Approach-avoidance conflict arises when an animal encounters a stimulus that is associated simultaneously with positive and negative valences [1]. The effective resolution of approach-avoidance conflict is critical for survival and is believed to go awry in a number of mental disorders, such as anxiety and addiction. An accumulation of evidence from both rodents and humans suggests that the ventral hippocampus (anterior in humans) plays a key role in approach-avoidance conflict processing [2-8], with one influential model proposing that this structure modulates behavioral inhibition in the face of conflicting goals by increasing the influence of negative valences [9]. Very little is known, however, about the contributions of specific hippocampal subregions to this process-an important issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced an avoidance of a conflict cue imbued with both learned positive and learned negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference for the conflict cue. In contrast, dorsal CA1- and CA3-inactivated rats showed no change in conflict behavior, and furthermore, additional behavioral tasks confirmed that the observed pattern of approach-avoidance findings could not be explained by other factors, such as differential alterations in novelty detection or locomotor activity. Our data demonstrate that ventral CA1 and CA3 subserve distinct and opposing roles in approach-avoidance conflict processing and provide important insight into the functions and circuitry of the ventral hippocampus.

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The infralimbic medial prefrontal cortex (IL) is important for suppressing learned behavior after extinction, but whether this function extends to responses acquired through appetitive Pavlovian conditioning is unclear. We trained male, Long-Evans rats to associate a white-noise conditional stimulus (CS; 10 s; 14 presentations per session) with 10% liquid sucrose (0.2 mL per CS presentation), and recorded entries into the fluid port during the CS. The CS was presented without sucrose in subsequent extinction and test sessions. Increasing IL activity with pretest microinfusions of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0, 0.3 nmol; 0.3 μl/side) reduced the reinstatement of CS-elicited port entries. The same result was obtained when IL neurons that expressed Channelrhodopsin-2 (ChR2) were optically stimulated during CS presentations at test (473 nm, 5 ms pulses at 20 Hz for 10.2 s, unilateral). Optical stimulation of ChR2-expressing IL neurons during CS presentations also reduced spontaneous recovery and context-induced renewal. Furthermore, optical stimulation (1) during intertrial intervals had no impact on renewal, (2) depolarized ChR2-expressing IL pyramidal neurons in vitro, and (3) preferentially increased Fos in ChR2-expressing neurons. These novel converging data highlight a critical role for the IL in suppressing the return of appetitive Pavlovian-conditioned responding following extinction.

Individual differences exist in the attribution of incentive salience to conditioned stimuli associated with food. Here, we investigated whether individual differences also manifested with a Pavlovian alcohol conditioned stimulus (CS). We compiled data from five experiments that used a Pavlovian autoshaping paradigm and tests of conditioned reinforcement. In all experiments, male, Long-Evans rats with unrestricted access to food and water were acclimated to 15% ethanol. Next, rats received Pavlovian autoshaping training, in which a 10 s presentation of a retractable lever served as the CS and 0.2 mL of 15% ethanol served as the unconditioned stimulus (US). Finally, rats underwent conditioned reinforcement tests in which nose-pokes to an active aperture led to brief presentations of the lever-CS, but nose-pokes to an inactive aperture had no consequence. Rats were categorized as sign-trackers, goal-trackers and intermediates based on a response bias score that reflected their tendencies to sign-track or goal-track at different times during training. We found that distinct groups of rats either consistently interacted with the lever-CS (“sign-trackers”) or routinely approached the port during the lever-CS (“goal-trackers”) across a majority of the training sessions. However, some individuals (“shifted sign-trackers”) with an early tendency to goal-track later shifted to comparable asymptotic levels of sign-tracking as the group identified as sign-trackers. The lever-CS functioned as a conditioned reinforcer for sign-trackers and shifted sign-trackers, but not for goal-trackers. These results provide evidence of robust individual differences in the extent to which a Pavlovian alcohol cue gains incentive salience and functions as a conditioned reinforcer.