerns the NAc, the core mediates the general excitatory effects of reward-related cues, whereas the shell mediates the effect of outcome-speciﬁc reward www.frontiersin.org June 2012 | Volume 6 | Article 93 | 1