Preexposure along a continuum: Differentiation and association.

In five experiments, we assessed the effects of pre-exposure to simple auditory stimuli on subsequent conditioning and discrimination learning. Experiment 1 showed that pre-exposure to a single stimulus retarded acquisition of conditioned responding to that stimulus. The same pre-exposure regimen facilitated the subsequent acquisition of a discrimination between two stimuli that flanked the pre-exposed stimulus along the frequency dimension. Experiment 2 replicated this midpoint pre-exposure effect on discrimination learning but also found that alternating pre-exposure to the discriminative stimuli retarded discrimination learning. Experiments 3 to 5 explored the causes of these effects. These experiments are the first to examine perceptual learning in animals using simple auditory stimuli and their results suggest that in at least some circumstances alternating pre-exposure to auditory stimuli results in an increase in generalization between them

Competing contextual processes rely on the infralimbic and prelimbic medial prefrontal cortices in the rat

Ambiguous relationships between events may be established using interference procedures such as latent inhibition, extinction or counterconditioning. Under these conditions, the retrieval of individual associations between a stimulus and outcome is affected by contextual cues. To examine the roles of the dorsal (prelimbic) and ventral (infralimbic) medial prefrontal cortex in the contextual modulation of such associations, we investigated the context specificity of latent inhibition. Male Lister hooded rats were pre-exposed to two separate stimuli, one in each of two distinct contexts. Both stimuli were then paired with the delivery of mild foot-shock in the same one of these contexts. Finally, the strength of the resultant conditioned emotional response (CER) to each stimulus was assessed in each context. For the sham-operated control rats, the CER was attenuated for each stimulus when it was tested in the context in which it had been pre-exposed. Rats who had received lesions to the infralimbic cortex showed this effect only in the conditioning context, whereas rats with lesions to the prelimbic cortex showed the effect only in the context in which conditioning had not taken place. These findings indicate that infralimbic and prelimbic cortices play distinct, and competing, roles in the contextual modulation of initial and later learning

A novel role for the rat retrosplenial cortex in cognitive control

By virtue of its frontal and hippocampal connections, the retrosplenial cortex is uniquely placed to support cognition. Here, we tested whether the retrosplenial cortex is required for frontal tasks analogous to the Stroop Test, i.e., for the ability to select between conflicting responses and inhibit responding to task-irrelevant cues. Rats first acquired two instrumental conditional discriminations, one auditory and one visual, set in two distinct contexts. As a result, rats were rewarded for pressing either the right or left lever when a particular auditory or visual signal was present. In extinction, rats received compound stimuli that either comprised the auditory and visual elements that signaled the same lever response (congruent) or signaled different lever responses (incongruent) during training. On conflict (incongruent) trials, lever selection by sham-operated animals followed the stimulus element that had previously been trained in that same test context, whereas animals with retrosplenial cortex lesions failed to disambiguate the conflicting response cues. Subsequent experiments demonstrated that this abnormality on conflict trials was not due to a failure in distinguishing the contexts. Rather, these data reveal the selective involvement of the rat retrosplenial cortex in response conflict, and so extend the frontal system underlying cognitive control

Preexposure along a continuum: differentiation and association.

In 5 experiments, we assessed the effects of preexposure to simple auditory stimuli on subsequent conditioning and discrimination learning. Experiment 1 showed that preexposure to a single stimulus retarded acquisition of conditioned responding to that stimulus. The same preexposure regimen facilitated the subsequent acquisition of a discrimination between 2 stimuli that flanked the preexposed stimulus along the frequency dimension. Experiment 2 replicated this midpoint preexposure effect on discrimination learning but also found that alternating preexposure to the discriminative stimuli retarded discrimination learning. Experiments 3 to 5 explored the causes of these effects. These experiments are the first to examine perceptual learning in animals using simple auditory stimuli, and their results suggest that in at least some circumstances alternating preexposure to auditory stimuli results in an increase in generalization between them

Pavlovian-to-instrumental transfer: Paradoxical effects of the pavlovian relationship explained

Four experiments with rats examined the origin of outcome-selective Pavlovian-to-instrumental transfer (PIT). Experiment 1 used a standard procedure, where outcomes were embedded within extended conditioned stimuli (CSs), to demonstrate the basic effect: Pavlovian stimuli augmented instrumental lever presses that had been paired with the same outcomes. Experiments 2 and 3 showed that after instrumental conditioning, whereas a conditioned stimulus (CS) trained using a backward conditioning procedure produced outcome-selective PIT, forward conditioning with a CS did not. These results are consistent with the idea that backward conditioning results in the outcome provoking its associated instrumental response during the CS and thereby allows a stimulus-response association to be acquired that directly generates outcome-selective PIT at test. Experiment 4 provided direct support for the assumptions that underlie this stimulus-response analysis. These results, and other paradoxical effects of the Pavlovian relationship, are incongruent with accounts of outcome-selective PIT that rely on a stimulus-outcome-response chain

Impaired conditional task performance in a high schizotypy population: Relation to cognitive deficits

Cognitive impairments in schizophrenia have been characterized as reflecting a core deficit in the maintenance or use of task-setting cues to mediate appropriate ongoing behaviour. This analysis suggests that cognitive deficits in schizophrenia will be particularly evident when different task-setting cues dictate when different responses are required by the same stimuli. One simple task in which task-setting cues are required is a biconditional discrimination. Here we examined the performance of participants with high and low schizotypy scores (Mason, Claridge, Jackson, 1995) on a biconditional discrimination and an otherwise equivalent, control discrimination that did not require the use of task-setting cues. Participants scoring highly on the Introvertive Anhedonia subscale (which has been allied to the negative and cognitive symptoms of schizophrenia) performed poorly on the biconditional, but not on the control, discrimination. No other subscales demonstrated a significant influence on either biconditional or control performance

Extreme elemental processing in a high schizotypy population: Relation to cognitive deficits

The cognitive deficits observed in schizophrenia have been characterized as a failure to utilize task-setting information to guide behaviour, especially in situations in which there is response conflict. Recently, we have provided support for this account; high schizotypy individuals demonstrated inferior biconditional discrimination performance compared to low scorers, but were not impaired on a simple discrimination that did not require the use of task-setting cues. These results may, however, also be explained by the way in which individuals with high schizotypy process stimulus compounds. Here, we examine the initial approaches to solving biconditional and control discrimination tasks of participants wit h high and low schizotypy scores. In particular, we focus on performance during the first block of training trials to capture processing style before the acquisition of the discrimination tasks. Participants scoring highly on the introvertive anhedonia subscale (which has been allied to the negative and cognitive symptoms of schizophrenia) demonstrated better biconditional performance during the first block of training trials than did low-schizotypy individuals, consistent with a highly elemental approach to stimulus processing. Subsequent recognition tests confirmed this analysis demonstrating that the pattern of performance observed in participants with high schizotypy was associated with a failure to discriminate conjunctions of items that had been seen before from those that had not. These results suggest that the negative/cognitive symptoms of schizophrenia may reflect an extreme bias towards elemental, as opposed to configural, processing of stimulus conjunctions. © 2013 © 2013 The Experimental Psychology Society

Lesions to the ventral, but not the dorsal, medial prefrontal cortex enhance latent inhibition

The acquisition of a conditioned response to a stimulus when it is paired with a reinforcer is retarded if the stimulus has previously been repeatedly pre-exposed in the absence of the reinforcer. This effect, called latent inhibition, has previously been found to be insensitive to lesions of the medial prefrontal cortex (mPFC) in rats. Using an on-baseline conditioned emotional response procedure, which is especially sensitive to small variations in the absolute magnitude of latent inhibition, we found increased latent inhibition following excitotoxic lesions of the mPFC (Experiment 1) or the ventral mPFC alone (Experiment 2) as compared with sham-operated control rats. Lesions restricted to the dorsal mPFC, however, were without effect (Experiment 2). These results are consistent with those of experiments employing another type of interference procedure, extinction. Together, these findings suggest that when different contingencies between a stimulus and a reinforcer are established in separate learning phases, lesions to the ventral mPFC result in increased interference between first-learned and second-learned contingencies. As a consequence, retrieval of the second-learned contingency is impaired, and performance is dominated by the first-learned contingency. These findings are discussed in light of the use of latent inhibition to model cognitive deficits in schizophrenia

Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Cav1.2 L-type voltage-gated calcium channels (VGCCs), has been strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. How genetic variation in CACNA1C contributes to risk for these disorders is however not fully known. Both schizophrenia and bipolar disorder are associated with impairments in reversal learning (RL), which may contribute to symptoms seen in these conditions. We used a translational RL paradigm to investigate whether genetic variation in CACNA1C affects RL in both humans and transgenic rats. Associated changes in gene expression were explored using in situ hybridization and quantitative PCR in rats and the BRAINEAC online human database. Risk-associated genetic variation in CACNA1C in healthy human participants was associated with impairments in RL. Consistent with this finding, rats bearing a heterozygous deletion of Cacna1c were impaired in an analogous touchscreen RL task. We investigated the possible molecular mechanism underlying this impairment and found that Cacna1c +/− rats show decreased expression of Bdnf in prefrontal cortex. Examination of BRAINEAC data showed that human risk-associated genetic variation in CACNA1C is also associated with altered expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results indicate that genetic variation in CACNA1C may contribute to risk for schizophrenia and bipolar disorder by impacting behavioral flexibility, potentially through altered regulation of BDNF expression in the prefrontal cortex. Tests of RL may be useful for translational studies and in the development of therapies targeting VGCCs