Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility.

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/-) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/- rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.

Absence of differential protection from extinction in human causal learning.

Elemental models of associative learning typically employ a common prediction-error term. Following a conditioning trial, they predict that the change in the strength of an association between a cue and an outcome is dependent upon how well the outcome was predicted. When multiple cues are present, they each contribute to that prediction. The same rule applies both to increases in associative strength during excitatory conditioning and the loss of associative strength during extinction. In five experiments using an allergy prediction task, we tested the involvement of a common error term in the extinction of causal learning. Two target cues were each paired with an outcome prior to undergoing extinction in compound either with a second excitatory cue or with a cue that had previously undergone extinction in isolation. At test, there was no difference in the causal ratings of the two target cues. Manipulations designed to bias participants toward elemental processing of cue compounds, to promote the acquisition of inhibitory associations, or to reduce generalization decrement between training and test were each without effect. These results are not consistent with common error term models of associative learning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

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. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility.

The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

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.

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 with 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.

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.

Rat prefrontal dopamine and cognitive control: impaired and enhanced conflict performance.

It has been proposed that the cognitive dysfunction observed in patients with schizophrenia reflects a failure in cognitive control, in particular an inability to use task-relevant information to guide behavior. Using a prefrontal-dependent task designed to reflect aspects of cue and response conflict seen in human cognitive paradigms, we examined the influence of prefrontal dopamine receptor manipulation on the contextual control of response conflict. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two discriminably different contexts. At test, audiovisual compounds of these training stimuli were presented, in extinction, in each of the training contexts. These compounds were formed in such a way that the individual elements previously dictated different responses during training, termed incongruent trials. Studies have shown that rats use contextual information to disambiguate the conflicting information provided by incongruent compounds, responding in manner that is appropriate to the stimulus element that was trained in the test context. Direct infusion of the D1 receptor agonist SKF-38393 into the prelimbic cortex was found to modulate incongruent trial performance in a manner that was dependent upon baseline performance: animals in the low baseline group demonstrated improved incongruent performance following infusion of SKF-38393 into the prelimbic cortex. In contrast, high performers showed a reduction in accuracy during incongruent compounds. This paradigm provides a reliable framework for assessing the efficacy of preclinical agents in treating the cognitive impairments seen in frontal-related disorders such as schizophrenia.

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.

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.

Contextual control of choice performance: behavioral, neurobiological, and neurochemical influences.

An important aspect of decision making is the ability of responses to be controlled by different cues in different situations or contexts, especially when there is conflict between alternative responses or actions.Recently, a context-dependent biconditional task has been developed for rats that mimic some aspects of response conflict seen in human cognitive paradigms, such as the Stroop task. In this task, contextual cues are used to disambiguate conflicting response information provided by audiovisual compound stimuli. Here we review current findings that investigate some of the behavioral, neurobiological, and neurochemical mechanisms that underlie this use of contextual or task-setting information to resolve response conflict, and discuss future ways in which this research can be extended.

Inactivation of the prelimbic, but not infralimbic, prefrontal cortex impairs the contextual control of response conflict in rats.

One fundamental function of the prefrontal cortex (PFC) is to guide context-appropriate behaviour in situations of response conflict. Haddon and Killcross recently developed a task in rats which mimics some aspects of response conflict seen in human cognitive paradigms such as the Stroop task. Using this paradigm they demonstrated that large PFC lesions including the prelimbic (PL), infralimbic (IL) and anterior cingulate cortices (ACC) selectively impaired performance on incongruent trials which required the use of task-setting contextual cues to control responding in the face of ambiguous response information. The current experiment was conducted to determine whether specific PFC regions were responsible for the deficit in incongruent performance. Rats were trained on two instrumental biconditional discriminations, one auditory and one visual, in two different contexts. Following acquisition, rats were implanted with guide cannulae aimed at the PL or the IL cortices of the rat prefrontal cortex. Following retraining, rats received microinfusions of the GABA(A) agonist muscimol or artificial cerebrospinal fluid (aCSF) into either the PL or the IL prior to presentations of novel congruent and incongruent audiovisual compounds of the training stimuli in extinction. Results showed that temporary inactivation of the PL cortex led to a selective deficit on incongruent compound trials, but left congruent, and hence biconditional task performance intact. By contrast, IL inactivation had no effect on the accuracy of responding during either congruent or incongruent trials. These results suggest that the PL cortex is necessary for the use of task-setting contextual cues to control responding to conflicting information.

Both motivational and training factors affect response conflict choice performance in rats.

Rats were trained on two biconditional discrimination tasks, in two different contexts, and were rewarded with two different outcomes. At test, they received presentations of audiovisual compounds of these training stimuli, in extinction. These compounds were formed in such way that the individual elements had dictated either the same (congruent trials) or different (incongruent trials) responses during training, and each stimulus element had previously been rewarded with a different outcome. Previous research has shown that rats use the contextual cues to disambiguate the conflicting response information provided by incongruent stimulus compounds. Experiment 1 demonstrated that this contextual control was goal-directed in the sense that it depended on the current value of the outcome and Experiment 2 demonstrated that both the training history of the biconditional stimuli and motivational influences influenced the contextual control of responding on incongruent trials. These results are discussed in relation to current models of choice behaviour.

Prefrontal cortex lesions disrupt the contextual control of response conflict.

The prefrontal cortex has been implicated in multiple forms of goal-directed behavior. Rats with pretraining lesions to the prefrontal cortex (PFC) or specific lesions to the anterior cingulate cortex (ACC) were trained and tested on a novel behavioral procedure measuring aspects of cue and response competition typical of tests of prefrontal function in humans. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two discriminably different contexts. At test, they received presentations of audiovisual compounds of these training stimuli in both contexts, in extinction. These compounds were formed in such way that the individual elements had dictated either the same (congruent trials) or different (incongruent trials) responses during training. Sham-operated rats used the contextual cues to disambiguate the conflicting response information provided by incongruent stimulus compounds. ACC lesions impaired the contextual control of instrumental responding during incongruent cues during only the initial period of cue presentation, whereas larger PFC lesions abolished incongruent cue performance completely. Neither biconditional discrimination acquisition, nor test performance during congruent stimulus compounds, were affected by the lesions. These findings are consistent with human and nonhuman primate studies, indicating a role for the PFC in the processes by which cues come to control behavior in the face of conflicting information and the ACC specifically in processes such as detection of response conflict. This procedure provides a good foundation for an improved understanding of the disruption to goal-directed behavior seen with frontal dysfunction in a number of neuropsychological disorders including schizophrenia.